2021/04/08 更新

写真a

アリヨシ ノリタカ
有吉 範高
ARIYOSHI Noritaka
所属
医歯薬学域 教授
職名
教授
外部リンク

学位

  • 博士(薬学)

研究キーワード

  • Pharmacokinetics

  • Clinical Pharmacology

  • Pharmacogenetics

  • 薬物動態

  • 医療薬学

  • 薬理遺伝学

研究分野

  • ライフサイエンス / 医療薬学

  • ライフサイエンス / 薬理学

  • ライフサイエンス / 薬理学

  • ライフサイエンス / 薬理学

  • ライフサイエンス / 薬系衛生、生物化学

学歴

  • 九州大学   Graduate School, Division of Pharmaceutical Sciences  

    - 1990年

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  • 九州大学    

    - 1990年

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    国名: 日本国

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  • 長崎大学   Faculty of Pharmaceutical Science  

    - 1988年

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  • 長崎大学   薬学部   薬学

    - 1988年

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    国名: 日本国

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経歴

  • - 千葉大学医学部 助教授

    2001年

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  • - Associate Professor,

    2001年

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  • Associate Professor,

    1997年 - 2001年

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  • 北海道大学大学院薬学研究科 助教授

    1997年 - 2001年

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  • Research Associate,

    1995年 - 1996年

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  • 米国ウィスコンシン大学マディソン校

    1995年 - 1996年

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  • Assistant Professor,

    1992年 - 1997年

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  • 九州大学薬学部 助手   School of Pharmaceutical Sciences

    1992年 - 1997年

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  • Chiba University School of Medicine

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  • ポストドクトラルフェロー

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  • ウィスコンシン大学

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  • 北海道大学

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  • Faculty of Pharmaceutical Sciences,

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  • 九州大学

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  • Faculty of Pharmaceutical Sciences,

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  • School of Medicine, USA

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▼全件表示

所属学協会

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委員歴

  • 日本薬物動態学会   Editorial Bord  

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    団体区分:学協会

    日本薬物動態学会

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  • 日本医療薬学会   評議員  

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    団体区分:学協会

    日本医療薬学会

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論文

  • An extremely high bioavailability of orally administered vancomycin in a patient with severe colitis and renal insufficiency 査読

    Shingo Yamazaki, Takaaki Suzuki, Tatsuya Suzuki, Hirokazu Takatsuka, Masayuki Ishikawa, Noriyuki Hattori, Takeshi Fujishiro, Hideaki Miyauchi, Takehiko Oami, Noritaka Ariyoshi, Shigeto Oda, Hisahiro Matsubara, Itsuko Ishii

    JOURNAL OF INFECTION AND CHEMOTHERAPY23 ( 12 ) 848 - 851   2017年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCIENCE BV  

    Because there is little absorption of orally administered vancomycin hydrochloride (VCM) through the normal intestinal microvillus membrane, the pharmacokinetics of VCM absorbed from the digestive tract are mostly unknown. Here we report a case of severe colitis and renal insufficiency in which the serum concentration of VCM reached the supratherapeutic range after oral administration. A 54-year-old man receiving outpatient chemotherapy for rectal cancer was admitted to our hospital for severe sepsis and acute renal failure. Multimodal therapy including continuous renal replacement therapy (CRRT) and mechanical ventilation was initiated, and oral VCM administration (0.5 g every 6 h) was begun for suspected severe pseudomembranous colitis with large amounts of watery stool. Despite continued CRRT, the serum VCM concentration increased to 30.6 mg/mL after 4 days. Based on pharmacokinetic analysis, the bioavailability of VCM was estimated to be over 54.5%. Colonoscopy showed that the mucosa was severely damaged throughout the large intestine, resulting in considerable exudation of plasma and blood. This case indicates the need for careful and early monitoring during high-dose oral VCM administration to patients with severe mucosal injury and renal insufficiency. (C) 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.jiac.2017.08.004

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  • 院内処方せんに導入した医薬品別検査値表示方式とその有用性 査読

    横山 威一郎, 橋本 杏里, 山口 洪樹, 山崎 香織, 松島 徹, 中村 貴子, 鈴木 貴明, 有吉 範高, 石井 伊都子

    医療薬学42 ( 11 ) 738 - 745   2016年11月

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    記述言語:日本語   出版者・発行元:(一社)日本医療薬学会  

    本邦で承認されている全ての医療用医薬品の警告・禁忌・原則禁忌(禁忌等)を内容ごとに分類し、処方鑑査での確認可能項目を調査した。医療用医薬品17756品目について添付文書に記載されている禁忌等は51804件で、内容ごとに分類すると14種類となった。禁忌等分類は、疾患・症状の件数が最も多く、半数を占めた。直接臨床検査値と結びつく、肝障害、臨床検査値、腎障害、透析の件数は5291件であり、全体の10.2%であった。確認可能項目は、処方せんに検査値を表示する前は7種類16483件であったのが、検査値表示開始後は11種類21774件となった。処方せんで確認できない項目は3種類30030件あり、全体の58.0%を占めた。採用薬2122品目のうち、禁忌等に該当は287品目505件、「腎」マークの表示に該当は75品目であった。臨床検査値関連の疑義照会によって処方変更に至った事例のうち禁忌に該当する事例は、医薬品別検査値表示開始前は6ヵ月間で0件であったが、表示開始直後は4件、最近の6ヵ月間では20件であった。

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  • Beta-migrating very low-density lipoprotein conjugates with acrolein in high-cholesterol diet-fed rabbits and localizes to atherosclerotic lesions with macrophages 査読

    Kanogawa, Yuri, Fujiyoshi, Masachika, Nakazato, Yuki, Watanabe, Kenta, Kurihara, Mizuki, Takezawa, Akari, Uchida, Masashi, Igarashi, Kazuei, Suzuki, Takaaki, Ariyoshi, Noritaka, Ishii, Itsuko

    INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY9 ( 11 ) 11149 - 11158   2016年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:E-CENTURY PUBLISHING CORP  

    Protein-conjugated acrolein (PC-Acro) is detected in atherosclerotic lesions, and we demonstrated previously that acrolein-conjugated low-density lipoproteins induce macrophage foam cell formation. Although it has been suggested that beta-migrating very low-density lipoprotein (beta VLDL) is taken up by macrophages during atherogenesis, the modification of beta VLDL with acrolein and its localization on lesions are still unclear. The purpose of this study was to clarify the localization of PC-Acro in atherosclerotic lesions and to determine the role of acrolein-conjugated beta VLDL in atherogenesis. Male New Zealand white rabbits were fed 0.5% cholesterol-containing rabbit chow for 8 weeks, and used as an animal model of atherosclerosis. PC-Acro and malondialdehyde (MDA)-conjugated protein levels, which has been used widely as a means to detect oxidized low-density lipoprotein (LDL), in plasma were increased in the 0.5% cholesterol-containing diet-induced animal model of atherosclerosis, whereas their level was unchanged in the control diet fed rabbit. PC-Acro was detected in beta VLDL by western blot analysis, and acrolein-conjugated beta VLDL was effectively taken up by THP-1 macrophages. By immunohistochemical analysis, PC-Acro and macrophages were detected at the internal elastic lamina of the aorta, which was the initial lesion of atherosclerosis. These results suggest that acrolein-conjugated beta VLDL has an important role in the initiation of atherosclerosis via the induction of macrophage foam cell formation in the atherosclerotic lesion.

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  • Correlation between antizyme 1 and differentiation of vascular smooth muscle cells cultured in honeycomb-like type-I collagen matrix 査読

    Itsuko Ishii, Takaaki Suzuki, Hiromi Kaneko, Masashi Uchida, Yukari Suzuki, Kyohei Higashi, Satoko Yagi, Noritaka Ariyoshi, Kazuei Igarashi, Mitsukazu Kitada

    Amino Acids42 ( 2-3 ) 565 - 575   2012年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Vascular smooth muscle cells (SMC) are able to proliferate when cultured on plates, but become differentiated when maintained in three-dimensional type I collagen matrices (honeycombs). SMC grown in honeycombs contained a low level of polyamines due to the presence of antizyme 1 (AZ1), a negative regulator of ornithine decarboxylase (ODC) and of polyamine uptake. To clarify the role of AZ1 in differentiation of SMC in honeycombs, an ODC gene was stably transfected into SMC (ODCSMC). Although proliferation of ODC-SMC on plates was accelerated together with an increase in phosphorylated focal adhesion kinase (FAK) and a decrease in a-actin and myosin, maker proteins of differentiation, growth of ODCSMC ceased in honeycombs similarly to normal SMC with a low level of phosphorylated FAK and a high level of a-actin and myosin. AZ1 expression in ODC-SMC on plates was low, but that in honeycombs was high. Antizyme in ODC-SMC in honeycombs not only decreased the level of ODC but also inhibited polyamine uptake activity. These results taken together suggest that low levels of polyamines caused by AZ1 in SMC in honeycombs inhibit phosphorylation of FAK and enhance expression of a-actin and myosin, resulting in differentiation through inhibition of focal adhesions. © Springer-Verlag 2011.

    DOI: 10.1007/s00726-011-1034-8

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  • Drug therapy and pharmacogenetics 査読

    Noritaka Ariyoshi

    Japanese Journal of Allergology61 ( 7 ) 941 - 947   2012年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Q172H Replacement Overcomes Effects on the Metabolism of Cyclophosphamide and Efavirenz Caused by CYP2B6 Variant with Arg262 査読

    Noritaka Ariyoshi, Miyuki Ohara, Mayumi Kaneko, Sakino Afuso, Takuya Kumamoto, Hiroyoshi Nakamura, Itsuko Ishii, Tsutomu Ishikawa, Mitsukazu Kitada

    DRUG METABOLISM AND DISPOSITION39 ( 11 ) 2045 - 2048   2011年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    There are a number of reports indicating that CYP2B6*6 (c.516G > T and c.785A > G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs.

    DOI: 10.1124/dmd.111.039586

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  • Degradation of filamin induces contraction of vascular smooth muscle cells in type-I collagen matrix honeycombs 査読

    Masashi Uchida, Itsuko Ishii, Kaori Hirata, Fumiko Yamamoto, Kaori Tashiro, Takayoshi Suzuki, Yuji Nakayama, Noritaka Ariyoshi, Mitsukazu Kitada

    Cellular Physiology and Biochemistry27 ( 6 ) 669 - 680   2011年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: Dedifferentiated rabbit vascular smooth muscle cells (SMCs) exhibit similar features to differentiated SMCs when cultured in three-dimensional matrices of type-I collagen called "honeycombs," but the mechanism is unknown. The role of filamin, an actin-binding protein that links actin filaments in SMCs, was investigated. Methods: Filamin and other related proteins were detected by western blot analysis and immunofluorescence staining. Honeycomb size was measured to confirm the contraction of SMCs. Results: Full-length filamin was expressed in subconfluent SMCs cultured on plates
    however, degradation of filamin, which might be regulated by calpain, was observed in confluent SMCs cultured on plates and in honeycombs. While filamin was co-localized with β-actin in subconfluent SMCs grown on plates, filamin was detected in the cytoplasm in SMCs cultured in honeycombs, and degraded filamin was mainly detected in the cytoplasmic fraction of these cells. In addition, β-actin expression was low in the cytoskeletal fraction of SMCs cultured in honeycombs compared with cells cultured on plates, and the size of the honeycombs used for culturing SMCs was significantly reduced. Conclusion: These data suggest that degradation of filamin in SMCs cultured in honeycombs induces structural weakness of β-non-muscle actin filaments, thereby permitting SMCs in honeycombs to achieve contractility. Copyright © 2011 S. Karger AG, Basel.

    DOI: 10.1159/000330076

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  • 造血幹細胞移植後のシクロスポリンによる腎障害の危険因子の解析

    宮本仁, 鈴木貴明, 今井千晶, 古賀ひとみ, 竹田真理子, 山崎伸吾, 仲佐啓詳, 中村裕義, 有吉範高, 中世古知昭, 北田光一

    日本医療薬学会年会講演要旨集20th   415   2010年10月

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    記述言語:日本語  

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  • Helices F-G are important for the substrate specificities of CYP3A7 査読

    Nao Torimoto, Itsuko Ishii, Ken-Ichi Toyama, Masayuki Hata, Kanako Tanaka, Hitoshi Shimomura, Hiroyoshi Nakamura, Noritaka Ariyoshi, Shigeru Ohmori, Mitsukazu Kitada

    DRUG METABOLISM AND DISPOSITION35 ( 3 ) 484 - 492   2007年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    CYP3A7 is a member of the human CYP3A family and a major form of P450 expressed in human fetal livers. Although CYP3A7 shares nearly 90% base sequence with CYP3A4, CYP3A7 shows striking functional differences in the catalytic preference for several substrates, such as dehydroepiandrosterone ( DHEA) or dehydroepiandrosterone 3-sulfate (DHEA-3S). First, to clarify the reason for the differences between CYP3A7 and CYP3A4, a homology model of CYP3A7 was constructed using the CYP3A4 crystal structure. Because these two structures were similar, four kinds of chimeric enzymes were constructed to determine which sequences are important for exhibiting the characteristics of CYP3A7. The results of kinetic analysis of DHEA and DHEA-3S 16 alpha-hydroxylations by CYP3A7, CYP3A4, and CYP3A chimeras suggested that the amino acid residues from Leu210 to Glu279 were important to express the specificity for substrates as CYP3A7. This region was on the F and G helices of the modeled CYP3A7. Furthermore, to assess which amino acid in this sequence is important for the substrate specificity of CYP3A7, a one-point mutation of CYP3A7 to CYP3A4 was made by site-directed mutagenesis. The mutants of K224T and K244E had lost DHEA and DHEA-3S 16 alpha-hydroxylation activities. The mutants also greatly decreased the metabolism of testosterone, erythromycin, nevirapine, and triazolam relative to those activities of CYP3A7 wild-type enzyme. From these results, it is expected that CYP3A7 can recognize specific substrates using the lysines in F-G loops.

    DOI: 10.1124/dmd.106.011304

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  • Identification of deletion-junction site of CYP2A6*4B allele lacking entire coding region of CYP2A6 in Japanese 査読

    N Ariyoshi, H Sekine, K Nakayama, K Saito, A Miyamoto, T Kamataki

    PHARMACOGENETICS14 ( 10 ) 701 - 705   2004年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

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  • Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples 査読

    Baker, JR, S Satarug, PEB Reilly, RJ Edwards, N Ariyoshi, T Kamataki, MR Moore, DJ Williams

    BIOCHEMICAL PHARMACOLOGY62 ( 6 ) 713 - 721   2001年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 kg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 mug/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and CYP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importantly, we show elevated levels of CYP2C9 protein to be associated with cadmium accumulation in liver. No mechanism that explains this association is apparent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an individual's non-workplace exposure to cadmium, or an individual's CYP2C9 genotype may be a risk factor for cadmium accumulation. A positive correlation was found between liver CYP3A4 protein and subject age. Levels of liver CYPIA2 protein, but not other CYP forms, were increased in people more exposed to cigarette smoke, but there was no association between CYPIA2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this sample group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasians. CYP2A6 gene types W/W, WIC, and CIC were not associated with variations in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twenty-five kidney samples tested but was detectable in liver samples of all but two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6(D)) in this sample group to be about 7%, typical of Caucasian populations. (C) 2001 Elsevier Science Inc. All rights reserved.

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  • Comparison of the levels of enzymes involved in drug metabolism between transgenic or gene-knockout and the parental mice 査読

    N Ariyoshi, S Imaoka, K Nakayama, Y Takahashi, K Fujita, Y Funae, T Kamataki

    TOXICOLOGIC PATHOLOGY29   161 - 172   2001年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    Drug-metabolizing enzymes are involved in the metabolic activation or detoxification of carcinogens. To evaluate animals developed as models for alternative carcinogenicity testing, we investigated whether or not a gene manipulation including the transgene of ras and the knocking out of a tumor suppressor gene such as p53 or XPA could alter the expression of representative drug-metabolizing enzymes directly or indirectly. Expression of several isoforms of cytochrome P450 (CYP) in the liver of rasH2, p53 (+/-), Tg. AC, and XPA (-/-) mice with or without treatment of prototype inducer, phenobarbital or 3-methylcholanthrene, was analyzed by Western immunoblotting in comparison with their parental strains of mice. In addition, the activities of 3 major phase II enzymes, UDP-glucronosyltransferase, sulfotransferase, and glutathione S-transferase, were compared between the gene-manipulated and the corresponding parental strains of mice. Results demonstrate that XPA gene knockout appeared to increase constitutive expression of CYP2B and CYP3A isoforms. Overexpression of human c-Ha-ras gene or p53 gene knockout appeared to increase constitutive UGT activity toward 4-nitrophenol. The content or activities of almost all other enzymes examined in the present study do not appear to be affected by the gene manipulation.

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  • A highly toxic coplanar polychlorinated biphenyl compound suppresses Delta 5 and Delta 6 desaturase activities which play key roles in arachidonic acid synthesis in rat liver 査読

    K Matsusue, Y Ishii, N Ariyoshi, K Oguri

    CHEMICAL RESEARCH IN TOXICOLOGY12 ( 12 ) 1158 - 1165   1999年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER CHEMICAL SOC  

    The effect of 3,3',4,4',5-pentacklorobiphenyl (PenCB) on the synthesis of unsaturated fatty acids was studied in male Wistar rats. The arachidonic acid (20:4) content in the total lipids of liver homogenates was significantly reduced on day 5 of PenCB administration, while those of linoleic acid (18:2) and bishomo-gamma-linolenic acid (20:3) were increased. These changes in the total lipids of liver homogenates were observed following doses of PenCB ranging from 0.5 to 25 mg/kg of body weight. The same changes in these fatty acids were seen with four subtypes of microsomal glycerophospholipids in the liver. The marked reduction in the molar ratio of 20:4 to 18:2 in the lipids suggests alteration of the activity of the enzymes responsible for the synthesis of unsaturated fatty acids. The activity of Delta 5 and Delta 6 desaturases (arachidonic acid synthetase) in the liver microsomes was 17 and 13% of that of pair-fed control animals, whereas the activity of 1-acylglycerophosphorylcholine or 1-acylglycerophosphate acyltransferase, which transfers 20:4 or 18:2 to phospholipids, was not affected by the treatment. Thus, the reduction in the level of 20:4 that was observed can be explained by a reduction in desaturase activity. These results are evidence that the coplanar PenCB has a significant effect on the reduced synthesis of physiologically essential long-chain unsaturated fatty acids.

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  • Metabolism of 2,3 ',4 ',5-tetrachlorobiphenyl by cytochrome P450 from rats, guinea pigs and hamsters 査読

    N Koga, N Kikuichi, T Kanamaru, H Kuroki, K Matsusue, C Ishida, N Ariyoshi, K Oguri, H Yoshimura

    CHEMOSPHERE37 ( 9-12 ) 1895 - 1904   1998年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The metabolism of 2,3',4',5-tetrachlorobiphenyl (TCB) was compared using liver microsomes and six isoforms of cytochrome P450 purified from rats, guinea pigs and hamsters. In microsomal study, the following species differences were observed: 1) Untreated guinea pigs and hamsters but not rats can metabolize this TCB to 3-hydroxy- or 4-hydroxy-2,3',4',5-TCB, 2) Guinea pig microsomes showed only 3-hydroxylating activity, whereas hamster microsomes showed higher activity of 4-hydroxylation than that of 3-hydroxylation. In common with three species, the 3-hydroxylation was accelerated by phenobarbital. The 4-hydroxylation in rats and hamsters was increased by pretreatment with 3-methylcholanthrene and 3,3',4,4',5-pentachlorobiphenyl. The hydroxylation activities of liver microsomes from the three species could be explained by an involvement of different isoforms of cytochrome P450. In addition, it is apparent that hamster CYP1A2 as well as hamster CYP2A8 is involved in the 4-hydroxylation of 2,3',4',5-TCB although it has no activity for 2,2',5,5'-TCB. (C) 1998 Elsevier Science Ltd. All rights reserved.

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  • Effect of highly toxic 3,3',4,4',5-pentachlorobiphenyl on the synthesis of unsaturated fatty acids 査読

    K Matsusue, N Ariyoshi, M Inoue, Y Ishii, K Oguri

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH43 ( 1 ) P19 - P19   1997年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

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  • Significant suppression of aldolase B, carbonic anhydrase III and alcohol dehydrogenase in liver cytosol of rats treated with a highly toxic coplanar PCB 査読

    H Kato, Y Ishii, M Hatsumura, T Ishida, Nakayama, I, N Ariyoshi, K Oguri

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH43 ( 1 ) P20 - P20   1997年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

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  • Hamster liver cytochrome P450 (CYP2A8) as a 4-hydroxylase for 2,5,2',5'-tetrachlorabiphenyl 査読

    N Koga, N Kikuichi, T Kanamaru, N Ariyoshi, K Oguri, H Yoshimura

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS225 ( 2 ) 685 - 688   1996年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    Metabolism of 2,5,2',5'-tetrachlorobiphenyl (TCB) was studied using liver microsomes of hamsters and two hamster P450 isoforms, CYP1A2 and 2A8. CYP2A8 catalyzed selectively 4-hydroxylation of 2,5,2',5-TCB at a rate of 21.7 pmol/min/nmol P450. In contrast, CYP1A2 showed no activity for hydroxylation of 2,5,2',5'-TCB. Immunological study revealed that rabbit antiserum against CYP2A8 almost completely inhibited the microsomal 4-hydroxylation but that against CYP1A2 did not. It was also shown that the induction pattern of CYP2A8 protein by P450 inducer was similar to that of the 4-hydroxylase activity in hamster liver microsomes. These results suggest that CYP2A8 plays a major role in the 4-hydroxylation of 2,5,2',5'-TCB in hamster liver. (C) 1996 Academic Press, Inc.

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  • EFFECT OF HIGHLY TOXIC COPLANAR PCB ON PEROXISOMAL ENZYME-ACTIVITY - THE SPECIES-DIFFERENCE BETWEEN RATS AND GUINEA-PIGS 査読

    M IWASAKI, H KATO, N ARIYOSHI, K OGURI

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH41 ( 1 ) P32 - P32   1995年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

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  • EFFECT OF COPLANAR PCB ON GLUCONEOGENESIS AND LIPID-METABOLISM - COMPARISON BETWEEN RATS AND GUINEA-PIGS 査読

    M HATSUMURA, T ISHIDA, Y ISHII, N ARIYOSHI, Y KOGA, K OGURI, H YOSHIMURA

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH40 ( 1 ) P27 - P27   1994年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

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  • INDUCTION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE AND P-450-4A SUBFAMILY IN GUINEA-PIGS BY TREATMENT WITH COPLANAR PCB 査読

    Y KOGA, M TSUDA, N ARIYOSHI, Y ISHII, H YAMADA, K OGURI, H YOSHIMURA, Y FUNAE

    JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH39 ( 1 ) P23 - P23   1993年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

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  • Induction of Bilirubin UDP-Glucuronyltransferase and P-450 4A Subfamily in Guinea Pigs 査読

    Yoshiko Koga, Yoshihiko Funaec, Hidetoshi Yoshimura, Noritaka Ariyoshi, Yuji Ishii, Hideyuki Yamada, Kazuta Oguri, Minoru Tsuda

    Eisei kagaku39 ( 1 )   1993年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1248/jhs1956.39.P23

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▼全件表示

書籍等出版物

  • Carcinogenesisにおける個体差

    Annual Review 呼吸器2002  2002年 

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  • 薬物代謝からみた肝・腎・心疾患患者への医薬品投与時の注意 薬物代謝酵素

    医薬ジャーナル社  2001年 

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  • 薬物動態・作用と遺伝子多型 薬物治療の患者個別化を目指した21世紀の新展開 CYP遺伝子多型と発現調節

    医薬ジャーナル社  2001年 

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  • 7.薬物相互作用/9.2遺伝的多型の遺伝子診断/11.6内分泌撹乱物質と薬物代謝

    薬物代謝学 第2版  2000年 

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  • 肝胆系における薬物代謝と肝障害-薬物代謝関連酵素の遺伝的多型

    消化器疾患-State of arts(Ver.2)  1999年 

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  • 呼吸器疾患における分子生物学の基礎とその臨床応用34,P450と多型

    呼吸器疾患の分子生物学  1998年 

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  • 環境要因感受性を支配する遺伝的要因 異物代謝の個人差と環境要因感受性

    環境と健康II  1998年 

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MISC

  • LC-MSによる新世代Bcr-Ablチロシンキナーゼ阻害薬の血中濃度測定

    後藤 優理, 有吉 範高, 中世古 知昭, 今井 千晶, 石井 伊都子

    JSBMS Letters39 ( Suppl. ) 96 - 96   2014年9月

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    記述言語:日本語   出版者・発行元:(一社)日本医用マススペクトル学会  

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  • 第二世代Bcr-Abl TKI治療実態下における血中濃度測定の試験的運用と課題

    有吉 範高, 後藤 優理, 今井 千晶, 中世古 知昭, 石井 伊都子

    TDM研究31 ( 3 ) 173 - 173   2014年5月

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    記述言語:日本語   出版者・発行元:(一社)日本TDM学会  

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  • 難治性口内炎に対するインドメタシンスプレー使用後のQOL評価

    金谷 典子, 新井 健一, 山崎 香織, 増田 和司, 鈴木 貴明, 田口 奈津子, 首藤 潔彦, 中世古 知昭, 仲佐 啓詳, 有吉 範高, 北田 光一

    日本病院薬剤師会雑誌50 ( 3 ) 275 - 279   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本病院薬剤師会  

    がん化学療法や放射線療法を施行した患者は難治性の口内炎を発症することが多く、その疼痛のために、摂食不良、不眠、会話困難などのquality of life(以下、QOL)が低下することが多い。口内炎の疼痛に対し、インドメタシンスプレーが使用され、その有用性が各施設より報告されているが、QOLについて詳細な評価がなされていない。そこで、本研究では、千葉大学医学部附属病院において、インドメタシンスプレーを使用した患者に対して薬剤師がアンケート調査を行い、QOLに及ぼす効果を評価することを目的とした。患者アンケートの結果、疼痛の軽減、QOLの向上が示唆された。(著者抄録)

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  • 造血幹細胞移植後のシクロスポリンによる腎障害の危険因子の解析

    宮本 仁, 鈴木 貴明, 山崎 伸吾, 今井 千晶, 古賀 ひとみ, 竹田 真理子, 仲佐 啓詳, 中村 裕義, 有吉 範高, 中世古 知昭, 北田 光一

    医療薬学39 ( 1 ) 45 - 51   2013年1月

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    記述言語:日本語   出版者・発行元:(一社)日本医療薬学会  

    造血幹細胞移植後にシクロスポリンA(CyA)の24時間持続点滴を受けた患者50名(男29名、女性21名、16〜62歳)を対象に、腎障害発現頻度とその危険因子について検討した。腎障害グレード2以上に分類されたのは26名であった。平均CyA血中濃度と最大血清クレアチニン値(Cre)との間に相関関係はみられなかった。危険因子について単変量解析を行い、更に解析した項目に関して多重ロジスティック回帰分析を行った結果、腎障害の有意な要因は女性、移植前処置を骨髄破壊的に行った患者、年齢(加齢)であった。また、最大Cre上昇率を用いて腎障害の要因を解析した重回帰分析の結果からは、腎障害の有意な要因は見出せなかった。

    DOI: 10.5649/jjphcs.39.45

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  • CYP1A1 is a major enzyme responsible for the metabolism of granisetron in human liver microsomes

    H Nakamura, N Ariyoshi, K Okada, H Nakasa, K Nakazawa, M Kitada

    CURRENT DRUG METABOLISM6 ( 5 ) 469 - 480   2005年10月

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    記述言語:英語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    Granisetron, a potent 5-HT3 receptor antagonist, has been reported to be mainly metabolized to 7-hydroxygranisetron and a lesser extent to 9'-desmethylgranisetron in humans. A previous study indicated that cytochrome P450 (CYP)3A4 is a major catalyst of 9'-demethylation, although the major CYP isoform(s) responsible for 7-hydroxylation are unknown. To clarify granisetron 7-hydroxylase, the in vitro metabolism of granisetron using expressed human CYPs and human liver microsomes was investigated. 7-Hydroxygranisetron was produced almost exclusively by CYP1A1, while, apparently, 9'-desmethylgranisetron was preferentially produced by CYP3A4. Marked inter-individual differences in the ratio of the formation of 7-hydroxygranisetron and 9'-desmethylgranisetron in human liver microsomes was observed. Granisetron 7-hydroxylase activity was strongly correlated with benzo[a]pyrene 3-hydroxylase activity (p < 0.0001), but not with testosterone 6 beta-hydroxylase activity in human liver microsomes. Furthermore, an anti-human CYP I A I antibody completely inhibited 7-hydroxylation in human liver microsomes, however, the reaction was not inhibited at all by an anti-CYP3A4 antibody. On the other hand, granisetron 9'-demethylase activity correlated significantly not only with testosterone 6 beta-hydroxylase activity (p < 0.0001) but also with benzo[a]pyrene 3-hydroxylase activity (p < 0.01). Consistent with this, both the anti-CYP1A1 and anti-human CYP3A4 antibodies inhibited the 9'-demethylase activity. These data indicate that CYP1A1 is a major enzyme responsible for the metabolism of granisetron via a main 7-hydroxylation pathway and an alternative 9'-demethylation route. This is the first report demonstrating the substantial contribution of CYP1A1 to the metabolism of a drug, although its role in the metabolism of environmental compounds is well established.

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  • Direct interaction between substrates and endogenous steroids in the active site may change the activity of cytochrome P450 3A4

    N Torimoto, Ishii, I, M Hata, H Nakamura, H Imada, N Ariyoshi, S Ohmori, T Igarashi, M Kitada

    BIOCHEMISTRY42 ( 51 ) 15068 - 15077   2003年12月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

    CYP3A4 exhibits unusual kinetic characteristics that result from the metabolism of multiple substrate including endogenous steroids and some drugs that coexist at the active site. To clarify the mechanism of the effect of endogenous steroids on the drug metabolism, the interaction between substrates, nevirapine (NVP) and carbamazepine (CBZ), and endogenous steroids was investigated by theoretical calculations. When the activities of NVP 2-hydroxylation and CBZ 10,11-epoxidation by expressed CYP3A4 were measured in the presence of steroids, NVP 2-hydroxylation was found to be remarkably increased by aldosterone and inhibited by estradiol. CBZ 10,11-epoxidation was increased by androstenedione. Three-dimensional computer modeling has shown that the active site of CYP3A4 is especially large, permitting access of two substrate molecules. The interactions between NVP and aldosterone and between CBZ and androstenedione were estimated by theoretical calculations assuming the substrate and steroids to be present in the active site at the same time. It was shown that NVP or CBZ would be stably fixed close to the oxygen atom at the sixth ligand of heme by interaction with steroids, suggesting that NVP and CBZ may be hydroxylated more easily due to the interaction with steroids. Estradiol was also expected to interact with NVP via a pi/pi interaction between a benzene ring, in which the NVP hydroxylation site is located, and a benzene ring of estradiol, suggested to inhibit the reaction. From these results, interactions between the substrate and endogenous steroids in the active site may change the activity of CYP3A4.

    DOI: 10.1021/bi034409n

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  • CYP3A4 and CYP3A7-mediated carbamazepine 10,11-epoxidation are activated by differential endogenous steroids

    H Nakamura, N Torimoto, Ishii, I, N Ariyoshi, H Nakasa, S Ohmori, M Kitada

    DRUG METABOLISM AND DISPOSITION31 ( 4 ) 432 - 438   2003年4月

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    記述言語:英語   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    Recently, we reported that several endogenous steroids affect CYP3A4-mediated drug metabolism, using human adult liver microsomes as an enzyme source. Especially, carbamazepine (CBZ) 10,11-epoxidation is activated by androstenedione (AND). In the present studies, we investigated the effects of endogenous steroids on the activity of CBZ 10,11-epoxidation by expressed CYP3A4 and CYP3A7. When expressed CYP3A4 was used as an enzyme source, the addition of AND to the reaction mixture also caused a drastic increase in the activity of CBZ 10,11-epoxidase, and resulted in a change in the kinetics from sigmoid to Michaelis-Menten type. On the other hand, expressed CYP3A7-mediated CBZ 10,11-epoxidation was activated by sulfate conjugate steroids, such as pregnenolone 3-sulfate, 17alpha-hydroxypregnenolone 3-sulfate, and dehydroepiandrosterone 3-sulfate (DHEA-S), whereas the unconjugated form corresponding to these three steroids did not activate the reaction. Especially, DHEA-S was found to be a potent activator of CBZ 10,11-epoxidation by expressed CYP3A7. The kinetic character of CBZ 10,11-epoxidation by CYP3A7 is Michaelis-Menten type regardless of the presence of DHEA-S. The presence of DHEA-S caused a decrease in K-m and increase in V-max for CYP3A7-mediated CBZ 10,11-epoxidation, whereas DHEA-S 16alpha-hydroxylation was not affected by the coexistence of CBZ. In conclusion, CYP3A4 and CYP3A7-mediated CBZ 10,11-epoxidations are activated by different types of endogenous steroids. This is the first report regarding CYP3A7 cooperativity.

    DOI: 10.1124/dmd.31.4.432

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  • Association of CYP2A6 gene deletion with cigarette smoking status in Japanese adults

    Masahiko Ando, Nobuyuki Hamajima, Noritaka Ariyoshi, Tetsuya Kamataki, Keitaro Matsuo, Yoshiyuki Ohno

    Journal of Epidemiology13 ( 3 ) 176 - 181   2003年

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    記述言語:英語   出版者・発行元:Japan Epidemiology Association  

    BACKGROUND: Genetic variation of CYP2A6 is shown to alter nicotine metabolism. This study was developed to investigate the genetic influence of the whole deletion-allele of CYP2A6 on active and passive smoking behavior. METHODS: Two hundred and forty Japanese adults, who visited Aichi Cancer Center as outpatients, were genotyped for the wild-type (CYP2A6*1A, CYP2A6*1B) and the whole deletion-type (CYP2A6*4C) polymorphism of CYP2A6. Information about active and passive smoking status was obtained by a self-administered questionnaire. Genetic influence of CYP2A6 polymorphism on smoking behavior was evaluated using the Mantel extension test. RESULTS: The frequency of the deletion allele was 18%. All 8 subjects carrying two deletion alleles had no smoking habit, and the homozygous deletion genotype showed a tendency to correlate with active smoking status after adjustment for sex and age (p=0.054). However, the proportion of never smokers among heterozygous subjects was almost the same as among subjects carrying no deletion allele (54% and 58%, respectively). Furthermore, CYP2A6 genotypes were correlated neither with the number of cigarettes smoked per day nor with the age at starting smoking (p=0.364 and 0.880, respectively). Among never smokers, CYP2A6 genotypes were not correlated with exposure to passive smoking at home or in the workplace (p=0.623 and 0.484, respectively). CONCLUSION: Despite the possible protection against active smoking behavior in subjects homozygous for the deletion allele, the CYP2A6 polymorphism has only a limited impact on public health because no protective effect was found in heterozygous subjects.

    DOI: 10.2188/jea.13.176

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  • CYPが関係した相互作用のメカニズム

    薬局54 ( 11 ) 3 - 12   2003年

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  • 臨床におけるCYP研究とその意義

    Jpn J Clin Pharmacol Ther34 ( 4 ) 141 - 148   2003年

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  • 移植された肝臓のCYP2D6活性は臓器提供者の活性を反映しないのか

    DRUG METABOLISM AND PHARMACOKINETICS18 ( 3 ) 8 - 9   2003年

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  • New allelic arrangement CYP2D6*36x2 found in a Japanese poor metabolizer of debrisoquine

    M Chida, N Ariyoshi, T Yokoi, N Nemoto, M Inaba, M Kinoshita, T Kamataki

    PHARMACOGENETICS12 ( 8 ) 659 - 662   2002年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    DOI: 10.1097/00008571-200211000-00011

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  • Genetic polymorphism of CYP2A6 gene and tobacco-induced lung cancer risk in male smokers

    N Ariyoshi, M Miyamoto, Y Umetsu, H Kunitoh, H Dosaka-Akita, Y Sawamura, J Yokota, N Nemoto, K Sato, T Kamataki

    CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION11 ( 9 ) 890 - 894   2002年9月

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    記述言語:英語   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Cytochrome P450 2A6 (CYP2A6) is the principal enzyme involved in the metabolic activation of tobacco-specific nitrosamines to their ultimate carcinogenic forms and metabolism of nicotine. We investigated the effects of the CYP2A6*4, an entire CYP2A6 gene deletion-type polymorphism, on lung cancer risk and daily cigarette consumption in Japanese male smokers via a hospital-based case control study. The frequency of the CYP2A6*4 variant was compared in 370 lung cancer patients and 380 control smokers. A markedly reduced adjusted odds ratio for lung cancer risk, 0.23 [95 % confidence interval, 0.08-0.67], was seen in the group with homozygous deletion (*4/*4) when the odds ratio for a group with homozygous wild (*1A/*1A) was defined to be 1.00 by logistic regression. The subjects with lung cancer were additionally divided into three groups according to the histological classification of the cancer and examined for an association with the CYP2A6 polymorphism. The *4/ *4 genotype was not found in patients with squamous cell carcinoma (0 of 105) or small cell carcinoma (0 of 44), indicating that subjects with the *4/*4 genotype have low risk for lung cancers, particularly those caused by tobacco smoke. Furthermore, a significant reduction of daily cigarette consumption was observed in smokers with the *4/*4 genotype, suggesting a possibility that complete lack of CYP2A6 appeared to affect the smoking behavior. These data suggest that male smokers possessing the *1A/*1A genotype have higher risk for tobacco-induced lung cancers.

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  • Characterization of a genotype previously designated as CYP2A6 D-type: CYP2A6*4B, another entire gene deletion allele of the CYP2A6 gene in Japanese

    N Ariyoshi, H Sekine, K Saito, T Kamataki

    PHARMACOGENETICS12 ( 6 ) 501 - 504   2002年8月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    CYP2A6 is known as an enzyme responsible for the metabolism of several clincally used drugs such as tegafur. Previously, we found two novel genotypes of the CYP2A6 gene, D-type and E-type, and the E-type was clarified to be homozygous for the CYP2A6* 4A allele. On the other hand, since the D-type was reported to lack regions from at least intron 5 to a part of exon 9 of the CYP2A6 gene, it caused a misunderstanding that the D-type would be a partial CYP2A6 gene-deleted allele. In this paper, we demonstrate that the D-type is a genotype heterozygous for the CYP2A6*4A and another novel entire CYP2A6 gene-deleted allele, CYP2A6*4B, by analyzing a Japanese family including parents genotyped as the CYP2A6*4A/4A and CYP2A6* 1A/*4B, respectively.

    DOI: 10.1097/00008571-200208000-00012

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  • A novel mutant allele of the CYP2A6 gene (CYP2A6*11) found in a cancer patient who showed poor metabolic phenotype towards tegafur

    S Daigo, Y Takahashi, M Fujieda, N Ariyoshi, H Yamazaki, W Koizumi, S Tanabe, K Saigenji, S Nagayama, K Ikeda, Y Nishioka, T Kamataki

    PHARMACOGENETICS12 ( 4 ) 299 - 306   2002年6月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was fourfold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6*4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6*11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The V-max value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the K-m values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6*4C and the new variant CYP2A6*11.

    DOI: 10.1097/00008571-200206000-00005

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  • Activation of microsomal epoxide hydrolase by interaction with cytochromes P450: kinetic analysis of the association and substrate-specific activation of epoxide hydrolase function

    K Taura, H Yamada, E Naito, N Ariyoshi, M Mori, K Oguri

    ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS402 ( 2 ) 275 - 280   2002年6月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The kinetics of the association between cytochrome P450 (P450) and microsomal epoxide hydrolase (mEH) was studied by means of resonant mirror based on the principle of surface plasmon resonance. The dissociation equilibrium constants (KD) for the affinity of P450 enzymes for mEH were estimated by resonant mirror using an optical biosensor cell covalently bound to rat mEH. Comparable KD values were obtained for CYP1A1 and 2131, and these were greater by one order of magnitude than that for the CYP2C11. To clarify the influences of P450 enzymes on the catalytic activity of mEH, the hydrolyzing activity for styrene oxide and benzo(a)pyrene-7,8-oxide [B(a)P-oxide] was analyzed in the presence or absence of P450s. Styrene oxide hydrolysis was activated by all P450s including the CYP1A, 2B, 2C, and 3A subfamilies. In agreement with the association affinity determined by resonant mirror, CYP2C11 tends to have enhanced activity for styrene oxide hydrolysis. On the other hand, B(a)P-oxide hydrolysis was enhanced by only CYP2C11 while CYP1A1 and CYP2B1 had no effect. These results suggest that (1) many P450 enzymes associate nonspecifically with mEH, (2) the CYP2C11 plays a greater role in the association/activation of mEH and (3) the P450-mediated activation of mEH depends upon the substrate of mEH. (C) 2002 Elsevier Science (USA). All rights reserved.

    DOI: 10.1016/S0003-9861(02)00079-6

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  • Effects of endogenous steroids on CYP3A4-mediated drug metabolism by human liver microsomes

    H Nakamura, H Nakasa, Ishii, I, N Ariyoshi, T Igarashi, S Ohmori, M Kitada

    DRUG METABOLISM AND DISPOSITION30 ( 5 ) 534 - 540   2002年5月

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    記述言語:英語   出版者・発行元:AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

    In the present study, we investigated the effects of 14 endogenous steroids on the CYP3A4-mediated drug metabolism by human liver microsomes in vitro. Nevirapine (NVP) 2-, 12-hydroxylations, carbamazepine (CBZ) 10,11-epoxidation, triazolam (TZM) 1'-, 4-hydroxylations, erythromycin (EM) N-demethylation, and 2-sulphamoylacetylphenol (SMAP) formation from zonisamide (ZNS) were investigated. The activities of the NVP 2-, 12-hydroxylations, the CBZ 10,11-epoxidation, and the TZM 4-hydroxylation were activated by endogenous androgens, such as androstenedione (AND), testosterone, and dehydroepiandrosterone. However, these androgens inhibited EM N-demethylation, TZM 1'-hydroxylation, and SMAP formation. To understand the mechanisms of these effects of androgens on CYP3A4 activities, we performed a kinetic analysis of the metabolism of CBZ and ZNS in the presence or absence of AND using the modified two-site equation model. The addition of AND to the reaction mixture caused a drastic increase in the activity of CBZ 10,11-epoxidase, especially at a low substrate concentration, and resulted in a change in the kinetics from the sigmoid to Michaelis-Menten type. On the other hand, the metabolism of ZNS was strongly inhibited by AND, although no allosteric change was observed in this case. These data demonstrate that endogenous steroids, especially androgens, strongly affect CYP3A4-mediated drug metabolism in vitro. The postulated mechanisms of the interactions between AND and CBZ or ZNS are discussed.

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  • CYP2D6.10 present in human liver microsomes shows low catalytic activity and thermal stability

    K Nakamura, N Ariyoshi, T Yokoi, S Ohgiya, M Chida, K Nagashima, K Inoue, T Kodama, N Shimada, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS293 ( 3 ) 969 - 973   2002年5月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    Comparing bufuralol 1'-hydroxylase activity among liver microsomes prepared from individuals whose CYP2D6 genotypes had been determined, we found that the activity tended to decrease depending on the number of the CYP2D6*10 allele. Pre-incubation of liver microsomes from individuals homozygous for the CYP2D6*10 allele resulted in a decrease in the enzyme activity more rapidly than those from individuals homozygous for the CYP2D6*1, suggesting that not only the catalytic activity but also the thermal stability of the enzyme appeared to be affected by the genetic polymorphism. To confirm this hypothesis, the kinetic parameters of CYP2D6.1 and CYP2D6.10 were compared for bufuralol 1'-hydroxylation and dextromethorphan O-demethylation using microsomes prepared from yeast transformed with plasmids carrying CYP2D6 cDNAs (*1A and *10B). Kinetic studies of these CYP2D6 forms indicated clear differences in the metabolic activities between the wild (CYP2D6.1) and the mutant enzymes (CYP2D6.10). Bufuralol 1'-hydroxylase activity in microsomes of yeast expressing CYP2D6.10 was rapidly decreased by heat treatment. supporting the idea that the thermal stability of the enzyme was reduced by amino acid replacement from Pro (CYP2D6.1) to Ser (CYP2D6.10). These data strongly suggest that the thermal instability together with the reduced intrinsic clearance of CYP2D6.10 is one of the causes responsible for the known fact that Orientals show lower metabolic activities than Caucasians for drugs metabolized mainly by CYP2D6, because of a high frequency of CYP2D6*10 in Orientals. (C) 2002 Elsevier Science (USA). All rights reserved.

    DOI: 10.1016/S0006-291X(02)00328-5

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  • Variation in coumarin 7-hydroxylase activity associated with genetic polymorphism of cytochrome P450 2A6 and the body status of iron stores in adult Thai males and females

    P Ujjin, S Satarug, Y Vanavanitkun, S Daigo, N Ariyoshi, H Yamazaki, PEB Reilly, MR Moore, T Kamataki

    PHARMACOGENETICS12 ( 3 ) 241 - 249   2002年4月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    The relationships between catalytic activity of cytochrome P450 2A6 (CYP2A6), polymorphism of CYP2A6 gene, gender and levels of body iron stores were analysed in a sample group of 202 apparently healthy Thais, aged 1947 years. Eleven individuals were found to have high activity of CYP2A6, judged by the relatively large amounts (11.2-14.6 mg) of 7-hydroyxcoumarin (7-OHC) excreted 3 h following administration of 15 mg of coumarin. Ten individuals, however, did not excrete any 7-OHC. Of these 10, four were found to have no CYP2A6 gene (whole gene deletion; CYP2A6*4 allele). The frequency of the CYP2A6 alleles; *1A, *1B and *4 in the whole sample group was 52, 40 and 8% while the frequency of the CYP2A6 gene types; *1A/* 1A, *1A/* 1B, *1B/* 1B, *1A/* 4, *1BI* 4, *4/* 4 was 29, 41, 16, 7, 5 and 2%. Subjects having CYP2A6* 1A/* 1B gene-type group were found to have higher rates of coumarin 7-hydroxylation compared with those of the CYP2A6* 1B/* 1B and CYP2A6* 1A/* 4 gene types. The inter-individual variability in CYP2A6 catalytic activity was therefore attributed in part to the CYP2A6 genetic polymorphism. Variation in CYP2A6 activity in this sample group was not associated with gender but, interestingly, it did show an inverse association with plasma ferritin; an indicator of body iron stores. Higher rates of coumarin 7-hydroxylation were found in individuals with low body iron stores (plasma ferritin < 20 μg/l) compared with subjects having normal body iron store status. Subjects (n = 16) with iron overload (plasma ferritin > 300 mug/l) also tended to have elevated rates of coumarin 7-hydroxylation. These results suggest an increased CYP2A6 expression in subjects who have excessive body iron stores. Further investigations into the underlying factors that may lead to increased expression of CYP2A6 in association with abnormal body iron stores are currently in progress in our laboratory. Pharmacogenetics 12:241-249 (C) 2002 Lippincott Williams Wilkins.

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  • CYP2A6 gene deletion reduces oral cancer risk in betel quid chewers in Sri Lanka

    Z Topcu, Chiba, I, M Fujieda, T Shibata, N Ariyoshi, H Yamazaki, F Sevgican, M Muthumala, H Kobayashi, T Kamataki

    CARCINOGENESIS23 ( 4 ) 595 - 598   2002年4月

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    記述言語:英語   出版者・発行元:OXFORD UNIV PRESS  

    We investigated the relationship between inter-individual difference in CYP2A6 genotype and susceptibility to oral cancer among habitual betel quid chewers in a Sri Lanka population. A total of 286 subjects showing oral malignant or premalignant lesions and 135 control subjects with no lesions were analyzed. The frequency of homozygotes for CYP2A6*4C mutation, a gene deletion type of polymorphism, was significantly lower in the case subjects than the controls. The odds ratio (OR) of the group homozygous for the deletion was significantly lower and calculated to be 0.14 (95% CI; 0.03-0.72). In the allelic base analysis, there was also a significant decrease in the OR of the deletion allele. Our data suggest that deficient CYP2A6 activity due to genetic polymorphism reduces oral cancer risk in betel quid chewers.

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  • 肺癌の診断と治療 –最新の研究動向― 遺伝子多型と肺癌リスクとの関連性

    日本臨床 別冊60 ( 5 ) 46 - 49   2002年

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  • Role of human cytochrome P450 (CYP) in the metabolic activation of nitrosamine derivatives: Application of genetically engineered Salmonella expressing human CYP

    T Kamataki, K Fujita, K Nakayama, Y Yamazaki, M Miyamoto, N Ariyoshi

    DRUG METABOLISM REVIEWS34 ( 3 ) 667 - 676   2002年

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    記述言語:英語   出版者・発行元:MARCEL DEKKER INC  

    The role of human cytochrome P450 (CYP) in the metabolic activation of tobacco-related N-nitrosamines was examined by Salmonella mutation test using a series of genetically engineered Salmonella typhimurium YG7108 strains each co-expressing a form of CYP (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP3A5) together with human NADPH-cytochrome P450 reductase. Seven tobacco-related N-nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, N-nitrosodiethylamine, N-nitrosopyrrolidine, N-nitrosopiperidine, N-nitrosonornicotine, N-nitrosoanabasine, and N-nitrosoanatabine were used. The CYP2A6 was found to be responsible for the mutagenic activation of essentially all tobacco-related N-nitrosamines examined. On the basis of the evidence, genetic polymorphism of the CYP2A6 gene appeared to be one of the factors determining cancer susceptibility caused by smoking. Previously, we found the whole deletion of the CYP2A6 gene (CYP2A6*4C) as a type of genetic polymorphism in Japanese. We hypothesized that individuals possessing the gene homozygous for CYP2A6*4C were incapable of activating tobacco-related N-nitrosamines and showed lower susceptibility to lung cancer induced by tobacco smoke. Thus, the relationship between the CYP2A6*4C and the susceptibility to the lung cancer was evaluated. The frequency of the CYP2A6*4C was significantly lower in the lung cancer patients than healthy volunteers, suggesting that the subjects carrying the CYP2A6*4C alleles are resistant to carcinogenesis caused by N-nitrosamines because of the poor metabolic activation capacity.
    Taking these results into account, CYP2A6 is an enzyme enhancing lung cancer risk.

    DOI: 10.1081/DMR-120005668

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  • ゲノム情報の活用と服薬のタイミングを考える テーラーメイド医療を目指した研究・治療の現状:薬理遺伝学的視点から

    薬局53 ( 10 ) 2 - 13   2002年

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  • 薬理学におけるトランスレーショナルリサーチー基盤研究から臨床までー 臨床薬理遺伝学と将来の薬物療法への展望

    有吉 範高

    日本薬理学雑誌120 ( 3 ) 181 - 186   2002年

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    記述言語:日本語   掲載種別:書評論文,書評,文献紹介等  

    DOI: 10.1254/fpj.120.181

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  • 薬剤師教育における薬系大学と病院薬剤部の人的交流

    日本医療薬学会会報6 ( 1 ) 8 - 10   2002年

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  • Perspectives on application of genetic polymorphisms for cancer chemotherapy

    N Ariyoshi, T Kamataki, M Kitada

    JAPANESE JOURNAL OF PHARMACOLOGY88   46P - 46P   2002年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JAPANESE PHARMACOLOGICAL SOC  

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  • The relationship between CYP2A6 gene deletion and susceptibility to oral cancer

    Z Topcu, Chiba, I, M Fujieda, T Shibata, N Ariyoshi, H Yamazaki, F Sevgican, M Muthumala, H Kobayashi, T Kamataki

    DRUG METABOLISM REVIEWS34   154 - 154   2002年

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARCEL DEKKER INC  

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  • Role of the dioxin-like toxic compound coplanar polychlorinated biphenyl, 3,3 ',4,4 ',5-pentachlorobiphenyl in reducing hepatic alcohol dehydrogenase levels in rats in vivo

    Y Ishii, H Kato, M Hatsumura, T Ishida, N Ariyoshi, H Yamada, K Oguri

    JOURNAL OF HEALTH SCIENCE47 ( 6 ) 575 - 578   2001年12月

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    記述言語:英語   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    The ability of a dioxin-like toxic compound, coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl (PCB126) to reduce the protein level of hepatic class 1 alcohol dehydrogenase (ADH), which plays an important role in the metabolism of ethanol, was studied. Male Wistar rats received PCB126 25 mg/kg i.p. At this dose the compound induces a wasting syndrome. PCB126 administration resulted in a significant suppression of the protein level of class 1 ADH, whereas the difference between free- and pair-fed controls was slight. These results suggest that dioxins also reduce class 1 ADH without involvement of decreased food consumption. These data offer new insights into the toxicity of dioxins via a marked decrease in the level of class 1 ADH.

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  • Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms

    Baker, JR, S Satarug, PEB Reilly, RJ Edwards, N Ariyoshi, T Kamataki, DJ Williams, MR Moore

    TOXICOLOGY164 ( 1-3 ) 61 - 62   2001年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

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  • A single nucleotide polymorphism of CYP2B6 found in Japanese enhances catalytic activity by autoactivation

    N Ariyoshi, M Miyazaki, K Toide, Y Sawamura, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS281 ( 5 ) 1256 - 1260   2001年3月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC  

    A single nucleotide polymorphism (SNP) resulting in a substitution from Gin to His was found in exon 4 of the CYP2B6 gene in Japanese. The frequency of the variant allele was found to be 19.9%. The mutant- and the wild-type enzymes were expressed in Escherichia coli, and the effects of the single amino acid substitution on the catalytic activity were examined by investigating the kinetic profiles of 7-ethoxycoumarin O-deethylase activity. The wild-type enzyme showed typical Michaelis-Menten kinetics, while the mutant-type enzyme represented the sigmoidal kinetics with a higher V-max value compared to that of the wild-type enzyme. Eadie-Hofstee plots further revealed an existence of allosteric effects for the reaction catalyzed by the variant. This is the first evidence demonstrating that only one amino acid substitution, Gln172His, caused by natural SNP enhances the catalytic activity of CYP by obtaining the character of homotropic cooperativity. stool Academic Press.

    DOI: 10.1006/bbrc.2001.4524

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  • A novel single nucleotide polymorphism altering stability and activity of CYP2A6

    N Ariyoshi, Y Sawamura, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS281 ( 3 ) 810 - 814   2001年3月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC  

    CYP2A6 is known as a major cytochrome P450 (CYP) responsible for the oxidation of nicotine and coumarin in humans. In this study, we explored genetic polymorphisms, which reduce CYP2A6 activity in Japanese. Two novel mutations in exon 9 of the CYP2A6 gene were found. A single nucleotide polymorphism of T1412C and G1454T resulted in Ile471Thr and Arg485Leu substitution, respectively. The frequency of the former variant allele was considerably high (15.7%), while the latter variant appeared to be a rare polymorphism. Heterologous expression of CYP2A6 using a cDNA possessing C instead of T-base at codon 471 in Escherichia coli caused remarkable reduction of the stability of holoenzyme at 37 degreesC. Furthermore, this variant enzyme almost lacked nicotine C-oxidase activity, although coumarin 7-hydroxylase activity was still observed. These data suggest that individuals homozygous for the T1412C variant allele or heterozygous for this and a defect allele such as the CYP2A6*4 may be poor metabolizer of nicotine, but not coumarin. (C) 2001 Academic Press.

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  • Accumulation of the 1-methyl-4-phenylpyridinium ion in suncus (Suncus murinus) brain: Implication for flavin-containing monooxygenase activity in brain microvessels

    T Mushiroda, N Ariyoshi, T Yokoi, E Takahara, O Nagata, H Kato, T Kamataki

    CHEMICAL RESEARCH IN TOXICOLOGY14 ( 2 ) 228 - 232   2001年2月

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    記述言語:英語   出版者・発行元:AMER CHEMICAL SOC  

    The metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was examined in an effort to evaluate the role of flavin-containing monooxygenase (FMO) expressed in the brain of suncus (Suncus murinus) and rats. MPTP was metabolized to generate both 1-methyl-4-phenylpyridinium ion (MPP+) and MPTP N-oxide by brain homogenates from rats. Although the level of MPP+-producing activity was similar in suncus and rats, a remarkable difference was found between the animal species in MPTP N-oxygenase activity, which was not detectable in brain homogenates from suncus, The concentrations of MPP+ in suncus brain after a single ip administration of MPTP were markedly higher than that in rats, probably because of the lack of FMO activity in the suncus brain. The MPTP N-oxygenase activity of microvessel homogenates of rat brain was 21-fold greater than that of whole brain homogenates. These results suggest that FMO(s) plays a significant role in the detoxification of MPTP in cerebral endothelial cells.

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  • Genetic polymorphisms of cytochrome P450 2A6 in a case-control study on lung cancer in a French population

    MA Loriot, S Rebuissou, M Oscarson, S Cenee, M Miyamoto, N Ariyoshi, T Kamataki, D Hemon, P Beaune, Stucker, I

    PHARMACOGENETICS11 ( 1 ) 39 - 44   2001年2月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Cytochrome P450 2A6 (CYP2A6) is involved in the C-oxidation of nicotine and in the metabolic activation of tobacco nitrosamines. Recent data have suggested that CYP2A6 genetic polymorphisms might play a role in tobacco dependence and consumption as well as in lung cancer risk, However, the previously published studies were based on a genotyping method that overestimated the frequencies of deficient alleles, leading to misclassification for the CYP2A6 genotype, In this study, we genotyped DNA from 244 lung cancer patients and from 250 control subjects for CYP2A6 (wild-type allele CYP2A6*1, and two deficient alleles: CYP2A6*2, and CYP2A6*4, the latter corresponding to a deletion of the gene) using a more specific procedure. In this Caucasian population, we found neither a relation between genetically impaired nicotine metabolism and cigarette consumption, nor any modification of lung cancer risk related to the presence of defective CYP2A6 alleles (odds ratio = 1.1, 95% confidence interval = 0.7-1.9). Pharmacogenetics 11:39-44 (C) 2001 Lippincott Williams & Wilkins.

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  • Pharmacogenetics

      42 ( 2 ) 176 - 185   2001年

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  • 喫煙による肺癌発生と遺伝子多型

    内科88 ( 5 ) 883 - 885   2001年

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  • 薬物代謝における遺伝多型と薬物療法 -CYP1A2-

    医薬ジャーナル37 ( 10 ) 79 - 85   2001年

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  • チトクロームP450遺伝子多型 2A-2Cおよび3AサブファミリーCYPの遺伝的多型

    細胞33 ( 12 ) 9 - 13   2001年

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  • 分子疫学と発癌リスク-遺伝子多型解析の現状と将来-

    Medical Practice19 ( 1 ) 58   2001年

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  • 薬物代謝酵素の遺伝的多型の変異原活性化における意義

    Environ. Mutagen Res.23   33 - 37   2001年

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  • 喫煙による肺発癌と遺伝子多型

    分子呼吸器病5 ( 4 ) 13 - 20   2001年

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  • 癌治療の個別化と展望

    臨床医薬17 ( 8 ) 1116 - 1121   2001年

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  • Application of the polymorphism of the CYP genes to the therapeutic management and counseling of patients

    Jpn. J. Pharm. Health Care Sci.27 ( 3 ) 228 - 234   2001年

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  • Effects of a highly toxic coplanar polychlorinated biphenyl, 3, 3', 4, 4', 5-pentachlorobiphenyl on intermediary metabolism : reduced triose phosphate content in rat liver cytosol.

    Fakuoka Acta Medica.92 ( 5 ) 190 - 200   2001年

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  • CYP2Aと遺伝子多型

    月刊薬事臨時増刊号43 ( 3 ) 86 - 93   2001年

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  • Structural characterization of a new variant of the CYP2A6 gene (CYP2A6*1B) apparently diagnosed as heterozygotes of CYP2A6*1A and CYP2A6*4C

    N Ariyoshi, Y Takahashi, M Miyamoto, Y Umetsu, S Daigo, T Tateishi, S Kobayashi, Y Mizorogi, MA Loriot, Stucker, I, P Beaune, M Kinoshita, T Kamataki

    PHARMACOGENETICS10 ( 8 ) 687 - 693   2000年11月

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    記述言語:英語   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    During the course of investigating the frequency of a CYP2A6 whole deletion-type polymorphism (CYP2A6*4C) in Japanese, an unexpectedly large population of heterozygotes for CYP2A6*4C and the wild-type (CYP2A6*1A) was found. Cloning of a cDNA encoding CYP2A6 from the liver of individuals judged as heterozygotes for CYP2A6*4C and the CYP2A6*1A was carried out to identify the causal allele(s) responsible for a possible overestimation. A clone isolated from the liver cDNA library possessed 58 bp sequences in the 3'-untranslated region, which was replaced with the corresponding region of the CYP2A7 gene. The same gene conversion existed in the genomic DNA, indicating that the replacement was not a cloning artifact. Based on the gene structure of the allele (CYP2A6*1B), this variant was thought to be one of the causal alleles responsible for overestimation of heterozygotes for CYP2A6*4C and CYP2A6*1A. To investigate this further, we developed a genotyping method which could distinguish the CYP2A6*1A, CYP2A6*1B and CYP2A6*4C alleles from each other. The results clearly showed that CYP2A6*1B was the sole allele responsible for the overestimation. We conclude that the new genotyping method allows determination of six genotypes of the CYP2A6 gene, simultaneously and precisely, in both Oriental and Caucasian populations. Pharmacogenetics 10:687-693 (C) 2000 Lippincott Williams & Wilkins.

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  • A high-level expression of CYP2A in the lung of the suncus (Suncus murinus) and its role in the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

    T Mushiroda, N Ariyoshi, K Kimura, E Takahara, O Nagata, H Kato, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS269 ( 2 ) 393 - 396   2000年3月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC  

    Northern blot analysis of mRNA prepared from the lung of Suncus murinus (suncus), which was classified as an ancestor of primates, revealed that the expression level of cytochrome P450 2A (CYP2A) mRNA was about 100-fold higher than in the lung from rats and mice. To confirm that the pulmonary CYP2A of the suncus had a catalytic activity, the metabolism of a specific substrate for CYP2A6, (+)-cis-3,5-dimethyl-2-(3-pyridyl) thiazolidin-4-one hydrochloride (SM-12502), was determined. The intrinsic clearance for SM-12502 S-oxidation by the suncus lung microsomes was calculated to be 99-fold higher than that by rat liver microsomes. The mutagen-producing activity of a 9000g supernatant fraction prepared from suncus lung was examined using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as a promutagen. The results showed that the suncus lung possessed 82-fold higher mutagen-producing activity than the rat lung, indicating that NNK was efficiently activated by the CYP2A isoform expressed in the suncus lung and that the suncus was a sensitive animal species to the genotoxicity of NNK contained in tobacco smoke. (C) 2000 Academic Press.

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  • 薬物代謝酵素の遺伝的多型と薬物動態-CYP2D

    月刊薬事臨時増刊号42 ( 4 ) 219 - 226   2000年

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  • CYP2A6の遺伝的多型に関する研究

    薬物動態15 ( 1 ) 57 - 61   2000年

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  • Analysis of the CYP2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population (vol 65, pg 570, 1999)

    T Tateishi, M Chida, N Ariyoshi, Y Mizorogi, T Kamataki, S Kobayashi

    CLINICAL PHARMACOLOGY & THERAPEUTICS66 ( 6 ) 581 - 581   1999年12月

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    記述言語:英語   出版者・発行元:MOSBY-YEAR BOOK INC  

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  • CYP2A6 gene deletion reduces susceptibility to lung cancer

    M Miyamoto, Y Umetsu, H Dosaka-Akita, Y Sawamura, J Yokota, H Kunitoh, N Nemoto, K Sato, N Ariyoshi, T Kamataki

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS261 ( 3 ) 658 - 660   1999年8月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC  

    CYP2A6 is an enzyme with a high ability to activate a nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to its potent and ultimate carcinogen. In the present study, we investigated the relationship between genetic polymorphism of CYP2A6 and lung cancer risk in a case-control study of Japanese subjects. Genotyping of the CYP2A6 gene in both healthy volunteers and lung cancer patients was conducted. The frequency with which the subjects carried homozygotes of the CYP2A6 gene deletion-type mutation (deletion), which causes lack of the enzyme activity, was lower in the lung cancer patients than in the healthy control subjects. The odds ratio (OR) of the group homozygous for the deletion was significantly lower and calculated to be 0.25 (95% CI; 0.08-0.83) when the OR for the population with homozygotes of the CYP2A6 wild-type gene was defined as 1.00, In the allelic-base analysis, there was also a significant decrease in the OR for the deletion allele, These data suggest that deficient CYP2A6 activity due to genetic polymorphism reduces lung cancer risk. (C) 1999 Academic Press.

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  • Analysis of the C Upsilon P2D6 gene in relation to dextromethorphan O-demethylation capacity in a Japanese population

    T Tateishi, M Chida, N Ariyoshi, Y Mizorogi, T Kamataki, S Kobayashi

    CLINICAL PHARMACOLOGY & THERAPEUTICS65 ( 5 ) 570 - 575   1999年5月

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    記述言語:英語   出版者・発行元:MOSBY-YEAR BOOK INC  

    Objective: To analyze the CYP2D6 allele frequencies in a Japanese population and to evaluate the effects of CYP2D6 variants on in vivo CYP2D6 activity as measured by the dextromethorphan metabolic ratio (MR).
    Methods: Ninety-eight unrelated, healthy Japanese men were phenotyped with dextromethorphan and genotyped by the polymerase chain reaction amplification method for 7 CYP2D6 alleles.
    Results:The CYP2D6*1, CYP2D6*10 CYP2D6*2 CYP2D6*5, CYP2D6*4, and CYP2D6*21 allele frequencies in our Japanese subjects were 0.423, 0.408, 0.092, 0.061, 0.020, and 0.010, respectively. Thirty-three subjects (33.7%) were heterozygous for *10/*1, and 18 (18.4%) and 17 (17.3%) subjects were homozygous for *1 and *10 respectively. Subjects who were homozygous for *10 showed the highest dextromethorphan MR among these 3 genotypes. Eighteen subjects (18.3%) were heterozygous for *2 but their dextromethorphan MR values were not greater than the MR values of subjects who were homozygous for *1. One subject was a poor metabolizer phenotypically, and he was homozygous for *5.
    Conclusions The CYP2D6 allele frequencies in our Japanese subjects differed from those determined in previous studies of white subjects or mainland Chinese subjects. Individuals homozygous for *10 who have relatively low in vivo CYP2D6 activity represent almost 20% of the Japanese population. In addition, we did not identify any subjects with amplified *2 among our 98 Japanese men.

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  • Pharmacogenetics

    Cancer Frontier1   57 - 63   1999年

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  • Highly toxic coplanar PCB126 reduces liver peroxisomal enzyme activities in rats

    N Ariyoshi, M Iwasaki, H Kato, S Tsusaki, M Hamamura, T Ichiki, K Oguri

    ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY5 ( 3 ) 219 - 225   1998年5月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    The effect of the highly toxic coplanar PCB congener, 3,4,5,3',4'-pentachlorobiphenyl (PCB126) on hepatic peroxisomes was studied in rats. The aim of this study was to investigate whether a toxic dose of the dioxin-like coplanar PCB modifies enzyme activities in peroxisomes where plays an important role in lipid metabolism. Treatment with PCB126, at a single i.p. administration of 25 mg/kg which evokes clear suppression of body weight gain, resulted in marked reduction (to about 40-50%) of catalase activity and peroxisomal fatty acyl-CoA beta-oxidizing system. Immunoblotting showed that expression of catalase was greatly reduced by the treatment in parallel with the activity. Light microscopy revealed a drastic reduction in granules possessing peroxidase activity, while electron microscopy demonstrated that no apparent morphological changes had taken place. Thus the reduction in catalase activity caused by PCB126 could be attributable to suppression of protein expression. The marked reduction of these peroxisomal enzyme activities might be related to hyperlipidemia caused by dioxin-related compounds in rats and humans. (C) 1998 Elsevier Science B.V. All rights reserved.

    DOI: 10.1016/S1382-6689(98)00007-6

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  • Characterization of the rat Star gene that encodes the predominant 3.5-kilobase pair mRNA - ACTH stimulation of adrenal steroids in vivo precedes elevation of Star mRNA and protein

    N Ariyoshi, YC Kim, Artemenko, I, KK Bhattacharyya, CR Jefcoate

    JOURNAL OF BIOLOGICAL CHEMISTRY273 ( 13 ) 7610 - 7619   1998年3月

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    記述言語:英語   出版者・発行元:AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

    The steroidogenic acute regulatory protein (STAR) participates in steroidogenesis through the mitochondrial transfer of cholesterol to cytochrome P450scc. The rat adrenal Star gene is transcribed as a 3.5-kilobase pair (kb) and 1.6 kb mRNA with the larger mRNA predominating (similar to 85% of total) in. vivo, Hypophysectomy (HPX) produced a 3-5-fold decrease in Star mRNA along with a loss of adrenal steroids, whereas P450scc mRNA decreased by less than 2-fold, Adrenocorticotropic hormone (ACTH) treatment of HPX rats maximally stimulated steroidogenesis rates within 5 min with over 10-fold elevation of steady state blood levels occurring within 10 min. For intact rats there was a 5-10-fold larger increase, paralleling previously observed elevations of cholesterol-cytochrome P450scc association and metabolism in subsequently isolated adrenal mitochondria, ACTH did not increase either total STAR protein or a group of modified forms until at least 30 min after completion of acute stimulation, indicating that elevated translation of STAR protein cannot alone mediate this acute stimulation. Parallel slow changes in STAR protein and corticosterone formation after ACTH treatment are consistent with participation of STAR forms as co-regulators of these hormonal responses, ACTH stimulation of HPX rats increased Star mRNA by 2.5-fold within 20 min and by 4.5-fold after 1 h, thus preceding the rise in the STAR protein, A 3.5-kb Star cDNA clone isolated from a rat adrenal cDNA library exhibited a 0.9-kb open reading frame and a 2.5-kb 3'-untranslated region (3'-UTR). The open reading frame sequence differed at only 12 amino acids from that of the mouse Star. The rat Star gene seven exons with exon 7 encoding the entire 2.5 kb of 3'-UTR of the 3,5-kb mRNA. The 3'-UTR sequence suggests that 1.6- and 3,5-kb mRNA are formed by an alternative usage of different polyadenylation signals, Multiple UUAUUUA(U/A)(U/A) motifs also suggest additional regulation through this extended 3'-UTR, Although elevation of STAR protein by ACTH does not cause the acute increase in adrenal cholesterol metabolism, changes in the turnover or distribution of an active STAR subfraction cannot be excluded.

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  • 残留性有機汚染物質と生物の存亡-物質文明の最果てに-

    道薬誌15 ( 5 ) 5 - 8   1998年

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  • Changes in the hepatic glutathione peroxidase redox system produced by coplanar polychlorinated biphenyls in Ah-responsive and -less-responsive strains of mice: mechanism and implications for toxicity

    M Hori, H Kondo, N Ariyoshi, H Yamada, A Hiratsuka, T Watabe, K Oguri

    ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY3 ( 4 ) 267 - 275   1997年9月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    The alteration in hepatic glutathione peroxidase (GPx) produced by polychlorinated biphenyls (PCBs) was studied in vivo in aryl hydrocarbon (Ah)-responsive C57BL and -less-responsive DBA strains of mice. 3,3',4,4',5-Pentachlorobiphenyl (PCB 126), one of the high-affinity ligands for the Ah receptor, significantly reduced Se-dependent GPx activity in C57BL mice, but not in DBA mice. A reduction in activity in C57BL mice was also observed following treatment with a high dose of 3,3',4,4'-tetrachlorobiphenyl with lesser affinity for the Ah receptor than PCB 126, but not by 2,2',5,5'-tetrachlorobiphenyl, a low-affinity ligand. To assess the effects on GPx in the liver, the content of reduced glutathione (GSH), an obligate co-factor for GPx, and the activity of two enzymes, gamma-glutamyl transpeptidase (gamma-GTP) and glutathione reductase (GR), which play a role in supplying GSH were determined after PCB treatment. The results showed that although the hepatic activity of gamma-GTP and GR was affected differently by PCB 126, the content of GSH was slightly increased rather than reduced in both strains of mice. The activity of non-Se-dependent GPx, which is due to the catalysis by some isozymes of glutathione S-transferase (GST), was significantly increased only in C57BL mice by PCB 126 treatment. Immunoblot analysis demonstrated that the induction of the class theta GST, which is a potent reducer of peroxides (Hiratsuka et al., 1995. Biochem. Biophys. Res. Commun. 212, 743) reflects the enhancement of the above activity. These results suggest that (i) the PCB-induced reduction in Se-dependent GPx activity is mediated by a mechanism involving the Ah receptor; and (ii) a concomitant increase in the class theta GST partially rescues the Ah-responsive mice from coplanar PCB-induced oxidative stress. (C) 1997 Elsevier Science B.V.

    DOI: 10.1016/S1382-6689(97)00025-2

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  • Species-specific alteration of hepatic glucose 6-phosphate dehydrogenase activity with coplanar polychlorinated biphenyl: Evidence for an Ah-receptor-linked mechanism

    M Hori, H Kondo, N Ariyoshi, H Yamada, K Oguri

    CHEMOSPHERE35 ( 5 ) 951 - 958   1997年9月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    We examined the in vivo effect of a highly toxic coplanar polychlorinated biphenyl (PCB) on the hepatic activity of glucose 6-phosphate dehydrogenase (G6PDH) in aryl hydrocarbon (Ah)-responsive (C57/BL) and -less-responsive (DBA) strains of mice. The activity in the C57BL strain was moderately increased by 3,3',4,4',5-pentachlorobiphenyl (PCB 126) in a dose dependent manner. However, this was not observed in DBA mice although greater doses were injected. 2,2',5,5'-Tetrachlorobiphenyl (PCB 52) with a non-planar structure did not increase G6PDH activity, The increase in G6PDH activity with PCB 126 was also seen in rats, but not in guinea pigs. The activity in the latter species was decreased rather than increased. These results suggest that the induction of hepatic G6PDH by coplanar PCB is mediated by a mechanism involving the Ah receptor, and the response was highly species-specific. (C) 1997 Elsevier Science Ltd.

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  • A highly toxic PCB produces unusual changes in the fatty acid composition of rat liver

    K Matsusue, Y Ishii, N Ariyoshi, K Oguri

    TOXICOLOGY LETTERS91 ( 2 ) 99 - 104   1997年4月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    The changes in lipid metabolism produced by a coplanar PCB were studied in rats. Male Wistar rats were given a single intraperitoneal injection of 3,3',4,4',5-pentachlorobiphenyl at a dose of 25 mg/kg. After 5 days of administration, total hepatic lipids were treated with 1 M KOH in methanol at 75 degrees C and the liberated fatty acids were analyzed by HPLC after conversion to fluorescent derivatives. In comparison with free-fed and pair-fed control groups, the proportion of arachidonic acid in the PenCB-treated rats was reduced by about 50%, while oleic and linoleic acids increased significantly. We also examined the individual glycerophospholipids, separated by TLC,to see if they were affected by alteration in the fatty acid composition of the whole liver. In all glycerophospholipids, the proportion of arachidonic acid was reduced significantly to the same degree while linoleic acid increased. Changes in the activity of desaturase isozymes have been postulated to explain this unusual lipid metabolism following administration of a toxic PCB and this may contribute to its toxicity. (C) 1997 Elsevier Science Ireland Ltd.

    DOI: 10.1016/S0378-4274(97)03881-2

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  • Significant suppression of rat liver aldolase B by a toxic coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl

    Y Ishii, H Kato, M Hatsumura, T Ishida, N Ariyoshi, K Oguri

    TOXICOLOGY116 ( 1-3 ) 193 - 199   1997年1月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    A toxic coplanar polychlorinated biphenyl, 3,3',4,4',5-pentachlorobiphenyl (PenCB), significantly suppresses the expression of liver aldolase B in rats, Hepatic aldolase activity in PenCB-treated rats was significantly reduced to about 50% of that in free- and pair-fed control groups. The reduced aldolase activity following PenCB-treatment was due to the marked suppression of the expression of aldolase B shown by immunoblot analysis after SDS-polyacrylamide gel electrophoresis and two-dimensional gel electrophoresis. The suppression of rat liver aldolase B could be a key biochemical lesion caused by PenCB. Copyright (C) 1997 Elsevier Science Ireland Ltd.

    DOI: 10.1016/S0300-483X(96)03543-3

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  • Cytochrome P450scc in rat adrenal cells mediated by regulation of the steroidogenic acute regulatory protein

    YC Kim, N Ariyoshi, Artemenko, I, ME Elliott, KK Bhattacharyya, CR Jefcoate

    STEROIDS62 ( 1 ) 10 - 20   1997年1月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE INC  

    Cholesterol conversion to pregnenolone by cytochrome P450scc in steroidogenic cells, including those of the adrenal cortex is determined by hormonal control of cholesterol availability. Intramitochondrial cholesterol movement to P450scc, which retains hormonal activation in isolated mitochondria, is apparently dependent an peripheral benzodiazepine receptor and the recently cloned steroidogenic acute regulatory (SrARJ protein. In rat adrenal cells, StAR is formed as a 37-kDa precursor that is transferred to the mitochondrial inner membrane following phosphorylation by hormonally activated protein kinase A, and processed to multiple forms, some of which turn over very rapidly. In bovine cells, StAR undergoes three modifications for ming a set of eight proteins seen in both glomerulosa and fasciculata cells. In the former, cyclic AMP and angiotensin ii each decrease two forms and elevate six forms. Significantly, the major change seen after activation may not involve phosphorylation of StAR. Cholesterol transfer across mitochondrial membranes is also activated in isolated mitochondria by GTP and low concentrations of Ca2+, apparently prior to activation by StAR. Depletion of StAR by cyclohexmide inhibits cholesterol transfer but is overcome by uptake of Ca2+ into the matrix. This activation of cellular- cholesterol transport is sustained in adrenal cells pereabilized by Streptolysin 0. In rat adrenal cells cAMP elevates 3.5- and 1.6-kb mRNA, hybridized by a 1.O-kb StAR cDNA. A 3.5-kb rat adrenal cDNA that encodes all except the 5' end of the longest StAR mRNA has been characterized. The corresponding gene sequence is distributed across seven exons. The shorter mRNA may arise from polyadeylation signals early in exon 7. However, the 3.5-kb mRNA comprises 80-90% of untreated rat adrenal StAR mRNA and may therefore provide the prime source for in vivo translation of StAR protein. (C) 1997 by Elsevier Science, Inc.

    DOI: 10.1016/S0039-128X(96)00153-5

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  • Effect of co-planar polychlorinated biphenyl on the hepatic glutathione peroxidase redox system in rats and guinea pigs

    M. Hori, N. Ariyoshi, H. Yamada, K. Oguri

    Fukuoka Acta Medica88 ( 5 ) 12 - 16   1997年

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    記述言語:日本語   出版者・発行元:Kyushu University School of Medicine  

    The effect of 3,3',4,4',5-pentachlorobiphenyl (PCB 126) on hepatic glutathione peroxidase (GPx) redox system was studied in vivo in rats and guinea pigs. PCB 126 treatment caused significant reduction of Se-dependent and -non-dependent GPx activity in rats. In agreement with this, the content of glutathione (GSH) and the activities of GSH reductase (GR) and γ-glutamyl transpeptidase (γ-GTP) were also decreased in this species. On the contrary, guinea pig liver Se-non-dependent GPx activity was significantly enhanced by PCB 126 treatment, while no effect on Se-dependent activity was observed. Neither the content of GSH nor the enzyme activities responsible for GSH supply in guinea pig liver was affected by PCB 126. These result suggested that the damage on GPx redox system is, at least, one of mechanisms by which co-planar PCB induces the toxicity in rats. However, in guinea pigs, this is not the case, and different mechanism from the damage on active oxygen quenching system is likely to be involved.

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  • Production of antibody against cytosolic 54kDa protein in rat liver evidence of the significant induction by a highly toxic coplanar polychlorinated biphenyl

    T. Ishida, Y. Ishii, K. Tasaki, N. Ariyoshi, K. Oguri

    Fukuoka Acta Medica88 ( 5 ) 3 - 11   1997年

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    記述言語:日本語   出版者・発行元:Kyushu University School of Medicine  

    We have reported that a 54kDa protein in rat liver cytosol is highly inducible by treatment with 3,3',4,4',5-pentachlorobiphenyl (PenCB) or 3- methylcholanthrene (MC) using SDS-polyacrylamide gel electrophoresis. Internal amino acid sequences of this protein in the rat liver were highly homologous to those of selenium binding protein (SeBP) or acetaminophen binding protein (APBP) in mouse liver cytosol. In this paper, the purification and characterization of this protein were demonstrated MC was given at a dose of 20 mg/kg for 3 consecutive days. The liver cytosolic 54kDa protein was purified twice from the MC-treated male Wistar rats by Rotofore Cell(TM) procedure to apparent single on SDS-polyacrylamide gel electrophoresis, and the rabbit antiserum against this protein was obtained. Male Wistar rats were given PenCB in corn oil at a single dose of 25 mg/kg i.p. The liver cytosol was prepared on the 5th day after the treatment and subjected to immunoblot analysis. The 54kDa protein was markedly induced in the liver cytosol of PenCB-treated rats. Immunoblot analysis after two- dimensional gel electrophoresis suggested that there could be isoforms of 54kDa protein. The induction of the 54kDa protein with PenCB was assumed to be mediated through Ah-receptor. The physiological role of the 54kDa protein was discussed together with SeBP and APBP, the role of which has not yet been elucidated.

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  • Metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl (PCB153) in guinea pig

    N. Ariyoshi, N. Koga, H. Yoshimura, K. Oguri

    Xenobiotica27 ( 9 ) 973 - 983   1997年

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    記述言語:英語  

    1. The in vitro and vivo metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl (PCB153) in guinea pig has been studied. 2. Seven metabolites were detected in the faeces of PCB153-treated animals and three were identical to those produced by dog liver microsomes. The detection of a metabolite where a chlorine atom was shifted from the 2- to 3-position strongly suggested the involvement of 2,3-arene oxide intermediate, and evidence for the concomitant formation of a 3,4-arene oxide intermediate was provided by identifying other two minor metabolites which were dechlorinated at the 4-position. 3. In vitro studies using liver microsomes from guinea pigs revealed that the 2,3-arene oxide and 5-hydroxylation pathways are the predominant metabolic routes compared with the 3,4-arene oxide pathway. Although the guinea pig is an another species that can metabolize PCB153 mainly to the 2,3-arene oxide intermediate, the rate of formation was only about one-tenth of the dog. 4. These results indicate that the ability to form this unusual 2,3-arene oxide intermediate may not be responsible for high excretion rate of this congener. Our data also suggest that the cytochrome P450-catalysed metabolism of PCB153 in the guinea pig and dog are similar, whereas for post-cytochrome P450 metabolism, the guinea pig resembles the rabbit.

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  • Significant induction of a 54-kDa protein in rat liver with homologous alignment to mouse selenium binding protein by a coplanar polychlorinated biphenyl, 3,4,5,3',4'-pentachlorobiphenyl and 3-methylcholanthrene

    Y Ishii, M Hatsumura, T Ishida, N Ariyoshi, K Oguri

    TOXICOLOGY LETTERS87 ( 1 ) 1 - 9   1996年9月

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    記述言語:英語   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    A 54-kDa protein in rat liver cytosol was significantly induced by treatment with 3,4,5,3',4'-pentachlorobiphenyl (25 mg/kg, single i.p.) and 3-methylcholanthrene (20 mg/kg, once a day for 3 days, i.p.). The protein exhibited pi of 6.8 on two-dimensional gel electrophoresis. The amino acid sequences of peptide fragments from the protein digested in situ were highly similar to a selenium binding protein in mice and to the isoform acetaminophen binding protein in mice. The present result clearly demonstrates that a coplanar polychlorinated biphenyl and 3-methylcholanthrene are responsible for induction of selenium binding protein homologues. The physiological role of the mouse proteins, however, is not yet elucidated.

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  • Role of cytochrome b(5) in the oxidative metabolism of polychlorinated biphenyls catalyzed by cytochrome P450

    K Matsusue, N Ariyoshi, K Oguri, N Koga, H Yoshimura

    XENOBIOTICA26 ( 4 ) 405 - 414   1996年4月

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS LTD  

    1. The role of cytochrome b(5) in the cytochrome P450-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted system consisting of CYP2B1 and CYP1A1 and rat liver microsomes.
    2. By addition of cytochrome b(5) to the reconstituted system containing CYP2B1, the 3-hydroxylation of 2,5,2,'5'- and 2,5,3',4'-TCB was increased about six-ford, but the 3- and 5-hydroxylation of 2,4,3',4'-TCB was decreased by about 50%.
    3. All hydroxylations of 3,4,3',4'-, 2,5,3',4'- and 2,4,3',4'-TCBs were decreased by addition of cytochrome b(5) to the reconstituted system containing CYP1A1.
    4. In stoichiometry measurements, changes in NADPH oxidation and coupling efficiency by addition of cytochrome b(5) was observed and these differed according to the position of chlorine atoms of TCBs and cytochrome P450 isoforms used in the systems.

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  • Role of cytochrome b(5) in the oxidative metabolism of polychlorinated biphenyls catalyzed by cytochrome P450

    K Matsusue, N Ariyoshi, K Oguri, N Koga, H Yoshimura

    XENOBIOTICA26 ( 4 ) 405 - 414   1996年4月

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS LTD  

    1. The role of cytochrome b(5) in the cytochrome P450-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted system consisting of CYP2B1 and CYP1A1 and rat liver microsomes.
    2. By addition of cytochrome b(5) to the reconstituted system containing CYP2B1, the 3-hydroxylation of 2,5,2,'5'- and 2,5,3',4'-TCB was increased about six-ford, but the 3- and 5-hydroxylation of 2,4,3',4'-TCB was decreased by about 50%.
    3. All hydroxylations of 3,4,3',4'-, 2,5,3',4'- and 2,4,3',4'-TCBs were decreased by addition of cytochrome b(5) to the reconstituted system containing CYP1A1.
    4. In stoichiometry measurements, changes in NADPH oxidation and coupling efficiency by addition of cytochrome b(5) was observed and these differed according to the position of chlorine atoms of TCBs and cytochrome P450 isoforms used in the systems.

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  • A coplanar PCB induces a selenium binding protein as a major cytosolic protein in rat liver

    Y Ishii, M Hatsumura, T Ishida, N Ariyoshi, K Oguri

    CHEMOSPHERE32 ( 3 ) 509 - 515   1996年2月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    We obtained evidence that a toxic coplanar polychlorinated biphenyl (PCB) induces a counterpart of murine 56kDa selenium binding protein in rat liver cytosol. A 54kDa protein in the liver cytosol was significantly induced by 3,3',4,4',5-pentachlorobiphenyl and proved to be a major cytosolic protein in the rat liver. The protein exhibited pi of 6.8 on two-dimensional gel electrophoresis. The amino acid sequence of peptide fragments from the protein digested in situ, was highly similar to a 56kDa selenium binding protein and similar to an acetaminophen binding protein in mice.

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  • Involvement of cytochrome b(5) in the metabolism of tetrachlorobiphenyls catalyzed by CYP2B1 and CYP1A1

    K Matsusue, N Ariyoshi, K Oguri, N Koga, H Yoshimura

    CHEMOSPHERE32 ( 3 ) 517 - 523   1996年2月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    The role of cytochrome b(5) in the cytochrome P450 (CYP)-dependent hydroxylation of tetrachlorobiphenyl (TCB) isomers was examined using a reconstituted mixed function oxygenase (MFO) system containing purified CYP2B1 or 1A1, and rat liver microsomes. Hydroxylations of 2,2',5,5'- and 3,3',4,4'-TCBs were catalyzed mainly by CYP2B1 and 1A1, respectively, in the reconstituted MFO system and those of 2,3',4',5- and 2,3',4,4'-TCBs were mediated by both cytochrome P450 systems. The activity toward 2,2',5,5'- and 2,3',4',5-TCB was significantly increased 6.5- and 5.5-fold, respectively, by addition of cytochrome b, in the reconstituted MFO system containing of CY2B1. Either hydroxylation activity toward 2,3',4,4'-TCB with the CYP2B1 system was very low or decreased by addition of cytochrome b(5). These results suggest that the involvement of cytochrome b(5) to the hydroxylation of TCBs is dependent on the TCB congener being metabolized, and the cytochrome P450 isoform involved in its metabolism.

    DOI: 10.1016/0045-6535(95)00318-5

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  • METABOLISM OF HIGHLY PERSISTENT PCB CONGENER, 2,4,5,2',4',5'-HEXACHLOROBIPHENYL, BY HUMAN CYP2B6

    N ARIYOSHI, K OGURI, N KOGA, H YOSHIMURA, Y FUNAE

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS212 ( 2 ) 455 - 460   1995年7月

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    記述言語:英語   出版者・発行元:ACADEMIC PRESS INC JNL-COMP SUBSCRIPTIONS  

    Metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl was studied with cDNA-expressed human P450 2B isoform, CYP2B6. 3-Hydroxy-2,4,5,2',4',5'-hexachlorobiphenyl was identified as a major metabolite, and the formation activity was compared with that of dog CYP2B11 and guinea pig P450(GP-1). The activity of 3-hydroxylation was comparable with that of P450(GP-1), but one-tenth of CYP2B11. These results indicate that P450 2B in humans as well as other animal species can metabolize 2,4,5,2',4',5'-hexachlorobiphenyl, and the reason why this PCB congener remained most abundantly in human bodies is discussed. (C) 1995 Academic Press, Inc.

    DOI: 10.1006/bbrc.1995.1991

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  • Studies on PCB toxicity involving 2C subfamily cytochrome P450

    N. Ariyoshi, S. Ito, A. Okudaira, M. Mise, K. Matsusue, H. Yamada, K. Oguri

    Fukuoka Acta Medica86 ( 5 ) 21 - 30   1995年

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    記述言語:日本語   出版者・発行元:Kyushu University School of Medicine  

    It has been demonstrated that PCB metabolism is mainly catalyzed by 1A and 2B subfamily cytochrome P450s, CYP 1A1/2 and CYP 2B1/2. These studies were conducted mostly with hepatic enzymes in rodents. The 1A and 2B subfamily P450s are constitutively expressed little, but markedly induced by xenobiotics such as 3-methylcholanthrene and phenobarbital in rodents. On the other hand, the recent studies showed that cytochrome P450s in human liver are remarkably different from isoform of rodents in constitution and enzyme activities. In the present study, we first tried to metabolize some PCBs with 2C subfamily cytochrome P450 (CYP2C) purified from dog liver microsomes. The data suggested that CYP2C may not be involved in PCB metabolism. Since CYP2C is the same most abundant enzyme as 3A subfamily P450 in human liver and plays a major role for metabolism of many drugs used clinically, and may also play an important role for metabolism of some steroid hormones, we further studied the inhibition of CYP2C-catalyzed steroid metabolism by typical PCB congeners. CYP2C-mediated steroid metabolism is greatly inhibited by 2,4,5,2',4',5'-hexachlorobiphenyl, but not by 3,4,5,3',4'-pentachlorobiphenyl. On the contrary, 3,4,5,3',4'-pentachlorobiphenyl markedly suppressed CYP2C expression in the dog liver. These results suggest that residual PCBs may affect the current situation of steroid hormones in Yusho patients, and may cause PCB-drug interactions.

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  • 2CサブファミリーP450を介したPCBの毒性作用発現に関する研究

    福岡医学雑誌86 ( 5 ) 153   1995年

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  • コプラナーPCBによるモルモット肝ペルオキシソーム酵素活性の変化

    福岡医学雑誌86 ( 5 ) 144   1995年

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  • Alteration of perixosomal enzyme activities in the liver of guinea pigs caused by coplanar PCB

    M. Iwasaki, H. Kato, N. Ariyoshi, K. Oguri

    Fukuoka Acta Medica86 ( 5 ) 12 - 20   1995年

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    記述言語:日本語   出版者・発行元:Kyushu University School of Medicine  

    The hyperlipidemia is a well-known typical symptom in Yusho patients and experimental animals treated with PCBs. We have found a significant induction of CYP4A1, which catalyzes ω-hydroxylation of fatty acids, in guinea pigs by the treatment with a coplanar PCB, 3,4,5,3',4'-pentachlorobiphenyl (PenCB), though the P450 is reduced in the treated rats. Peroxisome has β-oxidation enzymes distinct from mitochondrial enzymes, and also play an important role in lipid metabolism. Peroxisome proliferators have been shown to regulate the expression of CYP4A1 and peroxisomal enzymes by the same mechanism in the rat. In the present study, we examined the effect of PenCB treatment on peroxisomal enzymes in the liver of guinea pigs. As a result, the enzyme activities of hepatic peroxisome, e.g. fatty acid oxidizing system, catalase and urate oxidase, had a rising tendency by the treatment with PenCB in the animal. The results suggest that the regulation of peroxisomal enzymes and CYP4A1 is also associated in guinea pigs, and PenCB provides a similar effect of peroxisomal proliferators to the animal. The possible toxicity through the peroxisomal alteration was discussed.

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  • Effect of a coplanar PCB on lipid metabolism ; The remarkable difference between rats and Guinea pigs(共著)

    Fukuoka Acta Media86 ( 5 ) 135   1995年

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  • CoplanarPCBによる脂質代謝への影響:ラットとモルモット間の顕著な相違

    福岡医学雑誌86 ( 5 ) 135   1995年

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  • PURIFICATION AND CHARACTERIZATION OF DOG LIVER MICROSOMAL EPOXIDE HYDROLASE

    N ARIYOSHI, M TANAKA, Y ISHII, K OGURI

    JOURNAL OF BIOCHEMISTRY115 ( 5 ) 985 - 990   1994年5月

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    記述言語:英語   出版者・発行元:JAPANESE BIOCHEMICAL SOC  

    An epoxide hydrolase (mEH) in liver microsomes was purified to apparent homogeneity from a dog treated with phenobarbital. The purified enzyme had a minimum molecular weight of 47,000 as determined by SDS-PAGE. The dog mEH activity was characterized by use of a substrate, 7-glycidoxycoumarin (GOC), and some effecters of this enzyme. In vitro activators, metyrapone, and isoquinoline, stimulated the microsomal activity, but the former had no such effect on the purified enzyme in case of this substrate. All mEH inhibitors, 1,1,1-trichloropropene 2,3-oxide (TCPO), cyclohexene oxide, and 2-bromo-4'-nitroacetophenone (BrNAP), suppressed hydrolase activity. The NH2-terminal amino acid sequence of the purified enzyme was highly homologous (90%) to the sequences deduced from a cDNA clone of rat enzyme. Antiserum to the purified enzyme raised in rabbits cross-reacted with rat and guinea pig epoxide hydrolases. No gender-difference in this enzyme in liver microsomes was observed in dogs.

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  • INDUCTION OF BILIRUBIN UDP-GLUCURONOSYLTRANSFERASE AND CYP4A1 P450 BY COPLANAR PCBS - DIFFERENT RESPONSIVENESS OF GUINEA-PIGS AND RATS

    Y KOGA, M TSUDA, N ARIYOSHI, Y ISHII, H YAMADA, K OGURI, Y FUNAE, H YOSHIMURA

    CHEMOSPHERE28 ( 3 ) 639 - 645   1994年2月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Induction of hepatic microsomal bilirubin UDP-glucuronyltransferase and CYP4A1 P450 by 3,4,3',4'-tetrachlorobiphenyl (TCB) and 3,4,5,3',4'-pentachlorobiphenyl (PenCB) was studied in guinea pigs and rats. Both enzyme activities in guinea pigs were increased 4-fold or more over the control by PenCB treatment, while by treatment with a less toxic congener, TCB, these were increased to a lesser extent. On the contrary, the rat enzymes were significantly decreased by treatment with these co-planar polychlorinated biphenyls. These results suggest that the alterations of both bilirubin UDP-glucuronyltransferase and CYP4A P450 are the characteristic indices for the toxicities of polychlorinated hydrocarbons.

    DOI: 10.1016/0045-6535(94)90305-0

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  • MODIFICATION OF THE GLUCONEOGENESIS IS NOT INVOLVED IN THE COPLANAR PCB TOXICITY IN HIGHLY SENSITIVE GUINEA-PIGS

    K OGURI, M HATSUMURA, Y ISHII, Y KOGA, N ARIYOSHI, H YOSHIMURA

    CHEMOSPHERE27 ( 11 ) 2295 - 2303   1993年12月

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    記述言語:英語   出版者・発行元:PERGAMON-ELSEVIER SCIENCE LTD  

    Effect of a co-planar PCB, 3,4,5,3',4'-pentachlorobiphenyl (PenCB) on gluconeogenesis in guinea pigs was compared with that in rats. The key enzyme of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK), in liver cytosol of rats was reduced by PenCB treatment to about 50% of control level. Hypoglycemia was also seen in the rat. On the contrary, the liver cytosol PEPCK activity in guinea pigs was slightly increased by PenCB treatment. Plasma levels of alanine and tryptophan were increased in the rat treated with PenCB, but the level of glycogenic amino acid, alanine, was not raised significantly-in the guinea pig. Thus the modification of the gluconeogenesis was not involved in the PenCB toxicity in highly sensitive guinea pigs.

    DOI: 10.1016/0045-6535(93)90140-Z

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  • IDENTIFICATION OF IN-VITRO METABOLITES OF 2,4,6,2',4',6'-HEXACHLOROBIPHENYL FROM PHENOBARBITAL-TREATED DOG LIVER-MICROSOMES

    N ARIYOSHI, H YOSHIMURA, K OGURI

    BIOLOGICAL & PHARMACEUTICAL BULLETIN16 ( 9 ) 852 - 857   1993年9月

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    記述言語:英語   出版者・発行元:PHARMACEUTICAL SOC JAPAN  

    We studied in vitro metabolites of 2,4,6,2',4',6'-hexachlorobiphenyl (HCB, IUPAC PCB No. 155) produced by liver microsomes of a phenobarbital (PB)-treated beagle dog. The major metabolites were 3-hydroxy-2,4,6,2',4',6'-HCB (M-1), 4-hydroxy-2,6,2',4',6'-pentachlorobiphenyl (PenCB, M-2) and 3,4-dihydroxy-2,6,2',4',6'-PenCB (M-3). Furthermore, 4-hydroxy-2,3,6,2',4',6'-HCB (M4), which could be formed via the 3,4-epoxidation and the subsequent NIH-shift of the chlorine from the 4 to the 3 position, was also detected. We found that M-3 is a common secondary metabolite of the two major monohydroxy metabolites, M-1 and M-2. These results indicate that the dog seems to metabolize and eliminate this congener not only by a mechanism involving direct insertion of a hydroxyl group but also via an arene oxide intermediate.

    DOI: 10.1248/bpb.16.852

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  • Co-planar PCBによる肝ビリルビンUDP-グルクロン酸転移酵素の誘導:モルモットとラット間の顕著な相違(共著)

    福岡医学雑誌84 ( 5 ) 175   1993年

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  • Metabolism In Vivo of 2,4,6,2',4',6'-hexachlorobiphenyl in Dog and Partial Characterization of Cytochrome P450 lsozyme Responsible for Biotransformation of the Congener.

    Fukuoka Acta Medica84 ( 5 ) 181   1993年

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  • Inducing Ability of Co-planar PCBs toward Bilirubin UDP-glucuronyltransferase of Liver Microsomes : The Remarkable Difference between Guinea Pigs and Rats.

    Fukuoka Acta Medica84 ( 5 ) 175   1993年

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  • 2,4,6,2',4',6'-HexachlorobiphenylのイヌにおけるIn Vivo代謝とそれに関与するCytochrome P-450分子種の予備的検討

    福岡医学雑誌84 ( 5 ) 181   1993年

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  • METABOLISM OF 2,4,5,2',4',5'-HEXACHLOROBIPHENYL WITH LIVER-MICROSOMES OF PHENOBARBITAL-TREATED DOG - THE POSSIBLE FORMATION OF PCB 2,3-ARENE OXIDE INTERMEDIATE

    N ARIYOSHI, N KOGA, K OGURI, H YOSHIMURA

    XENOBIOTICA22 ( 11 ) 1275 - 1290   1992年11月

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS LTD  

    1. Metabolism of 2,4,5,2',4',5'-hexachlorobiphenyl (HCB) was investigated in vitro using liver microsomes of one male beagle dog after phenobarbital treatment.
    2. Three major metabolites were isolated and identified as 3-hydroxy-2,4,5,2',4',5'-HCB, 2-hydroxy-4,5,2',4',5'-pentachlorobiphenyl (PenCB), and 2-hydroxy-3,4,5,2',4',5'-HCB, by comparison of g.l.c.-mass spectrometry and H-1-n.m.r. data with those of authentic samples.
    3. 2-Hydroxy-3,4,5,2',4',5'-HCB was found as a metabolite of 2,4,5,2',4',5'-HCB for the first time using dog liver microsomes. Present results indicate that this metabolite and the dechlorinated PenCB are derived from a metabolic intermediate, namely, 2,3-epoxy-2,4,5,2',4',5'-HCB. 2,3-Epoxide formation is a new metabolic pathway of PCB.

    DOI: 10.3109/00498259209053156

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  • PURIFICATION AND CHARACTERIZATION OF 2 FORMS OF 2,3,4,7,8-PENTACHLORODIBENZOFURAN INDUCIBLE CYTOCHROME-P-450 IN HAMSTER LIVER

    N KOGA, N ARIYOSHI, H NAKASHIMA, H YOSHIMURA

    JOURNAL OF BIOCHEMISTRY107 ( 6 ) 826 - 833   1990年6月

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    記述言語:英語   出版者・発行元:JAPAN BIOCHEMICAL SOC  

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受賞

  • 医療薬学フォーラム2002/第10回クリニカルファーマシー シンポジウム優秀ポスター賞

    2002年  

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共同研究・競争的資金等の研究

  • 薬効制御蛋白質の遺伝的多型,医薬品適正使用

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    資金種別:競争的資金

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  • Genetic Polymorphisms of Proteins controling drug efficacy

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    資金種別:競争的資金

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  • 遺伝子多型解析の臨床現場への応用

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    資金種別:競争的資金

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