Faculty Profiles - ARIYOSHI Noritaka

Papers - ARIYOSHI Noritaka

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

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

Journal of Epidemiology 13 ( 3 ) 176 - 181 2003

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

PHARMACOGENETICS 12 ( 8 ) 659 - 662 2002.11

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

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

CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION 11 ( 9 ) 890 - 894 2002.9

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：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.

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

N Ariyoshi, H Sekine, K Saito, T Kamataki

PHARMACOGENETICS 12 ( 6 ) 501 - 504 2002.8

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

PHARMACOGENETICS 12 ( 4 ) 299 - 306 2002.6

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS 402 ( 2 ) 275 - 280 2002.6

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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

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

DRUG METABOLISM AND DISPOSITION 30 ( 5 ) 534 - 540 2002.5

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

DOI： 10.1124/dmd.30.5.534

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

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

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 293 ( 3 ) 969 - 973 2002.5

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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. Reviewed International journal

Pailin Ujjin, Soisungwan Satarug, Yuvaree Vanavanitkun, Satoshi Daigo, Noritaka Ariyoshi, Hiroshi Yamazaki, Paul E B Reilly, Michael R Moore, Tetsuya Kamataki

Pharmacogenetics 12 ( 3 ) 241 - 9 2002.4

Language：English Publishing type：Research paper (scientific journal)

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 19-47 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, *1B/*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 microg/l) compared with subjects having normal body iron store status. Subjects (n = 16) with iron overload (plasma ferritin > 300 microg/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.

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

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

CARCINOGENESIS 23 ( 4 ) 595 - 598 2002.4

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

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 REVIEWS 34 ( 3 ) 667 - 676 2002

Language：English Publishing type：Research paper (scientific journal) Publisher：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

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 REVIEWS 34 154 - 154 2002

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 SCIENCE 47 ( 6 ) 575 - 578 2001.12

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

DOI： 10.1248/jhs.47.575

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

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

BIOCHEMICAL PHARMACOLOGY 62 ( 6 ) 713 - 721 2001.9

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

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

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

TOXICOLOGIC PATHOLOGY 29 161 - 172 2001.9

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

代謝研究は創薬にどう活かされるかレトロスペクティブな評価とプロスペクティブな活用 Cytochrome P450とmEH及びUGTとの蛋白質間相互作用

田浦健一郎, 山田英之, 内藤絵里, 竹田修三, 石井祐次, 有吉範高, 森正明, 小栗一太

薬物動態 16 ( Suppl. ) S94 - S95 2001.9

Language：Japanese Publisher：(一社)日本薬物動態学会

ラット肝を用いて異種薬物代謝酵素間における蛋白-蛋白相互作用の有無を検討した.その結果,小胞体膜上のcytochrome P450はmEH(microsomal epoxide hydrolase)やUGT(UDP-glucuronosyltransferase)等の異種薬物代謝酵素と相互作用することで多段階の薬物代謝反応を効率的に実行している可能性が示唆された

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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

TOXICOLOGY 164 ( 1-3 ) 61 - 62 2001.7

CYP遺伝子多型解析の病棟業務への応用

斉藤嘉津彦, 清水瓊子, 岡崎正子, 伊林至洋, 端和夫, 前野康次郎, 石井清二, 土橋和文, 島本和明, 戸田貴大, 黒澤菜穂子, 大和田栄治, 加藤芳伸, 大山徹, 梅津有理, 千田道洋, 有吉範高, 鎌滝哲也, 板谷幸一

医療薬学 27 ( 3 ) 228 - 234 2001.6

Language：Japanese Publisher：(一社)日本医療薬学会

脳神経外科で初めて多型解析を利用した例として,脳動静脈奇形の術後に痙攣発作予防の目的で投与されたフェニトインのTDMを行った32歳女の例を提示し,経過及び薬物代謝酵素遺伝子解析後の服薬指導内容を述べた.また薬物代謝酵素遺伝子解析を希望した患者に対する情報提供として使用している「解析結果報告書」及び「解析結果の説明書」を紹介した

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コプラナーPCBによる中間代謝への影響ラット肝サイトソルのトリオースリン酸含量の低下について(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)

石井祐次, 加藤晴敏, 初村恵, 石田卓巳, 有吉範高, 山田英之, 小栗一太

福岡医学雑誌 92 ( 5 ) 190 - 200 2001.5

Language：English Publisher：福岡医学会

トリオースリン酸代謝酵素群(グリセルアルデヒド-3-リン酸デヒドロゲナーゼ,トリオースリン酸イソメラーゼ,グリセロキナーゼ,トランスアルドラーゼ,及びトランスケトラーゼ)に及ぼす3,3',4,4',5-pentachlorobiphenyl(PenCB)の影響を調べた.又,PenCBによるアルコール脱水素酵素(ADH)の発現抑制が,どの程度トリオースリン酸代謝に影響を及ぼしているかを検討した.PenCB処理により,これら酵素群の活性はいずれも50%程度まで有意に低下していた.ピラゾールで阻害される活性をADH由来とした場合,ADHは約30%の寄与があることが分かり,特にこの部分への抑制が顕著であった.摂餌対照群とPenCB処理群では肝臓中のトリオースリン酸の含量が,自由摂餌群に比べて著しく低かった.PenCB処理によってトリオースリン酸代謝の回転が落ち,栄養を補給してもエネルギーとして利用されにくいシステムが出来ている可能性がある

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2001&ichushi_jid=J01325&link_issn=&doc_id=20010910240013&doc_link_id=%2Fdk5fukuo%2F2001%2F009205%2F014%2F0190-0200%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdk5fukuo%2F2001%2F009205%2F014%2F0190-0200%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

A novel single nucleotide polymorphism altering stability and activity of CYP2A6

N Ariyoshi, Y Sawamura, T Kamataki

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 281 ( 3 ) 810 - 814 2001.3

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

DOI： 10.1006/bbrc.2001.4422

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