Faculty Profiles - ARIYOSHI Noritaka

Papers - ARIYOSHI Noritaka

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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 COMMUNICATIONS 281 ( 5 ) 1256 - 1260 2001.3

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

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

PHARMACOGENETICS 11 ( 1 ) 39 - 44 2001.2

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

DOI： 10.1097/00008571-200102000-00005

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 TOXICOLOGY 14 ( 2 ) 228 - 232 2001.2

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

DOI： 10.1021/tx0001225

INTERACTION OF CYTOCHROME P450 AND MICROSOMAL EPOXIDE HYDROLASE AND UDP-GLUCURONOSYLTRANSFERASE

TAURA Ken-ichiro, YAMADA Hideyuki, NAITO Eri, TAKEDA Shuso, ISHII Yuji, ARIYOSHI Noritaka, MORI Masa-aki, OGURI Kazuta

Drug Metabolism and Pharmacokinetics 16 94 - 95 2001

Language：English Publisher：The Japanese Society for the Study of Xenobiotics

Interaction between cytochrome P450 (P450) and other sorts of drug metabolizing enzymes was studied by affinity chromatography with CYP1A1-conjugated column. Solubilized rat liver microsomes were charged onto the column and the eluate was analyzed by immunoblotting. The result showed that the CYP1A1 column effectively trapped microsomal epoxide hydrolase (mEH) and UDP-glucuronosyltransferase (UGT) as well as NADPH-P450 reductase. Non-drug metabolizing enzymes such as calnexin and protein disulfide isomerase did not show any affinity to the column. Neither BSA- nor glycine-conjugated column could trap microsomal protein. These results strongly suggest the specific interaction between P450 and mEH/UGT. When estimated using stereo-selective hydrolysis for styrene oxide as the index, the function of rat mEH was enhanced by co-incubation with CYP1A1, 2B1 and 2C11. The same picture was also seen for the interaction between dog mEH and CYP2B11/3A12. These results suggest that P450 interacts with mEH and UGT to facilitate a series of multistep metabolic conversion.

DOI： 10.2133/dmpk.16.supplement_94

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

PHARMACOGENETICS 10 ( 8 ) 687 - 693 2000.11

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

DOI： 10.1097/00008571-200011000-00003

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 COMMUNICATIONS 269 ( 2 ) 393 - 396 2000.3

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

DOI： 10.1006/bbrc.2000.2312

日本人と欧米人における CYP2A6 遺伝子多型の解析

宮本昌美, 梅津有理, 醍醐聡, BEAUNE Philippe, LORIOT Marie-Anne, STUCKER Isabelle, 木下盛敏, 名倉弘哲, 立石智則, 小林真一, 溝呂木能浩, 有吉範高, 鎌滝哲也

臨床薬理 31 ( 2 ) 301 - 302 2000.2

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 Reviewed

K Matsusue, Y Ishii, N Ariyoshi, K Oguri

CHEMICAL RESEARCH IN TOXICOLOGY 12 ( 12 ) 1158 - 1165 1999.12

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

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 & THERAPEUTICS 66 ( 6 ) 581 - 581 1999.12

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 COMMUNICATIONS 261 ( 3 ) 658 - 660 1999.8

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

DOI： 10.1006/bbrc.1999.1089

THE STUDY ON CYP2A6 GENETIC POLYMORPHISM

ARIYOSHI Noritaka, NUNOYA Ken-ichi, TAKAHASHI Yuki, UMETSU Yuri, MIYAMOTO Masami, DAIGO Satoshi, YOKOI Tsuyoshi, KWON Jun-Tack, KADLUBAR Fred F., SHINHA Rashimi, BEAUNE Philippe, KIMURA Kanzo, KAMATAKI Tetsuya

Drug Metabolism and Pharmacokinetics 14 100 - 101 1999

Language：English Publisher：The Japanese Society for the Study of Xenobiotics

CYP2A6 is known as an enzyme responsible for the metabolism of coumarin. As its toxicological significance, aflatoxin B₁ and NNK are metabolically activated by this CYP to mutagens. In our recent studies, we found that a newly developed drug, SM-12502, was a specific substrate of CYP2A6, and 3 out of 28 Japanese were poor metabolizers (PM) of this drug. Genomic analysis of CYP2A6 gene in the PM indicated that an existence of a new CYP2A6 gene variant which lacks the entire region of open reading frame for the enzyme. The frequency of the individual who possess the mutation homozygously was estimated as 3-4% in Japanese. During the course of investigation of the frequency, we found an another CYP2A6 variant whose 60 by region in the 3'-untranslated region was substituted by the corresponding sequences of CYP2A7 gene. In this study, we investigated the frequency of these polymorphic alleles as well as reported v1 (CYP2A6*2) variant among different race.

DOI： 10.2133/dmpk.14.supplement_100

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

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

CHEMOSPHERE 37 ( 9-12 ) 1895 - 1904 1998.10

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

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 PHARMACOLOGY 5 ( 3 ) 219 - 225 1998.5

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

Metabolism of antihistaminics, promethazine and CYP2D6 genetic polymorphism.

Jpn. J. Clin. Pharmacol. Ther. 29 ( 1 ) 237 - 238 1998.3

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 Reviewed

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

JOURNAL OF BIOLOGICAL CHEMISTRY 273 ( 13 ) 7610 - 7619 1998.3

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

DOI： 10.1074/jbc.273.13.7610

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

CHEMOSPHERE 35 ( 5 ) 951 - 958 1997.9

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

DOI： 10.1016/S0045-6535(97)00181-1

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 PHARMACOLOGY 3 ( 4 ) 267 - 275 1997.9

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

Co-planar PCBの肝glutathione peroxidase-redox systemに対する影響ラット及びモルモットでの検討

堀美穂, 有吉範高, 山田英之

福岡医学雑誌 88 ( 5 ) 144 - 148 1997.5

Language：Japanese Publisher：福岡医学会

活性酸素消去系の損傷とそれに基づく酸化的ストレスの役割について検討した.この目的の為,本研究ではラットとモルモットのcoplanar PCBに対する感受性の違いに注目した.即ち活性酸素消去系の障害が動物種を越えた共通の毒性発現機構なら,感受性動物のモルモットの方が感受性の低いラットよりも障害の程度が顕著なはずであるとの作業仮説を立てて検討を行ったが,上記の推定を支持する結果は得られなかった.即ち,PCB 126処理ラットでは主要な活性酸素消去系の一つであるGPx活性が有意に低下したが,感受性の高いモルモットではむしろ活性増加した.肝GSH含量並びにこの供給に働くGR及びγ-GTP活性の変動もラットでのみ障害の発生が観察された

Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=1997&ichushi_jid=J01325&link_issn=&doc_id=19970730500002&doc_link_id=%2Fdk5fukuo%2F1997%2F008805%2F003%2F0144-0148%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdk5fukuo%2F1997%2F008805%2F003%2F0144-0148%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

K Matsusue, Y Ishii, N Ariyoshi, K Oguri

TOXICOLOGY LETTERS 91 ( 2 ) 99 - 104 1997.4

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

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

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

JAPANESE JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH 43 ( 1 ) P19 - P19 1997.2

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