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Application of Peroxisomal Drug Metabolism Reactions to the Evaluation of Pharmacological and Toxicological Actions of Drugs

Research Project

Project/Area Number 62480426
Research Category

Grant-in-Aid for General Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field Biological pharmacy
Research InstitutionTokyo College of Pharmacy

Principal Investigator

SUGA Tetsuya  Tokyo College of Pharmacy, Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (20057318)

Co-Investigator(Kenkyū-buntansha) HORIE Shuichi  Teikyo University Faculty of Pharmaceutical Sciences Lecturer, 薬学部, 講師 (60157063)
WATANABE Takafumi  Tokyo College of Pharmacy, Faculty of Pharmaceutical Sciences Associate Professo, 薬学部, 助教授 (70096692)
Project Period (FY) 1987 – 1989
Project Status Completed (Fiscal Year 1989)
Budget Amount *help
¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1989: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1988: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1987: ¥4,000,000 (Direct Cost: ¥4,000,000)
KeywordsPeroxisome / Drug metabolism / beta-Oxidation / Enzyme induction / Carcinogenesis / Screening method / Active oxygen / ペルオキシゾーム / 薬効・毒性
Research Abstract

The present study has been performed to apply the reactions of peroxisomal drug metabolism to the evaluation of the pharmacological and toxicological actions of drugs. The results obtained in this study are summarized as follows.
1. The characteristics of peroxisomal drug metabolism reactions: It was established that the oxidative chain- shortening of acyl moieties of drugs were done exclusively by peroxisomal beta-oxidation system, being due to the substrate specificities of enzymes related to these reactions.
2. Factors affecting the induction of peroxisomal enzymes by drugs: The structure-reaction relationship and species differences as well as the effect of calcium antagonists in related to enzyme induction were examined.
3. The screening methods for the determination of peroxisomal enzyme activities: Using cultured rat hepatocytes, a similar effects of drugs to those in in vivo experiments were obtained.
4. The pharmacological and toxicological evaluation of the induction of peroxisomal enzymes by drugs: From the results obtained by a long-term experiment on the effects of drugs such as clofibrate, a hypothesis that the oxidative stress caused by the induction of peroxisomal oxidases may be a major process to lead the hepatocarcinogenesis was unlikely to be acceptable.
The results in the present study indicate that the determination of peroxisomal drug metabolizing activities is important to provide the information for the evaluation of the pharmacological and toxicological actions of drugs, especially in the cases of peroxisomal proliferators.

Report

(4 results)
  • 1989 Annual Research Report   Final Research Report Summary
  • 1988 Annual Research Report
  • 1987 Annual Research Report
  • Research Products

    (56 results)

All Other

All Publications (56 results)

  • [Publications] Toshihiko Ikeda: "Induction of cytochrome P-450 and peroxisomal proliferation in rat liver by perfluorinated octane sulphonic acid(PFOS)" Peroxisomes in Biol.Med.304-308 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Takafumi Watanabe: "Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats:Comparison of probucol,CGA,KCD-232,MLM-160,AL-369 and clinofibrate with clofibrate" J.Pharmacobio-Dyn.10. 142-147 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Satoshi Ishii: "Purification and proterties of peroxisomal carnitine palmitoyltransferase in chick embryo liver" Biochim.Biophys.Acta. 924. 530-542 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Junji Yamada: "Participation of peroxisomes in the metabolism of xenobiotic acyl compouns:Comparison between peroxisomal and mitochondrial β-oxidation of ω-phenyl fatty acids in rat liver" Biochim.Biophys.Acta. 921. 292-301 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Satoshi Ishii: "Intraparticulate localization of peroxisomal carnitine acyltransferase in chick embryo liver" Chem.Pharm.Bull.35. 4188-4193 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Shuichi Horie: "Existence of fatty acyl-CoA oxidinzing system in(micro)peroxisomes of rabbit aorta" Biochem.Med.Metab.Biol.38. 252-257 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Kinya Kubo: "Metabolism of eicosapentaenoic acid in the liver of rats:Participation of the peroxisomal β-oxidation system in chain-shortening" Chem.Pharm.Bull.36. 305-311 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Toshihiko Ikeda: "Induction of peroxisome proliferation in rat liver by dietary treatment with 2,2,4,4,6,8,8-heptamethylnonane" Xenobiotica. 18. 1271-1280 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Takafumi Watanabe: "Species differences in the effects of bezafibrate, a hypolipidemic agent,on bepatic peroxisome-associated enzymes" Biochem.Pharmacol.38. 367-371 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hisashi Suzuki: "compartmentation of dicarboxylic acid β-oxidation in rat liver: Importance of peroxisomes in the metabolism of dicarboxylic acids" Biochim.Biophys.Acta,. 990. 25-30 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Shuichi Horie: "Identity of acyl-CoA oxidase with glutaryl-CoA oxidase" Life Sci.44. 1141-1148 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Shuichio Horie: "Participation of peroxisomes in lipid biosynthesis in the harderian gland of guinea big" biochem.J.262. 677-680 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Shuichi Horie: "Existence of acetyl-CoA-dependent chain elongation system in hepatic peroxisomes of rat:Effects of clofibrate and di-(2-ethylhexyl)phthalate on the activity" Arch.Biochem.Biophys.274. 64-73 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] shuichi Horie: "Turnover of fatty acyl-CoA oxidase in the liver of rats fed on a partially hydrogenated marine oil" Lipids. 24. 890-894 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Hiroki Itoga: "Characteristics of the suppressive effect of nicardipine on peroxisome induction in rat liver" Biochim.Biophys.Acta. 1051. 21-28 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Shuichi Horie: "Differential regulation of hepatic peroxisomal β-oxidation activity in rats treated with clofibrate and partially hydrogenated marine oil" Biochem.Biophys.Res.Commun.166. 907-913 (1990)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 須賀哲弥: "医薬品有害作用の予測" R&Dプランニング, 480 (1987)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 須賀哲弥: "トキシロコロジ-" 同文書院, 544 (1988)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 須賀哲弥: "毒性生化学(上)" 地人書館, 338 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] 須賀哲弥: "ペルオキシゾ-ムと神経疾患" 科学評論社, 249 (1989)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] T.Ikeda, K.Fukuda, I.Mori, M.Enomoto, T.Komai and T.Suga: "Induction of cytochrome P-450 and peroxisomal proliferation in rat liver by perfluorinated octane sulphonic acid (PFOS)" Peroxisomes in Biol. Med. ed. by H.D.Fahimi and H.Sies pp 304-308 (1987).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] T.Watanabe, M.Mitsukawa, S.Horie, T.Suga and K. Seki: "Effects of some hypolipidemic agents on biochemical values and hepatic peroxisomal enzymes in rats: Comparison of probucol, CGA, KCD-232, MLM-160, AL-369 and clinofibrate with clofibrate" J.Pharmacobio-Dyn. 10, 142-147 (1987).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Ishii, H.Ishii, T.Watanabe and T.Suga: "Purification and properties of peroxisomal carnitine palmitoyltransferase in chick embryo liver" Biochim.Biophys.Acta 924, 530-542 (1987).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] J.Yamada, S.Ogawa, S.Horie, T.Watanabe and T.Suga: "Participation of peroxisomes in the metabolism of xenobiotic acyl compounds:Comparison between peroxisomal and mitochondrial beta-oxidation of omega-phenyl fatty acids in rat liver" Biochim.Biophys.Acta, 921, 292-301 (1987).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Ishii, H.Ishii, T.Watanabe and T.Suga: "Intraparticulate localization of peroxisomal carnitine acyltransferase in chick embryo liver" Chem.Pharm.Bull. 35, 4188-4193 (1987).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Horie, T.Kurusu, T.Watanabe and T.Suga: "Existence of fatty acyl-CoA oxidizing system in (micro)peroxisomes of rabbit aorta" Biochem.Med.Metab.Biol. 38, 252-257 (1987).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] K.Kubo, T.Watanabe and T.Suga: "Metabolism of eicosapentaenoic acid in the liver of rats: Participation of the peroxisomal beta-oxidation system in chain-shortening" Chem.Pharm.Bull. 36, 305-311 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] T.Ikeda, M.Ida-Enomoto, I.Mori, K.Fukuda, H.Iwabuchi, T.Komai and T.Suga: "Induction of peroxisome proliferation in rat liver by dietary treatment with 2, 2, 4, 4, 6, 8, 8-heptamethylnonane" Xenobiotica 18, 1271-1280 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] T.Watanabe, S.Horie, J.Yamada, M.Isaji, T.Nishikaze, J.Naito and T.Suga: "Species differences in the effects of bezafibrate, a hypolipidemic agent, on hepatic peroxisome-associated enzymes" Biochem.Pharmacol. 38, 367-371 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] H.Suzuki, J.Yamada, T.Watanabe and T.Suga: "Compartmentation of dicarboxylic acid beta-oxidation in rat liver: Importance of peroxisomes in the metabolism of dicarboxylic acids" Biochim.Biophys.Acta 990, 25-30 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Horie, S.Ogawa and T.Suga: "Identity of acyl-CoA oxidase with glutaryl-CoA oxidase" Life Sci. 44, 1141-1148 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Horie and T.Suga: "Participation of peroxisomes in lipid biosynthesis in the harderian gland of guinea pig" Biochem.J. 262, 677-680 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Horie, T.Suzuki and T.Suga: "Existence of acetyl-CoA-dependent chain elongation system in hepatic peroxisomes of rat: Effects of clofibrate and di-(2-ethylhexyl)phthalate on the activity" Arch.Biochem.Biophys. 274, 64-73 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Horie and T.Suga: "Turnover of fatty acyl-CoA oxidase in the liver of rats fed on a partially hydrogenated marine oil" Lipids, 24, 890-894 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] H.Itoga, H.Tamura, T.Watanabe and T.Suga: "Characteristics of the suppressive effect of nicardipine on peroxisome induction in rat liver" Biochim.Biophys.Acta 1051, 21-28 (1990).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] S.Horie and T.Suga: "Differential regulation of hepatic peroxosomal beta-oxidation activity in rats treated with clofibrate and partially hydrogenated marine oil" Biochem.Biophys.Res.Commun. 166, 907-913 (1990).

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1989 Final Research Report Summary
  • [Publications] Shuichi Horie: "Identity of acyl-CoA oxidase with glutaryl-CoA oxidase" Life Sci.44. 1141-1148 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shuichi Horie: "Participation of peroxisomes in lipid biosynthesis in the harderian gland of guinea pig" Biochem.J.262. 677-680 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shuichi Horie: "Existence of acetyl-CoA-dependent chain elongstion system in hepatic peroxisomes of rat: Effect of clofibrate and di-(2-ethylhexyl)phthalate in the activity" Arch.Biochem.Biophys.274. 64-73 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shuichi Horie: "Turnover of fatty acyl-CoA oxidase in the liver of rats fed on a partially hydrogenated marine oil" Lipids. 24. 890-894 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Hiroki Itoga: "Characteristics of the suppressive effect of nicardipine on peroxisome induction in rat liver" Biochim.Biophys.Acta. 1051. 21-28 (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] Shuichi Horie: "Differential regulation of hepatic peroxisomal β-oxidation activity in rats treated with clofibrate and partially hydrogenated marine oil" Bioche.Biophys.Res.Commun.166. 907-913 (1990)

    • Related Report
      1989 Annual Research Report
  • [Publications] 須賀哲弥: "ペルオキシゾ-ムと神経疾患" 科学評論社, 249 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] 須賀哲弥: "毒性生化学(上)" 地人書館, 338 (1989)

    • Related Report
      1989 Annual Research Report
  • [Publications] Kinya Kubo.: Chem.Pharm.Bull.36. 305-311 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Kunio Seki.: Chem.Pharm.Bull.36. 1117-1121 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Kunio Seki.: J.Pharm.Pharmacol.40. 473-477 (1987)

    • Related Report
      1988 Annual Research Report
  • [Publications] Toshihiko Ikeda.: Xenobiotica. 18. 1271-1280 (1988)

    • Related Report
      1988 Annual Research Report
  • [Publications] Takafumi Watanabe.: Biochem.Pharmacol.38. 367-371 (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Hisashi Suzuki.: Biochim.Biophys.Acta. 990. 25-30 (1989)

    • Related Report
      1988 Annual Research Report
  • [Publications] Toshihiko.Ikeda: Per.in Biol.and Med. 304-308 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Tkafumi.Watanabe: J.Pharmacobio-Dyn. 10. 142-147 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Satoshi.Ishii: Biochim.Biophys.Acta. 924. 530-542 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Junji.Yamada: Biochim Biophys.Acta. 921. 292-301 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Satoshi.Ishii: Chem.Pharm.Bull. 35. 4188-4193 (1987)

    • Related Report
      1987 Annual Research Report
  • [Publications] Shuichi Horie: Biochim.Med.Met.Biol. 38. 252-257 (1987)

    • Related Report
      1987 Annual Research Report

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Published: 1987-04-01   Modified: 2016-04-21  

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