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Investigation and evaluation of genetic polymorphisms of drug metabolizing

Research Project

Project/Area Number 12470523
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field 応用薬理学・医療系薬学
Research InstitutionKanazawa University

Principal Investigator

YOKOI Tsuyoshi  Kanazawa Univ., Facul. Pharm. Sci., Professor, 薬学部, 教授 (70135226)

Co-Investigator(Kenkyū-buntansha) NAKAJIMA Miki  Kanazawa Univ., Facul. Pharm. Sci., Associate Professor, 薬学部, 助教授 (70266162)
山崎 浩史  金沢大学, 薬学部, 助教授 (30191274)
Project Period (FY) 2000 – 2001
Project Status Completed (Fiscal Year 2001)
Budget Amount *help
¥11,700,000 (Direct Cost: ¥11,700,000)
Fiscal Year 2001: ¥5,500,000 (Direct Cost: ¥5,500,000)
Fiscal Year 2000: ¥6,200,000 (Direct Cost: ¥6,200,000)
Keywordsdrug metabolizing enzyme / cytochrome P450 / Nicotine / genotyping / transporter / Phenotyping / troglitazone / CYP2A6 / 人種差 / 肝障害 / キノン体代謝物
Research Abstract

Identification of genetic polymorphisms had led the profound understanding of the genetic variability in humans. Interindividual variation of drug effects in humans can be attributed in part to the difference in the genes that encoding drug metabolizing enzymes. The reliable genotyping protocols to identify poor metabolizers are already in practice for certain drug-metabolizing enzymes, such as CYP2C9, CYP2C19, CYP2D6, and thiopurine methyltransferase, for the prevention of severe side effects and toxicity from some medications. In this study, there are 3 parts as follows; 1. Relationship between interindividual difference in nicotine metabolism and CYP2A6 genetic polymorphism in humans was proved. Because CYP2A6 catalyzes the metabolism of some pharmaceuticals such as methoxyflurane, halothane, logigamone, the genetic polymorphism of CYP2A6 gene would be clinically important.; 2, Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells were investigated. It is sugge … More sted that a factor contributing to the idiosyncratic hepatptoxicity of troglitazone could be apoptosis in hepatocytes in human. In addition, the formation of a novel quinone epoxide metabolites of troglitazone with cytotoxic to HepG2 cells were studied. Since epoxides are generally regarded as the chemically reactive species, a novel metabolite found in this study may play a role in idiosyncrasy of troglitazone hepatotoxicity via individual differences either in the formation or degradation of this metabolite.; 3, The genetic polymorphism of human organic anion transporters OATP-X (SLC21A6) and OATP-B (SLC21A9) was studied. Allele frequencies in the Japanese population and functional analysis were performed. The frequencies of OATP-C^*1b and OATP-C^*5 alleles were determined as 53.7% and 0.7%, respectively in the Japanese population. Furthermore, a novel allele, OATP-C^*15, was also found with the frequency of 10.3%. The OATP-B^*3 allele was present at high frequency (30.9%) in Japanese and its intrinsic functionality was less than half that of OATP-B^*1. The newly found OATP-B allele as well as OATP-C alleles may influence physiological functions and be one of factors that cause inter-individual variations of drug effects. Less

Report

(3 results)
  • 2001 Annual Research Report   Final Research Report Summary
  • 2000 Annual Research Report
  • Research Products

    (31 results)

All Other

All Publications (31 results)

  • [Publications] Yui Yamamoto et al.: "Formation of a novel epoxide form of quinone metabolite of troglidazone with cytotoxicity to HepG2 cells"Drug Metab. Dispos.. 30. 155-160 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yui Yamamoto et al.: "Cytotoxicity and apoptosis produced by troglitazone by human henatome cells"Life Sci.. 70. 471-482 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomoko Komatsu et al.: "Involvement of microsomal cytochrom P450 and cytosolic thymidine phosphorylase in 5-flurouracil formation from tegafur in human liver"Clin. Cancer Res. 7. 675-681 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miki Katoh et al.: "Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport"Eur. J. Pharmacol. Sci. 12. 505-513 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Jun-Tack Kwon et al.: "Ncotine metabolism and CYP2A6 allele frequencies in Koreans"Pharmacogenetics. 11. 317-323 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miki Nakajima et al.: "Relationship between interindividual differences of nicotine metabolism and CYP2A6 genetic polymorphism in humans"Clin. Parmacol. Ther. 69. 72-78 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 中嶋美紀, 横井 毅: "生物薬化学実験講座,第15巻「薬物代謝酵素」"廣川書店. 375 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] 横井 毅(分担): "薬物代謝学 医療薬学・毒性学の基礎として"東京化学同人. 282 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Hiroshi Yamazaki, et al: "In vitro inhibitory effects of troglitazone and its metabolites on drug oxidation activities of human cytochrome P450 enzymes: comparison with pioglitazone and rosiglitazone"Xenobiotica. 30. 61-70 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miki Nakijima, et al.: "Deficient cotinine formation form nicotine is ascribed to the deletion of CYP2A6 gene in humans"Clin. Phramacol. Ther,. 67. 57-69 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miki Katoh, et al.: "Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport"Eur. J. Pharmacol. Sci. 12. 505-513 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Miki Nakajima, et al.: "Relationship between interindividual differences of nicotine metabolism and CYP2A6 genetic polymorphism in humans"Clin. Phramacol. Ther,. 69. 72-78 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Jun-Tack Kwon, et al: "Ncotine metabolism and CYP2A6 allele frequencies in Koreans"Pharmacogenetics. 11. 317-323 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Tomoko Komatsu, et al.: "Involvement of microsomal cytochrome P450 enzymes and cytosolic thymidine phosphorylase in 5-flurouracil formation from tegafur in human liver"Clin Cancer Res. 7. 675-681 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yui Yamamoto, et al.: "Cytotoxicity and apoptosis produced by troglitazone in human hepatome cells"Life Sci.,. 70. 471-482 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yui Yamamoto, et al.: "Formation of a novel epoxide form of quinone metabolite of troglidazone with cytotoxicity to HepG2 cells"Drug Metaob. Dispos.. 30. 155-160 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Takashi Nozawa, et al.,: "Genetic polymorphisms of human organic anion transporters OATP-C (SLC21A6) and OATP-B (SLC21A9) : allele frequencies in Jananese population and functional analysis"J. Pharmacol. Exp. Ther. in press. (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2001 Final Research Report Summary
  • [Publications] Yui Yamamoto et al.: "Formation of a novel epoxide form of quinone metabolite of troglidazone with cytotoxicity to HepG2 cells"Drug Metab. Dispos.. 30. 155-160 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yui Yamamoto et al.: "Cytotoxicity and apoptosis produced by trogilitazone in human hepatome cells"Life Sci.. 70. 471-482 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Tomoko Komatsu et al.: "Involvement of microsomal cytochrome P450 and cytosolic thymidine phosphorylase in 5-flurouracil formation from tegafur in human liver"Clin. Cancer Res. 7. 675-681 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miki Katoh et al.: "Inhibitory effects of CYP3A4 substrates and their metabolites on P-glycoprotein-mediated transport"Eur. J. Pharmacol. Sci. 12. 505-513 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Jun-Tack Kwon et al.: "Ncotine metabolism and CYP2A6 allele frequencies in Koreans"Pharmacogenetics. 11. 317-323 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miki Nakajima et al.: "Relationship between interindividual differences of nicotine metabolism and CYP2A6 genetic polymorphism in humans"Clin. Pharmacol. Ther. 69. 72-78 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Miki Nakajima et.al: "Relationship between interindividual differences of nicotine metabolism and CYP2A6 genetic polymorphism in humans"Clin.Phramacol.Ther. 69. 72-78 (2001)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miki Katoh et al.: "Inhibitory potencies of 1, 4-dihydropyrodine calcium antagonists to Pglycoprotein- mediated transport : Comparison with the effects on CYP3A4."Pharm.Res.. 17. 1189-1197 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Chie Emoto et al.: "Characterization of cytochrome P450 enzymes involved in drug oxidations in mouse intestinal microsomes."Xenobiotica. 30. 943-953 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Tomoko Komatsu et al.: "Formation of a dihydroxy metabolite of phenytoin in human liver microsomes/cytosol : roles of P450 2C9, 2C19 and 3A4."Drug Metab.Dispos.. 28. 1361-1368 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Miki Katoh et al.: "Prediction of drug-drug interactions via cytochrome P450 by 1, 4-dihydropyrodine calcium antagonists."Eur.J.Clin.Pharmacol.. 55. 843-852 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] Katsuhiro Ohyama et al.: "Inhibitory effects of aminodarone and its metabolites on human cytochrome P450 enzyme activities : Prediction of in vivo drug interactions."Brit.J.Clin,Pharmacol.. 49. 244-253 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 中嶋美紀,横井毅: "生物薬化学実験講座,第15巻「薬物代謝酵素」"廣川書店. 375 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] 横井毅(分担): "薬物代謝学 医療薬学・毒性学の基礎として"東京化学同人. 282 (2000)

    • Related Report
      2000 Annual Research Report

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Published: 2000-04-01   Modified: 2016-04-21  

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