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Effect of polymorphism of UDP-glucuronosyltransferase(UGT1A9)on drug metabolism

Research Project

Project/Area Number 18590508
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Applied pharmacology
Research InstitutionShiga University of Medical Science

Principal Investigator

SATO Hiroshi  Shiga University of Medical Science, Undergraduate School of Medicine, Professor (90090430)

Co-Investigator(Kenkyū-buntansha) MARUO Yoshihiro  Shiga Uniyerstiy of Medical Science, Undergraduate School of Medicine, Assistant Professor (80314160)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsUDP-glucuronosyltransferases / polymorphism / T1A9 is / propofol / adverse effects of drugs / 副作用 / UDPグルクロン酸転移酵素 / UGTIA9 / グルクロン酵転移酵素 / propofol / Y486D / 日本人 / 遺伝子
Research Abstract

UDP-glucuronosyltransferases (UGTs) are a part of a major excretion pathway for endobiotics and xenobiotics. UGT1A9 is one of UGTs which catalyzes conjugation of endogenous estrogenic and thyroid hormones, acetaminophen, SN-38 (an active metabolite of irinotecan) and phenols. Especially, UGT1A9 is the only isoform which catalyzes the glucuronidation of propofol (2,6-diisopropylphenol)in liver. In the present study, we analyzed polymorphisms and mutations of UGT1A9 in healthy 100 adult Japanese volunteers. A transversion of 766G>A=resulting in the amino acid substitution of D256N was detected in exon 1. The allele frequency of D256N is 0.005. We investigated the effects of D256N and Y483D, which locates on the common exon of UGT1, on propofol glucuronidation by in vitro expression study. The Km of wild-type, D256N and Y483D for propofol glucuronidation were 111.2 uM, 43.6 uM and 64.5 uM, respectively. The Vmax of D256N and Y483D were 8.1 and 28.8% and the efficiencies (Vmax/Km) were 19.1 and 57.1% of the wild-type, respectively. Glucuronidation activities of Y483D for 1-naphthol, naringenin, and mycophenolic acid were about a half of wild type, however, those of D256N were less than 10%. This study indicates the importance of D256N considering the individual difference in adverse effects of drugs that are primaliry catalyzed by UGT1A9.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (8 results)

All 2008 2006 Other

All Journal Article (7 results) (of which Peer Reviewed: 4 results) Remarks (1 results)

  • [Journal Article] Conformational change of UGT1A1 by a novel missense mutation (p.L131P)causing Crigler-Najjar syndrome type I.2008

    • Author(s)
      Maruo Y, et. al.
    • Journal Title

      J Pediatr Gastroenterol Nutr 46

      Pages: 308-311

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Conformational change of UGT1A1 by a novel missense mutation (p.L131P) causing Crigler-Najjar syndrome type2008

    • Author(s)
      H., Takahashi, Y., Maruo, A., Mori, M., Iwai, H., Sato, Y., Takeuchi
    • Journal Title

      Pediatr Gastroenterol Nutr CONCERNED, YEAR 46(3)

      Pages: 308-311

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Crigler-Najjar Syndrome type II caused by a homozygous triple mutation of UGTlAl.2006

    • Author(s)
      Maruo et al.
    • Journal Title

      Journal of Pediatric Gastroenterology and Nutrition 42

      Pages: 236-236

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effect of D256N and Y483D on propofol glucuronidation by human UDP-glucuronosyltransferase(UGT1A9).

    • Author(s)
      Takahashi H, et. al.
    • Journal Title

      Basic & Clinical Pharmacology & Toxicology (掲載確定)(印刷中)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Effect of D256N and Y483D on propofol glucuronidation by human UDP-glucuronsyltransferase(UGT1A9)

    • Author(s)
      H., Takahashi, Y., Maruo, A., Mori, M., Iwai, H., Sato, Y., Takeuchi
    • Journal Title

      Basic & Clinical Pharmacology & Toxicology CONCERNED, YEAR (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] Effect of D256N and Y483D on propofol glucuronidation by human UDP- glucuronosyltransferase( UGT1A9)

    • Author(s)
      Takahashi H, et. al.
    • Journal Title

      Basic & Clinical Pharmacology & Toxicology (掲載確定)(印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Conformational change of UGT1A1 by a novel missense mutation (p.L131P) causing Crigler-Najjar syndrome type l

    • Author(s)
      Maruo Y, et. al.
    • Journal Title

      Pediatr Gastroenterol Nutr (掲載確定)(印刷中)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Remarks] 「研究成果報告書概要(和文)」より

    • URL

      http://www.shiga-med.ac.jp/db/pub_top.php

    • Related Report
      2007 Final Research Report Summary

URL: 

Published: 2006-04-01   Modified: 2016-04-21  

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