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

2007 Fiscal Year Final Research Report Summary

• Project/Area Number: 18590508
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Shiga 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
• Keywords: UDP-glucuronosyltransferases / polymorphism / T1A9 is / propofol / adverse effects of drugs / 副作用

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.

Research Products

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