| 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)
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| 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.
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