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

udp -葡萄糖醛酸转移酶（UGTs）是内源性和外源性药物主要排泄途径的一部分。UGT1A9是一种能催化内源性雌激素和甲状腺激素、对乙酰氨基酚、SN-38（伊立替康的活性代谢物）和酚类化合物偶联的UGTs。特别是，UGT1A9是肝脏中唯一催化异丙酚（2,6-二异丙基酚）葡萄糖醛酸化的异构体。在本研究中，我们分析了100名健康的日本成年志愿者UGT1A9的多态性和突变。在外显子1中检测到766G>A=的翻转导致D256N的氨基酸取代。D256N的等位基因频率为0.005。我们通过体外表达研究了位于UGT1共同外显子上的D256N和Y483D对异丙酚糖醛酸化的影响。野生型、D256N和Y483D对异丙酚葡萄糖醛酸化作用的Km分别为111.2 uM、43.6 uM和64.5 uM。D256N和Y483D的Vmax分别为野生型的8.1和28.8%，效率（Vmax/Km）分别为野生型的19.1%和57.1%。Y483D对1-萘酚、柚皮素和霉酚酸的糖醛酸化活性约为野生型的一半，而D256N的糖醛酸化活性低于10%。考虑到主要由UGT1A9催化的药物不良反应的个体差异，本研究表明D256N的重要性。

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.