权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

UDP-葡萄糖醛酸基转移酶(UGT1A9)多态性对药物代谢的影响

基本信息

批准号：
18590508
负责人：
SATO Hiroshi
金额：
$ 2.57万
依托单位：
Shiga University of Medical Science
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590508/
关键词：
UDP-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

项目摘要

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.

UDP-葡萄糖醛酸基转移酶（UGT）是内源性和外源性物质主要排泄途径的一部分。UGT 1A 9是一种UGT，可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产物）和酚类的结合。特别是，UGT 1A 9是唯一催化肝脏中丙泊酚（2，6-二异丙基苯酚）葡萄糖醛酸化的亚型。在本研究中，我们分析了100名日本健康成年志愿者UGT 1A 9的多态性和突变。在外显子1中检测到766 G>A=的颠换，导致D256 N的氨基酸替换。D256 N等位基因频率为0.005。我们通过体外表达研究了位于UGT 1共同外显子的D256 N和Y 483 D对丙泊酚葡萄糖醛酸化的影响。野生型、D256 N和Y 483 D对丙泊酚葡萄糖醛酸化的Km分别为111.2 uM、43.6 uM和64.5 uM。D256 N和Y 483 D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%。Y 483 D对1-萘酚、柚皮素和霉酚酸的葡萄糖醛酸化活性约为野生型的一半，而D256 N的葡萄糖醛酸化活性不到10%。这项研究表明，考虑到UGT 1A 9主要催化的药物不良反应的个体差异，D256 N的重要性。