National Engineering Research Center for Miniaturized Detection Systems, School of Life Sciences, Northwest University, 229 North Taibai Road, Xi'an 710069, China.
Pharmacogenomics. 2014 Apr;15(6):785-98. doi: 10.2217/pgs.14.29.
7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, is mainly eliminated hepatically through glucuronidation by UGT1A1 and UGT1A9 enzymes. This study comprehensively investigates the effects of UGT1A1 and UGT1A9 genetic polymorphism on SN-38 glucuronidation activity.
MATERIALS & METHODS: Genetic polymorphisms and combinational haplotypes of UGT1A1 and UGT1A9, SN-38 glucuronidation activities, and protein levels of UGT1A1 and UGT1A9 were determined using a set of over 45 Chinese livers.
UGT1A1 reduced function variants UGT1A1*6, *28, *60 and 1B exhibited additive effect. The number of UGT1A1 reduced function alleles was associated with decreased SN-38G formation rates and UGT1A protein levels. UGT1A9 I399C>T and UGT1A91b, which were highly linked, were associated with increased SN-38 glucuronidation activity and UGT1A protein levels. However, further analysis based on UGT1A9-1A1 haplotypes confirmed that their increased effect was partly due to their close linkage with UGT1A1 reduced function alleles.
UGT1A1 genetic polymorphisms have a more important function in human liver SN-38 glucuronidation activity than UGT1A9. Original submitted 7 November 2013; Revision submitted 30 January 2014.
伊立替康的活性代谢产物 7-乙基-10-羟基喜树碱（SN-38）主要通过 UGT1A1 和 UGT1A9 酶的葡萄糖醛酸化作用从肝脏中消除。本研究全面研究了 UGT1A1 和 UGT1A9 遗传多态性对 SN-38 葡萄糖醛酸化活性的影响。
使用一组超过 45 个中国人肝脏，确定了 UGT1A1 和 UGT1A9 的遗传多态性和组合单倍型、SN-38 葡萄糖醛酸化活性以及 UGT1A1 和 UGT1A9 的蛋白水平。
UGT1A1 功能降低的变异 UGT1A1*6、28、60 和1B 表现出累加效应。UGT1A1 功能降低等位基因的数量与 SN-38G 形成率和 UGT1A 蛋白水平降低相关。UGT1A9 I399C>T 和 UGT1A91b 高度连锁，与 SN-38 葡萄糖醛酸化活性和 UGT1A 蛋白水平升高相关。然而，基于 UGT1A9-1A1 单倍型的进一步分析证实，它们的增加效应部分归因于它们与 UGT1A1 功能降低等位基因的紧密连锁。
UGT1A1 遗传多态性在人类肝脏 SN-38 葡萄糖醛酸化活性中比 UGT1A9 具有更重要的作用。原始提交日期为 2013 年 11 月 7 日；修订提交日期为 2014 年 1 月 30 日。
