Chen Yakun, Chen Shuqing, Li Xin, Wang Xiewei, Zeng Su
Department of Drug Metabolism & Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310031, China.
Drug Metab Dispos. 2006 Sep;34(9):1462-7. doi: 10.1124/dmd.106.009761. Epub 2006 May 31.
UDP-glucuronosyltransferase 1A3 (UGT1A3) contributes to glucuronidation of many important endogenous compounds and xenobiotics, including some flavonoids. Recently, a total of six single nucleotide polymorphisms (SNPs) have been identified in the human UGT1A3 gene. Among them, four SNPs (A17G, Q6R; T31C, W11R; C133T, R45W; and T140C, V47A) cause amino acid substitutions. Variants caused by these SNPs showed an activity change in estrone metabolism, whereas their activities toward other substrates were not examined. In the present study, three common flavonoids, quercetin, luteolin, and kaempferol, were used as substrates for glucuronidation by wild-type and variant UGT1A3s. Our results demonstrated that the activities of three variants, UGT1A3.2, UGT1A3.3, and UGT1A3.5, were remarkably lower than that of UGT1A3.1. In contrast, UGT1A3.4 exhibited an increase in glucuronidation efficiency of approximately 4 times and a clear preference to quercetin 7- and 3-hydroxyl groups. The frequency distributions of UGT1A3 alleles and SNPs in UGT1A3 in a Chinese Han population were statistically different from the reported value in German-Caucasians (p < 0.05). UGT1A3 variants have an altered glucuronidation activity toward quercetin, luteolin, and kaempferol and may alter human susceptibility to flavonoid exposure.
尿苷二磷酸葡萄糖醛酸基转移酶1A3（UGT1A3）参与许多重要内源性化合物和外源性物质（包括一些黄酮类化合物）的葡萄糖醛酸化反应。最近，在人类UGT1A3基因中总共鉴定出6个单核苷酸多态性（SNP）。其中，4个SNP（A17G、Q6R；T31C、W11R；C133T、R45W；以及T140C、V47A）导致氨基酸替换。由这些SNP引起的变体在雌酮代谢中表现出活性变化，而它们对其他底物的活性未进行检测。在本研究中，三种常见的黄酮类化合物，槲皮素、木犀草素和山奈酚，被用作野生型和变体UGT1A3进行葡萄糖醛酸化反应的底物。我们的结果表明，三种变体UGT1A3.2、UGT1A3.3和UGT1A3.5的活性显著低于UGT1A3.1。相比之下，UGT1A3.4的葡萄糖醛酸化效率提高了约4倍，并且对槲皮素的7-羟基和3-羟基有明显偏好。中国汉族人群中UGT1A3等位基因和SNP的频率分布与德国高加索人群的报道值在统计学上存在差异（p<0.05）。UGT1A3变体对槲皮素、木犀草素和山奈酚的葡萄糖醛酸化活性发生改变，可能会改变人类对黄酮类化合物暴露的易感性。
