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Drug Metabolism and Disposition Fast Forward
First published on May 31, 2006; DOI: 10.1124/dmd.106.009761

0090-9556/06/3409-1462-1467$20.00
DMD 34:1462-1467, 2006

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Genetic Variants of Human UGT1A3: Functional Characterization and Frequency Distribution in a Chinese Han Population

Yakun Chen, Shuqing Chen, Xin Li, Xiewei Wang, and Su Zeng

Department of Drug Metabolism & Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China

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.

Address correspondence to: Dr. Su Zeng, Department of Drug Metabolism & Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310031, China. E-mail: zengsu060{at}sohu.com




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T. Kubota, B. C. Lewis, D. J. Elliot, P. I. Mackenzie, and J. O. Miners
Critical Roles of Residues 36 and 40 in the Phenol and Tertiary Amine Aglycone Substrate Selectivities of UDP-Glucuronosyltransferases 1A3 and 1A4
Mol. Pharmacol., October 1, 2007; 72(4): 1054 - 1062.
[Abstract] [Full Text] [PDF]


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