Received for publication February 14, 2006.
Revised May 17, 2006.
Accepted for publication May 30, 2006.

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

Abstract

UDP-glucuronosyltransferase1A3 (UGT1A3) contributes to glucuronidations 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, while their activities towards other substrates were not examined. In the present study, three common flavonoids, quercetin, luteolin and kaempferol, were used as substrates for glucuronidations 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 approximately four times increase in the glucuronidation efficiency 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-Caucasian (*p < 0.05). UGT1A3 variants have an altered glucuronidation activity towards quercetin, luteolin and kaempferol, and may alter human susceptibility to flavonoids exposure.

Key words: genetic polymorphism, phase II drug metabolism, site-directed mutagenesis, UDP glucuronyltransferases

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