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Correlation between the UDP-Glucuronosyltransferase (UGT1A1) TATAA Box Polymorphism and Carcinogen Detoxification Phenotype

Significantly Decreased Glucuronidating Activity against Benzo(a)pyrene-7,8-dihydrodiol(-) in Liver Microsomes from Subjects with the UGT1A1*28 Variant

¹ Departments of Interdisciplinary Oncology, ² Biochemistry and Molecular Biology, and ³ Pharmacology and Therapeutics, Cancer Epidemiology and Prevention Program, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, Florida

Of the hepatic UDP-glucuronosyltransferases (UGTs), only UGT1A1 and UGT1A9 exhibit activity against benzo(a)pyrene-trans-7R,8R-dihydrodiol [BPD(-)], precursor to the highly mutagenic anti-(+)-benzo(a)pyrene-7R,8S-dihydrodiol-9S,10R-epoxide. The UGT1A1*28 allelic variant contains an additional (TA) dinucleotide repeat in the "TATAA" box [(TA)₆>(TA)₇] of the UGT1A1 promoter that has been linked to decreased expression of the UGT1A1 gene and decreased bilirubin conjugation, leading to the relatively nondebilitating condition known as Gilbert’s syndrome. To determine whether the UGT1A1 TATAA box polymorphism may play a role in the overall glucuronidation of BPD(-) in humans, we compared UGT1A1 TATAA box genotype with BPD(-) glucuronidating activity in normal liver microsomes. Significant decreases in UGT1A1 protein (P < 0.005) and bilirubin conjugation activity (P < 0.001) were observed in liver microsomes from subjects homozygous for the UGT1A1*28 allelic variant compared with subjects homozygous for the wild-type UGT1A1*1 allele. Significant decreases in BPD(-) glucuronidation activity (P < 0.02) were observed in subjects with the UGT1A1(*28/*28) genotype compared with subjects having the wild-type UGT1A1(*1/*1) genotype in assays of liver microsomes that included 0.1 mM -naphthylamine, a competitive inhibitor of UGT1A9 and not UGT1A1. Similar phenotype:genotype correlations were observed when we compared subjects with the UGT1A1(*28/*28) genotype with subjects having the UGT1A1(*1/*28) genotype. In assays with -naphthylamine, the K_m of liver microsomes against BPD(-) was similar to that reported for UGT1A1-overexpressing baculosomes (319 µM versus 290 µM; Fang et al., Cancer Res., 62: 1978–1986, 2002). These data suggest that the UGT1A1 TATAA box polymorphism plays a role in an individual’s overall ability to detoxify benzo(a)pyrene and in cancer risk.

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