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

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 UGTIA] TATAA box genotype with BPD(-) glucuronidating activity in normal liver microsomes. Significant decreases in UGTlAl 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 UGTIAI(*281*28) genotype compared with subjects having the wild-type UGT1A1(*1/*1) genotype in assays of liver microsomes that included 0.1 mm alpha naphthylamine, a competitive inhibitor of UGT1A9 and not UGT1A1 Similar phenotype:genotype correlations were observed when we compared subjects with the UGTIAI(*28/*28) genotype with subjects having the UGTIAI(*1/*28) genotype. In assays with alpha-naphthylamine, the K., of liver microsomes against BPD(-) was similar to that reported for UGT1A1-overexpressing baculosomes (319 mum versus 290 mum; 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.