BACKGROUND UGT1A10 exhibits glucuronidating activity against metabolites of the tobacco smoke carcinogen, benzo(a)pyrene, and is expressed highly in numerous target tissues for tobacco‐related cancers including the upper aerodigestive tract. The current study was conducted to determine the prevalence of genetic polymorphisms in the UGT1A10‐specific region of the UDP‐glucuronosyltransferase family 1A locus and their relationship with risk for orolaryngeal carcinoma. METHODS The authors analyzed UGT1A10‐specific sequences in a population of black, white, and Asian individuals. Ten UGT1A10 alleles were identified by direct sequencing of UGT1A10 sequences amplified by polymerase chain reaction (PCR) using DNA purified from buccal cell swabs that were taken from individual subjects. RESULTS In addition to three silent polymorphisms, three missense polymorphisms were found at codons 139 (Glu > Lys), 240 (Thr > Met), and 244 (Leu > Ile). Using PCR‐restriction fragment length polymorphism analysis of buccal cell DNA, the prevalence of the UGT1A10240Met variant was less than 0.01% in whites and blacks. Similarly, the prevalence of both the UGT1A10139Lys and UGT1A10244Ile variants was less than 0.01% in whites but it was significantly higher (0.04 and 0.05, respectively, P < 0.01) in blacks. None of the missense UGT1A10 variants were found in any of the Asian individuals examined. In a case–control study of black individuals, a significant association with orolaryngeal carcinoma risk was found in persons with at least 1 UGT1A10139Lys allele (crude odds ratio, 0.29 [95% confidence interval, 0.10–0.81]; adjusted odds ratio, 0.20 [95% confidence interval, 0.05–0.87]). No association was observed for the codon 244 (Leu > Ile) polymorphism. CONCLUSIONS The data from the current study show that the UGT1A10 gene has several low‐frequency missense polymorphisms and that the codon 139 polymorphism is an independent risk factor for orolaryngeal carcinoma in blacks. Cancer 2003;98:872–80. © 2003 American Cancer Society. DOI 10.1002/cncr.11587

Abstract2-Amino-9H-pyrido [2,3-b]indole (AαC) is a carcinogenic heterocyclic aromatic amine (HAA) that is produced in high quantities in tobacco smoke, and also forms in charred meats. The bioactivation of AαC occurs by cytochrome P450-mediated (P450 1A2) N-oxidation of the exocyclic amine group, to form 2-hydroxyamino-9H-pyrido [2,3-b]indole (HONH-AαC). The HONH-AαC metabolite can then undergo further activation by phase II enzymes to form the penultimate ester species, which bind to DNA. Some epidemiological studies suggest a role for NAT2 genetic polymorphisms in human susceptibilities to various cancers from tobacco smoke and from consumption of well-done meats, where the exposures to AαC can be substantial. In this investigation, we have measured the genotoxicity of AαC in nucleotide excision repair-deficient Chinese hamster ovary (CHO) cells stably transfected with human P450 1A2 and either the NAT2*4 (rapid, wild-type acetylator) or the NAT2*5B (the most common slow acetylator) allele, to determine the role of NAT2 phenotype in the biological effects of AαC. Mutations at the hypoxanthine phosphoribosyl transferase (hprt) locus were induced in a dose-dependent manner by AαC, and were found to be highest in cells transfected with P450 1A2 and NAT2*4, followed by cells transfected with P450 1A2 and NAT2*5B. The level of formation of the deoxyguanosine (dG) adduct N- (deoxyguanosin-8-yl)-2-amino-9H-pyrido[2,3-b]indole (dG-C8-AαC) paralleled the mutagenic potency, in these cell lines. However, AαC did not form DNA adducts or induce mutations in untransfected CHO cells, or in cells only expressing P450 1A2. These findings clearly demonstrate that NAT2 genetic polymorphism plays a major role in the genotoxic potency of AαC.