The impact of NAT2 acetylator genotype on mutagenesis and DNA adducts from 2-amino-9H-pyrido[2,3-b]indole

Robert J. Turesky, Jean Bendaly, Isil Yasa, Mark A. Doll, David W. Hein

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

2-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 that 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.

Original languageEnglish (US)
Pages (from-to)726-733
Number of pages8
JournalChemical research in toxicology
Volume22
Issue number4
DOIs
StatePublished - Apr 20 2009

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