Abstract:  2-Amino-9H-pyrido[2,3-b]indole (AaC) is a carcinogenic heterocyclic aromatic amine (HAA) that occurs in tobacco smoke. UDP-glucuronosyltransferases (UGTs) are important enzymes that detoxicate many procarcinogens, including HAAs and their genotoxic N-hydroxylated metabolites. The UGT-catalyzed metabolic products of AaC and 2-hydroxyamino-9H-pyrido[2,3-b]indole (HONH-AaC) formed with human liver microsomes  were characterized by  1H-NMR and mass spectrometry.  AaC and HONH-AaC underwent N2-glucuronidation, by UGTs, to form, respectively, N2-(�-D-glucosidurony1)-2-amino-9H-pyrido [2,3-b]indole and N2-(�-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AaC-HON2-Gl). HONH-AaC also underwent glucuronidation to form a novel O-linked conjugate, O-(�-D-glucosidurony1)-2-hydroxyamino-9H-pyrido[2,3-b]indole (AaC-HN2-O-Gl). This biologically reactive metabolite covalently bound to calf thymus DNA, to form the N-(deoxyguanosin-8-yl)-AaC (dG-C8-AaC) adduct,  at a 50-fold higher level than the adduct formed with HONH-AaC.  AaC-HN2-O-Gl was produced in greater amounts than AaC-HON2-Gl  by recombinant UGT isoforms incubated with low concentrations  of HONH-AaC or human hepatocytes exposed to AaC (<10 �M). Thus, UGTs, usually important enzymes in the detoxication of many procarcinogens, may serve as a mechanism of bioactivation of HONH-AaC.

Novel pathway to bioactivate the tobacco carcinogen 2-amino-9-pyrido[2,3-b]indole by UDP-glucuronosyltransferase

244th National Meeting (2012)

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