title: Detoxification of carcinogenic aromatic and heterocyclic amines by enzymatic reduction of the N-hydroxy derivative.
abstract: The metabolic activation pathways associated with carcinogenic aromatic and heterocyclic amines have long been known to involve N-oxidation, catalyzed primarily by cytochrome P4501A2, and subsequent O-esterification, often catalyzed by acetyltransferases (NATs) and sulfotransferases (SULTs). We have found a new enzymatic mechanism of carcinogen detoxification: a microsomal NADH-dependent reductase that rapidly converts the N-hydroxy arylamine back to the parent amine. The following N-OH-arylamines and N-OH-heterocyclic amines were rapidly reduced by both human and rat liver microsomes: NOH-4-aminoazobenzene, N-OH-4-aminobiphenyl (N-OH-ABP), N-OH-aniline, N-OH-2-naphthylamine, N-OH-2-aminofluorene, N-OH-4,4'-methylenebis(2-chloroaniline) (N-OH-MOCA), N-OH-1-naphthyamine, N-OH-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (N-OH-PhIP), N-OH-2-amino-alpha-carboline (N-OH-AalphaC), N-OH-2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-OH-MeIQx), and N-OH-2-amino-3-methylimidazo[4,5-f]quinoline (N-OH-IQ). In addition, primary rat hepatocytes and human HepG2 cells efficiently reduced N-OH-PhIP to PhIP. This previously unrecognized detoxification pathway may limit the bioavailability of carcinogenic N-OH heterocyclic and aromatic amines for further activation, DNA adduct formation, and carcinogenesis.
authors.affiliation: Division of Molecular Epidemiology, National Center for Toxicological Research, Jefferson, AR 72079-9501, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: King
authors.forename: C H
authors.initials: CH
authors.lastname: Teitel
authors.forename: J G
authors.initials: JG
authors.lastname: Shaddock
authors.forename: D A
authors.initials: DA
authors.lastname: Casciano
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D000818:Animals; D002273:Carcinogens / Q000378:metabolism*; D002478:Cells, Cultured; D018736:DNA Adducts / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D011804:Quinolines / Q000378:metabolism*; D051381:Rats
chemical_list: D002273:Carcinogens; D018736:DNA Adducts; D007093:Imidazoles; D011804:Quinolines; D000587:Oxidoreductases Acting on CH-NH Group Donors