Rs. King et al., Detoxification of carcinogenic aromatic and heterocyclic amines by enzymatic reduction of the N-hydroxy derivative, CANCER LETT, 143(2), 1999, pp. 167-171
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 ca
talyzed 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 bac
k to the parent amine. The following N-OH-arylamines and N-OH-heterocyclic
amines were rapidly reduced by both human and rat liver microsomes: N-OH-4-
aminoazobenzene, N-OH-4-aminobiphenyl (N-OH-ABP), N-OH-aniline, N-OH-2-naph
thylamine, 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-A alpha C), N-OH-
2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (N-OH-MeIQx), and N-OH-2-amin
o-3-methylimidazo[4,5-f]quinoline (N-OH-IQ). In addition, primary rat hepat
ocytes and human HepG2 cells efficiently reduced N-OH-PhIP to PhIP. This pr
eviously unrecognized detoxification pathway may limit the bioavailability
of carcinogenic N-OH heterocyclic and aromatic amines for further activatio
n, DNA adduct formation, and carcinogenesis. (C) 1999 Published by Elsevier
Science Ireland Ltd.