Detoxification of carcinogenic aromatic and heterocyclic amines by enzymatic reduction of the N-hydroxy derivative

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...

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Bibliographic Details
Published in:Cancer letters 1999-09, Vol.143 (2), p.167-171
Main Authors: King, Roberta S, Teitel, Candee H, Shaddock, Joseph G, Casciano, Daniel A, Kadlubar, Fred F
Format: Article
Language:English
Subjects:
A αC
Animals
Aromatic amine
arylamines
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Carcinogens - metabolism
Cells, Cultured
Detoxification
DNA Adducts - metabolism
Foods and miscellaneous
Heterocyclic amine
heterocyclic amines
Humans
Imidazoles - metabolism
Medical sciences
MeIQx
Microsomes, Liver - metabolism
N-hydroxy
Oxidoreductases Acting on CH-NH Group Donors - metabolism
PhIP
Quinolines - metabolism
Rats
Tumors
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Summary: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: N-OH-4-aminoazobenzene, N-OH-4-aminobiphenyl (N-OH-ABP), N-OH-aniline, N-OH-2-naphthylamine, N-OH-2-aminofluorene, N-OH-4,4′-methylene bis(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- α-carboline (N-OH-A αC), 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.
ISSN:0304-3835
1872-7980
DOI:10.1016/S0304-3835(99)00119-6