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

被引:54
作者
King, RS
Teitel, CH
Shaddock, JG
Casciano, DA
Kadlubar, FF [1 ]
机构
[1] Natl Ctr Toxicol Res, Div Mol Epidemiol, Jefferson, AR 72079 USA
[2] Natl Ctr Toxicol Res, Div Genet Toxicol, Jefferson, AR 72079 USA
关键词
heterocyclic amine; aromatic amine; detoxification; N-hydroxy; PhIP; A alpha C; IQ; MeIQx;
D O I
10.1016/S0304-3835(99)00119-6
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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'-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-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. (C) 1999 Published by Elsevier Science Ireland Ltd.
引用
收藏
页码:167 / 171
页数:5
相关论文
共 7 条
[1]   HUMAN CYTOCHROME P-450PA (P-450IA2), THE PHENACETIN O-DEETHYLASE, IS PRIMARILY RESPONSIBLE FOR THE HEPATIC 3-DEMETHYLATION OF CAFFEINE AND N-OXIDATION OF CARCINOGENIC ARYLAMINES - (AROMATIC-AMINES HETEROCYCLIC AMINES CARCINOGEN METABOLISM) [J].
BUTLER, MA ;
IWASAKI, M ;
GUENGERICH, FP ;
KADLUBAR, FF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (20) :7696-7700
[2]   Isolation and characterization of the protein components of the liver microsomal O-2-insensitive NADH-benzamidoxime reductase [J].
Clement, B ;
Lomb, R ;
Moller, W .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (31) :19615-19620
[3]  
CRIBB AE, 1995, DRUG METAB DISPOS, V23, P406
[4]   REDUCED PYRIDINE NUCLEOTIDE-DEPENDENT N-HYDROXY AMINE OXIDASE AND REDUCTASE ACTIVITIES OF HEPATIC MICROSOMES [J].
KADLUBAR, FF ;
MCKEE, EM ;
ZIEGLER, DM .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1973, 156 (01) :46-57
[5]   PROPERTIES OF A NADH-DEPENDENT N-HYDROXY AMINE REDUCTASE ISOLATED FROM PIG LIVER-MICROSOMES [J].
KADLUBAR, FF ;
ZIEGLER, DM .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 1974, 162 (01) :83-92
[6]  
Oldham J.W., 1979, TCA MANUAL, V5, P1047
[7]   Activation of heterocyclic aromatic amines by rat and human liver microsomes and by purified rat and human cytochrome P450 1A2 [J].
Turesky, RJ ;
Constable, A ;
Richoz, J ;
Varga, N ;
Markovic, J ;
Martin, MV ;
Guengerich, FP .
CHEMICAL RESEARCH IN TOXICOLOGY, 1998, 11 (08) :925-936