TY - JOUR
T1 - Metabolic activation of carcinogenic heterocyclic aromatic amines by human liver and colon
AU - Turesky, Robert J.
AU - Lang, Nicholas P.
AU - Butler, Mary Ann
AU - Teitel, Candee H.
AU - Kadlubar, Fred F.
PY - 1991/10
Y1 - 1991/10
N2 - The metabolic activation of the food-borne rodent carcinogens 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo [4,5-f]quinoline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-bpyridine (PhIP) and 2-amino-6-methyldlpyrido{1 ,2-a :3' ,2'-d]imidazole (Glu-P-1) was compared with that of the known human carcinogen 4-aminobiphenyl (ABP), using human liver microsomes, human and rat liver cytosols, and human colon cytosol. All of these aromatic amines were readily activated by N-hydroxylation with human liver microsomes (2.3-5.3 nmol/min/mg protein), with PhIP and ABP exhibiting the highest rates of cytochrome P450IA2-dependent N-oxidation, followed by MeIQ IQ and Glu-P-1. In contrast, while ABP and 2-aminofluorene were readily N-acetylated (1.7-2.3 nmol/min/mg protein) by the polymorphic human liver cytosolic N-acetyltransferase, none of the heterocyclic amines were detectable as substrates (<0.05 mnol/min/mg protein). Likewise, only low activity was observed (0.11 nmol/min/mg protein) for the N-acetylation of p-aminobenzoic acid, a selective substrate for the human monomorphic liver N-acetyl-transferase. The radiolabeled N-hydroxy (N-OH) arylamine metabolites were synthesized and their reactivity with DNA was examined. Each derivative bound covalently with DNA at neutral pH (7.0), with highest levels of binding observed for N-OH-IQ and N-OH-PhIP. Incubation at acidic pH (5.0) resulted in increased levels of DNA binding, suggesting formation of reactive arylnitrenium ion intermediates. These N-OH arylamines were further activated to DNA-bound products by human hepatic O-acetyltransferase. Acetyl coenzyme A (AcC0A)-dependent, cytosol-catalyzed DNA binding was greatest for N-OH-ABP and N-OH-Glu-P-1, followed by N-OH-PhIP, N-OH-MeIQx and N-OH-IQ; and both rapid and slow acetylator phenotypes were apparent. Rat liver cytosol also catalyzed AcCoA-dependent DNA binding of the N-OH arylamines; and substrate specificities were comparable to human liver, except that N-OH-MeIQ and N-OH-PhIP gave relatively higher and lower activities respectively. Human colon cytosols likewise displayed AcCoA dependent DNA binding activity for the N-OH substrates. Metabolic activity was generally lower than that found with the rapid acetylator liver cytosols; however, substrate specificity was variable and phenotypic differences in colon
AB - The metabolic activation of the food-borne rodent carcinogens 2-amino-3-methylimidazo [4,5-f]quinoline (IQ), 2-amino-3,8-dimethylimidazo [4,5-f]quinoline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-bpyridine (PhIP) and 2-amino-6-methyldlpyrido{1 ,2-a :3' ,2'-d]imidazole (Glu-P-1) was compared with that of the known human carcinogen 4-aminobiphenyl (ABP), using human liver microsomes, human and rat liver cytosols, and human colon cytosol. All of these aromatic amines were readily activated by N-hydroxylation with human liver microsomes (2.3-5.3 nmol/min/mg protein), with PhIP and ABP exhibiting the highest rates of cytochrome P450IA2-dependent N-oxidation, followed by MeIQ IQ and Glu-P-1. In contrast, while ABP and 2-aminofluorene were readily N-acetylated (1.7-2.3 nmol/min/mg protein) by the polymorphic human liver cytosolic N-acetyltransferase, none of the heterocyclic amines were detectable as substrates (<0.05 mnol/min/mg protein). Likewise, only low activity was observed (0.11 nmol/min/mg protein) for the N-acetylation of p-aminobenzoic acid, a selective substrate for the human monomorphic liver N-acetyl-transferase. The radiolabeled N-hydroxy (N-OH) arylamine metabolites were synthesized and their reactivity with DNA was examined. Each derivative bound covalently with DNA at neutral pH (7.0), with highest levels of binding observed for N-OH-IQ and N-OH-PhIP. Incubation at acidic pH (5.0) resulted in increased levels of DNA binding, suggesting formation of reactive arylnitrenium ion intermediates. These N-OH arylamines were further activated to DNA-bound products by human hepatic O-acetyltransferase. Acetyl coenzyme A (AcC0A)-dependent, cytosol-catalyzed DNA binding was greatest for N-OH-ABP and N-OH-Glu-P-1, followed by N-OH-PhIP, N-OH-MeIQx and N-OH-IQ; and both rapid and slow acetylator phenotypes were apparent. Rat liver cytosol also catalyzed AcCoA-dependent DNA binding of the N-OH arylamines; and substrate specificities were comparable to human liver, except that N-OH-MeIQ and N-OH-PhIP gave relatively higher and lower activities respectively. Human colon cytosols likewise displayed AcCoA dependent DNA binding activity for the N-OH substrates. Metabolic activity was generally lower than that found with the rapid acetylator liver cytosols; however, substrate specificity was variable and phenotypic differences in colon
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U2 - 10.1093/carcin/12.10.1839
DO - 10.1093/carcin/12.10.1839
M3 - Article
C2 - 1934265
AN - SCOPUS:0026040316
SN - 0143-3334
VL - 12
SP - 1839
EP - 1845
JO - Carcinogenesis
JF - Carcinogenesis
IS - 10
ER -