title: Metabolic oxidation of the carcinogens 4-aminobiphenyl and 4,4'-methylene-bis(2-chloroaniline) by human hepatic microsomes and by purified rat hepatic cytochrome P-450 monooxygenases.
abstract: Metabolic N-oxidation and ring-oxidation of carcinogenic arylamines by hepatic cytochromes P-450 are generally regarded as critical activation and detoxification pathways, respectively. Two arylamines with known human exposure, 4-aminobiphenyl (ABP) and 4,4'-methylene-bis(2-chloroaniline) (MOCA), have been examined as substrates for 10 different purified rat hepatic cytochromes P-450 and for human liver microsomal preparations from 22 individuals. Metabolites were analyzed by high-performance liquid chromatography and flow scintillation techniques. As reported for certain other carcinogenic arylamines, the isosafrole-inducible isozyme, P-450ISF-G, had the highest catalytic activity for ABP N-oxidation (13.6 nmol/min/nmol P-450), but P-450BNF-B, P-450UT-A, P-450UT-F, and P-450PB-B also showed appreciable activity. Ring-oxidation of ABP occurred only to a minor extent. In contrast, N-oxidation of MOCA was preferentially catalyzed by the phenobarbital-inducible enzymes, P-450PB-B and P-450PB-D (9.0 and 6.6 nmol/min/nmol P-450, respectively). MOCA ring-oxidation and methylene carbon oxidation showed varied cytochrome P-450 selectivity and accounted for 14 to 79% of total oxidation products. There was a 44-fold variation in rates of ABP N-oxidation in the 22 human liver microsomal preparations, while rates of N-oxidation of MOCA varied only 8-fold. Ring/methylene carbon-oxidation of MOCA accounted for 6-19% of total oxidation products in the case of the human microsomal preparations, whereas ring-oxidation of ABP accounted for less than 7% of total oxidation. In addition, there was a strong correlation (R = 0.90) between rates of ABP N-oxidation and phenacetin O-deethylation, which is considered a human genetic polymorphism. Moreover, both the ABP N-oxidation and phenacetin O-deethylation activities of human liver microsomes showed a good correlation (R = 0.72) with the levels of cytochrome P-450 immunochemically related to rat P-450ISF-G. These data indicate that specific inducible and constitutive cytochromes P-450 are involved in the metabolic activation and detoxification of the carcinogens ABP and MOCA. Therefore, individual profiles of cytochromes P-450, affected by both environmental and genetic factors, may be significant determinants of individual susceptibility to arylamine carcinogenesis.
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
authors.forename: M A
authors.initials: MA
authors.lastname: Butler
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
authors.forename: F F
authors.initials: FF
authors.lastname: Kadlubar
mesh_terms: D000611:Aminobiphenyl Compounds / Q000378:metabolism*; D000818:Animals; D001559:Benzhydryl Compounds / Q000378:metabolism*; D001589:Benzphetamine / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology*; D006801:Humans; D008753:Methylenebis(chloroaniline) / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D010084:Oxidation-Reduction; D010615:Phenacetin / Q000378:metabolism; D011110:Polymorphism, Genetic; D051381:Rats
chemical_list: D000611:Aminobiphenyl Compounds; D001559:Benzhydryl Compounds; D002273:Carcinogens; D001589:Benzphetamine; C006757:4-biphenylamine; D008753:Methylenebis(chloroaniline); D003577:Cytochrome P-450 Enzyme System; D010615:Phenacetin