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Contributions of two inducible forms of cytochrome P-450 in rat liver microsomes to the metabolic activation of various chemical carcinogens.

Using the liver 9000 × g supernatant fraction of uninduced rats and monospecific antibodies against microsomal reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase and two inducible forms of cytochrome P-450, PB-P-450 (major cytochrome P-450 component of the liver microsomes of phenobarbital-treated rats) and MC-P-448 (major cytochrome P-450 component of the liver microsomes of 3-methylcholanthrene-treated rats), in the Ames test system, the contributions of these 2 forms of cytochrome P-450 to the mutagenicities of 3-amino-1-methyl-5 H -pyrido[4,3- b ]indole, 2-acetylaminofluorene, and aflatoxin B1 were studied. The mutagenicities of these three carcinogens were completely inhibited by antibody to reduced nicotinamide adenine dinucleotide phosphate-cytochrome P-450 reductase. The mutagenicities of 3-amino-1-methyl-5 H -pyrido[4,3- b ]indole, 2-acetylaminofluorene, and aflatoxin B1 were inhibited 85, 85, and 40%, respectively, by antibody to MC-P-448 (anti-MC-P-448 immunoglobulin) and also inhibited 5, 30, and 60%, respectively, by antibody to PB-P-450 (anti-PB-P-450 immunoglobulin). These results indicate the importance of these two forms of cytochrome P-450 in the activation of the carcinogens by the liver 9000 × g supernatant fraction of uninduced rats.

We also examined the correlation between the induction of the two forms of cytochrome P-450 and the change of mutagenic activities at various time points after a single dose of various carcinogens to rats. Benzo( a )pyrene and 3-methylcholanthrene induced only MC-P-448 about 15 and 20 times, respectively, as much as that in untreated rats at the maximal levels of induction. The 9000 × g supernatant-mediated mutagenicities of benzo( a )pyrene and 3-methylcholanthrene varied in parallel with the content of MC-P-448 in microsomes, and the induced mutagenicity of benzo( a )pyrene was completely inhibited by anti-MC-P-448 immunoglobulin. o -Aminoazotoluene induced both MC-P-448 and PB-P-450 about 10 and 5 times as much, respectively, while the induced mutagenicity of o -aminoazotoluene was inhibited 90 and 10% by the antibodies to MC-P-448 and PB-P-450, respectively. Both MC-P-448 and mutagenic activity of 2-acetylaminofluorene were induced about three times by a single dose of 2-acetylaminofluorene to rats. Administration of aflatoxin B1 showed neither induction of cytochrome P-450 nor an increase of mutagenic activity of aflatoxin B1. It is concluded that there is a good correlation between the increase of mutagenic activity and the contents of the two cytochrome P-450 species in microsomes by administration of various carcinogens to rats.