The metabolism of various carcinogens and other chemicals by genetically regulated increases in cytochrome P1-450 content was studied with the use of liver from 3-methylcholanthrene (MCA)-treated C57BL/6N and DBA/2N mice. ['P1-450' is defined as that form(s) of cytochrome that increases during polycyclic aromatic inducer treatment of the laboratory animal or cells in culture. Two forms of P1-450 have been characterized electrophoretically and catalytically, and even more than two are believed to exist]. Genetic differences were seen in the DNA binding of metabolites in vitro for: dibenz[a,h]anthracene, benz[a]anthracene, benzo[a]pyrene (BP), MCA, 7,12-dimethylbenz[a]anthracene, 2-acetylaminofluorene, and dopamine (approximately in descending order). Any difference for dibenz[a,c]anthracene or benzidine was very small. Marked genetic differences were observed in the mutagenicity (with Salmonella typhimurium tester strains TA1538, TA98, or TA100) in vitro for: 6-aminochrysene, dibenz[a,h]anthracene, dibenz[a,c]anthracene, β-naphthylamine, MCA, 2-acetylaminofluorene, BP, benz[a]anthracene, and α-naphthylamine (approximately in descending order); the difference for 7,12-dimethylbenz[a]anthracene was very small. Important discrepancies for certain carcinogens therefore existed between genetic differences in metabolites binding to DNA and genetic differences in the metabolites causing mutation in this bacterial in vitro assay. These data may be useful for future studies with any of these chemicals in the extrapolation of genetic differences observed in vitro to differences in the risk of cancer associated with the Ah locus in the intact animal. Such genetic data for MCA and BPO tumorigenesis have already been helpful in understanding the mechanism of chemical carcinogenesis.
ASJC Scopus subject areas
- Cancer Research