Mutagenesis of certain activated carcinogens in vitro associated with genetically mediated increases in monooxygenase activity and cytochrome P 1-450.
A bacterial mutagenesis assay and genetic differences in microsomal CO-binding cytochromes were combined in vitro to evaluate the metabolic activation of several known carcinogens to frameshift mutagens. With the use of liver fractions from C57BL/6N and DBA/2N control mice and mice treated in vivo with 3-methylcholanthrene, beta-naphthoglavone, phenobarbital, or 2,3,7,,-tetrachlorodibenzo-p-dioxin, the in vitro mutagenicity of 3-methylcholanthrene, 6-aminochrysene, and 2-acetylaminofluorene --but not benzo[a]pyrene==is closely associated with the genetically mediated difference in both aromatic hydrocarbon-inducible aryl hydrocarbon (benzo[a]pyrene) hydroxylase activity and new cytochrome P1-450 formation; such an association between 7,12-dimethylbenz[a]anthracene or benz[a]anthracene activation to mutagens in vitro and these genetic differences between C57BL/6N and DBA/2N mouse strains in uncertain. The Salmonella typhimurium histidine mutant TA1538 is more effective than tester strains TA1537 and TA1535 in the determination of 3-methylcholanthrene mutagenesis in vitro. The relationships between the histidine revertant rate as a function of both liver protein concentration per plate and mutagen concentration per plate are illustrated for 3-methylcholanthrene, benzo[a]pyrene, 6-aminochrysene, and 2-acetylaminofluorene. With the use of offspring from the appropriate genetic crosses, the aromatic hydrocarbon-inducible hydroxylase activity appears to be expressed as an autosomal dominant trait, whereas the mutagenesis of 3-methylcholanthrene in vitro appears to be expressed additively; this apparent discrepancy probably reflects different proportional amounts of phenolic benzo[a]pyrene, compared with mutagenic 3-methylcholanthrene metabolites, formed by the monooxygenase(s). 3-Methylcholanthrene, 6-aminochrysene, and 2-acetylaminofluorene--but not benzo[a]pyrene--are each more mutagenic in vitro per molecule of cytochrome P1-450 than per molecule of CO-binding cytochrome other than P1450. Diethylmaleate, a compound which depletes flutathione content in liver, and 1,1,1-trichloropropene-2,3-epoxide, an inhibitor of epoxide hydrase (EC 4.2.1.63), were also studied in vitro. Diethylmaleate, and especially 1,1,1-trichloropropene-2,3-epoxide, increases the mutagenicity of benzo[a]pyrene, whereas no increases occur with 3-methylcholanthrene, 6-aminochrysene, or 2-acetylaminofluorene activation to mutagens in vitro. Both diethylmaleate and 1,1,1-trichloropropene-2,3-epoxide cause decreases in 2-acetylaminofluorene mutagenesis in vitro when liver fractions from phenobarbital-treated mice are used.
D015073:2-Acetylaminofluorene / Q000494:pharmacology; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D001551:Benz(a)Anthracenes / Q000494:pharmacology; D001580:Benzopyrenes / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D003433:Crosses, Genetic; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005260:Female; D005796:Genes; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009153:Mutagens / Q000494:pharmacology*; D010105:Oxygenases / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D013045:Species Specificity
D001551:Benz(a)Anthracenes; D001580:Benzopyrenes; D002273:Carcinogens; D009153:Mutagens; D008748:Methylcholanthrene; D015127:9,10-Dimethyl-1,2-benzanthracene; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D010105:Oxygenases; D010634:Phenobarbital