Mutagenic activation of 2-acetylaminofluorene by guinea-pig liver homogenates: essential involvement of cytochrome P-450 mixed-function oxidases.
2-Acetylaminofluorene (AAF) was highly mutagenic to Salmonella typhimurium strain TA98, when activated by a liver post-mitochondrial supernatant fraction (S9 fraction) from guinea-pigs, in spite of the resistance of this species to AAF carcinogenesis and the low capacity of the liver of this species for N-hydroxylation of AAF. The mutagenicity was comparable to or higher than that resulting from activation by mouse- or rat-liver S9 fraction, and was not enchanced by treatment with cytochrome P-450 inducers, a combination of phenobarbital and 5,6-benzoflavone. In an attempt to understand this unexpected result we examined whether a cytochrome P-450 mixed-function oxidase system participated in the mutagenic activation of AAF by guinea-pig liver, as it does in the case of mouse liver. The mutagenic activation was: (1) completely dependent on the addition of a co-factor, NADPH, to the mutation assay system, (2) completely suppressed by antiserum against NADPH--cytochrome c reductase, and (3) sensitive to a cytochrome P-450 inhibitor, 7,8-benzoflavone. These results indicate that the cytochrome P-450 enzyme system is essentially involved even in the mutagenic activation of AAF by guinea-pig-liver S9 fraction. Based on both the present and other data, the mechanism of the mutagenic activation is discussed to explain the observed high mutagenic potential of AAF in the presence of guinea-pig-liver S9 fraction.
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D001711:Biotransformation; D002474:Cell-Free System; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003579:Cytochrome Reductases / Q000378:metabolism*; D006168:Guinea Pigs / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*
D001571:Benzoflavones; D009153:Mutagens; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene; D003579:Cytochrome Reductases