In vitro activation of the promutagens 2-acetamidofluorene, cyclophosphamide and 7,12-dimethylbenzanthracene by constitutive ferret and rat hepatic S-9 fractions.
The ability of the ferret to metabolically activate promutagenic compounds was compared with that of the rat, using the Salmonella/microsome assay. Three compounds which require biotransformation to mutagenic metabolites, 2-acetamidofluorene (2-AAF), cyclophosphamide (CPA), and 7,12-dimethylbenzanthracene (DMBA), were studied. Metabolic activation was provided by ferret or rat hepatic S-9 fractions at 5 levels for each chemical, and optimal S-9 levels as well as dose-response curves were obtained. Interspecies mutagenic activity was quantitated on the basis of mg liver, mg S-9 protein, and nmoles P-450. The slopes of the dose-response curves and the lowest chemical dose required for a significant response were also compared. Although constitutive levels of rat hepatic cytochrome P-450 were shown to be higher than those of the ferret, in vitro mutagenic activation by ferret S-9, at S-9 levels which caused activation in both species, was greater than or equivalent to activation by rat S-9 for these chemicals, based on all parameters studied. The results showed that the equilibrium between activation and detoxification reactions is dependent upon the chemical dose and S-9 level present.
D015073:2-Acetylaminofluorene / Q000378:metabolism*; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000378:metabolism*; D000818:Animals; D001551:Benz(a)Anthracenes / Q000378:metabolism*; D001711:Biotransformation; D003520:Cyclophosphamide / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005289:Ferrets; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity
D001551:Benz(a)Anthracenes; D009153:Mutagens; D015127:9,10-Dimethyl-1,2-benzanthracene; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D015073:2-Acetylaminofluorene