Metabolic activation of a protein pyrolysate promutagen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline by rat liver microsomes and purified cytochrome P-450.
The enzymatic activation of a promutagenic pyrolysate, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), was studied using the Ames mutagenesis test system. The enzyme catalyzing the mutagenic activation of MeIQx is mainly localized in the microsomal fraction. A large number of revertants was observed in the presence of hepatic microsomes obtained from 3-methylcholanthrene (3-MC)- or polychlorinated biphenyl (PCB)-treated rats but only a minimal number with the hepatic microsomes from untreated or phenobarbital (PB)-treated rats. In addition, the microsomal activation was reduced efficiently by known inhibitors of cytochrome P-450-mediated reactions such as 7,8-benzoflavone, ellipticine and flavone. Among five forms of purified rat cytochrome P-450, the highest sp. act. (no. of revertants induced/nmol cytochrome P-450) for the activation of MeIQx was observed with a high-spin form of cytochrome P-450, P-448-H, followed by the low-spin form, P-448-L, and to a lesser extent by PB-inducible forms, P-450b and P-450e. P-450-male, which is a main constitutive form of cytochrome P-450 in male rat livers, showed considerable catalysis for the mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and MeIQx. These results indicate that the metabolic activation of MeIQx is catalyzed mainly by two forms of cytochrome P-450, P-448-H and P-488-L, in the livers of PCB- or 3-MC-treated rats, but also that P-450-male may play an important role in the activation in livers of intact male rats.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D009153:Mutagens / Q000493:pharmacokinetics; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011810:Quinoxalines / Q000493:pharmacokinetics*; D051381:Rats; D011919:Rats, Inbred Strains; D013347:Subcellular Fractions / Q000378:metabolism
D009153:Mutagens; D011810:Quinoxalines; D008748:Methylcholanthrene; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital