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© 1988 Oxford University Press
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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
Department of Pharmacology, School of Medicine, Keio University 35-Shinanomachi, Shinjuku-ku, Tokyo, Japan 160
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.
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