Activation of 3,3'-dichlorobenzidine in rat liver microsomes to mutagens: involvement of cytochrome P-450d.
Studies were carried out, using antibodies to specific cytochrome P-450 isozymes, to identify the isozymes involved in the NADPH-dependent activation of 3,3'-dichlorobenzidine (DCB) by rat hepatic microsomes to mutagens in the Ames test. DCB activation was not affected by a monoclonal antibody specific for P-450c or by a monoclonal antibody specific for P-450b, but was inhibited 69% by a polyclonal antibody made against P-450d. DCB activation was also inhibited 46% by antibody specific for NADPH-cytochrome P-450 reductase. Further, addition of methimazole, a high affinity substrate for the flavin-containing monooxygenase, reduced the residual mutagenicity in the systems containing antibody to P-450d and cytochrome P-450 reductase to 9% and 19%, respectively, of the appropriate control values. It is concluded that P-450d contributes to a majority of the P-450-dependent activation of DCB in hepatic microsomes. The results also suggest that the flavin-containing monooxygenase may contribute to the microsomal activation of DCB.
D015101:3,3'-Dichlorobenzidine / Q000378:metabolism*; D000818:Animals; D001560:Benzidines / Q000378:metabolism*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*; D004790:Enzyme Induction; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D009153:Mutagens / Q000378:metabolism*; D009251:NADPH-Ferrihemoprotein Reductase / Q000276:immunology; D010105:Oxygenases / Q000502:physiology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001560:Benzidines; D007527:Isoenzymes; D009153:Mutagens; C000939:2,4-dichloro-6-phenylphenoxyethylamine; D015101:3,3'-Dichlorobenzidine; D008713:Methimazole; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D009251:NADPH-Ferrihemoprotein Reductase