Inhibition of 2-aminofluorene mutagenesis in bacteria by inducers of cytochrome P-450d.
Certain chemical inducers of rat liver microsomal cytochrome P-450d are tightly bound to the cytochrome. We investigated the ability of two inducers of cytochrome P-450d, Aroclor 1254 and isosafrole, to inhibit the microsomal activation of 2-aminofluorene to a mutagen as measured in Salmonella typhimurium. Butanol treatment of microsomes from isosafrole-treated rats removed an inhibitory metabolite of isosafrole and increased 2-aminofluorene mutagenesis by approximately 2-fold over controls. Butanol treatment of microsomes from Aroclor 1254-treated rats failed to either remove any of the Aroclor 1254 associated with microsomal cytochrome P-450 or affect 2-aminofluorene-induced mutagenesis. However, addition of Aroclor 1254 to butanol-treated microsomes from isosafrole-treated rats almost completely inhibited 2-aminofluorene mutagenesis. Aroclor 1254 completely inhibited the cytochrome P-450d-dependent estradiol 2-hydroxylase activity of butanol-treated microsomes from isosafrole-treated rats. Thus, we suspect that certain congeners from Aroclor 1254, a widely used mixture for induction of cytochrome P-450 activities, could inhibit cytochrome P-450d and partially mask its ability to metabolize some chemicals to mutagens.
D000818:Animals; D001140:Aroclors / Q000494:pharmacology*; D001711:Biotransformation; D020111:Chlorodiphenyl (54% Chlorine); D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004790:Enzyme Induction; D005449:Fluorenes / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000633:toxicity; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009152:Mutagenicity Tests; D009153:Mutagens / Q000493:pharmacokinetics; D011078:Polychlorinated Biphenyls / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012486:Salmonella typhimurium / Q000235:genetics
D001140:Aroclors; D005449:Fluorenes; D009153:Mutagens; D020111:Chlorodiphenyl (54% Chlorine); C012177:2-aminofluorene; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls