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.