Metabolic activation of 2-amino-9H-pyrido[2,3-b]indole by rat-liver microsomes.

Microsomal activation was required for the expression of the mutagenicity of 2-amino-9H-pyrido[2,3-b]indole (A alpha C) toward Salmonella typhimurium TA98. Pretreatment of rats with PCB, 3-methylcholanthrene or phenobarbital increased the mutagenic activating ability of hepatic microsomes by 16-, 10- and 2-fold, respectively, as compared with the untreated. The mutagenic activation of A alpha C by microsomes from PCB-treated rats was inhibited by ellipticine and alpha-naphthoflavone, whereas SKF 525-A and metyrapone showed a slight or no inhibitory effect, indicating that the P-448 form of cytochrome P-450 is involved in the mutagenic activation of A alpha C. Metabolic activation of A alpha C was studied by a high-performance liquid chromatography and Salmonella/microsome assay system, and the mutagenic metabolites formed were determined to be the N-hydroxy and nitroso derivatives, from the results of reaction with oxidizing or reducing agents. These results strongly indicate that N-hydroxylation of A alpha C by the P-448 type of cytochrome P-450 is essential for the mutagenic activation.