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.
D000818:Animals; D001711:Biotransformation; D002243:Carbolines / Q000378:metabolism* / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000378:metabolism; D051381:Rats; D012486:Salmonella typhimurium / Q000235:genetics
D002243:Carbolines; D007211:Indoles; D009153:Mutagens; C017822:2-amino-9H-pyrido(2,3-b)indole