Microsomal metabolism and activation of the environmental carcinogen 2-amino-3-methyl-9H-pyrido[23-b]indole

2-Amino-3-methyl-9H-pyrido[2,3-b]indole (MeA alpha C) is a mutagenic and carcinogenic heterocyclic amine formed as a pyrolysis product during cooking of food and combustion of tobacco. Hepatic microsomes from PCB-induced rats metabolized MeA alpha C to four products, of which three were non-mutagenic and one was mutagenic without S9 activation. The three non-mutagenic products, which accounted for 83% of the metabolism of MeA alpha C, were characterized by mass spectrometry and NMR spectroscopy as 6-hydroxy-MeA alpha C, 7-hydroxy-MeA alpha C and 3-hydroxy-methyl-A alpha C. The mutagenic metabolite, accounting for 17% of the metabolism of MeA alpha C, was characterized as N2-hydroxy-MeA alpha C by comparison with the HPLC retention time and UV spectrum of N2-hydroxy-MeA alpha C obtained by chemical synthesis. N2-Hydroxy-MeA alpha C was very reactive and a part of it bound covalently to microsomal proteins during incubation and a part was degraded to other products during incubation or chromatography. N2-Hydroxy-MeA alpha C was mutagenic in Salmonella typhimurium TA98 without metabolic activation, resulting in 5070 revertants/microgram, which was > 20 times the specific mutagenic activity of the parent compound.