MICROSOMAL ACTIVATION OF 2-AMINO-3-METHYLIMIDAZO[4,5-F]QUINOLINE, A PYROLYSATE OF SARDINE AND BEEF EXTRACTS, TO A MUTAGENIC INTERMEDIATE

Abstract

The mechanism involved in the metabolic activation of 2-amino-3-methylimidazo[4,5-f]quinoline, a suspected carcinogen, which is a pyrolysate isolated from broiled foods, to a mutagenic intermediate was studied in vitro. In a system containing rat hepatic microsomes and NADPH, 2-amino-3-methylimidazo[4,5-f]quinoline was converted to a product which was directly mutagenic to Salmonella typhimurium. The structure of the mutagenic metabolite was determined as the 2-N-hydroxy derivative on the basis of the chemical properties and the mass spectral evidence of the azoxy adduct with o-nitrosotoluene. The activation reaction was mediated by microsomal enzymes and was inhibited by carbon monoxide, 7,8-benzoflavone, and other chemicals which were known to inhibit the cytochrome P-450-dependent reaction. With the use of 4 forms of purified cytochrome P-450, the N-hydroxylation of 2-amino-3-methylimidazo[4,5-f]quinoline and the induction to the reverse mutation of the bacteria were clearly demonstrated to be catalyzed mainly by a high-spin form of cytochrome P-450, P-448 II-a.