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Microsomal Activation of 2-Amino-3-methylimidazo[4,5-f]quinoline, a Pyrolysate of Sardine and Beef Extracts, to a Mutagenic Intermediate¹

Department of Pharmacology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan

The mechanism involved in the metabolic activation of 2-amino-3-methylimidazo[4,5-f]quinoline, which is a pyrolysate isolated from broiled foods, to a mutagenic intermediate was studied in vitro. In a system containing hepatic microsomes and reduced nicotinamide adenine dinucleotide phosphate, 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 four forms of purified cytochrome P-450, the N-hydroxylation of 2-amino-3-methylimidazo[4,5-f]quinoline and the induction of 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.

¹ This work was supported by a grant-in-aid for cancer research from the Ministry of Health and Welfare of Japan.

² To whom all requests for reprints should be addressed, at Department of Pharmacology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160, Japan.

Received 3/29/83. Accepted 8/31/83.