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2-Amino-3,4-dimethylimidazo[4,5-f]quinoline Induces and Inhibits Cytochrome P450 from the IA Subfamily in Chick and Rat Hepatocytes¹

VA Medical Center, White River Junction, Vermont 05009 [J. F. S., B. K. S., S. G. W., L. K. L., W. J. B., E. L. S., P. R. S.]; Departments of Biochemistry [J. F. S., N. G., E. L. S., P. R. S.] and Pathology [B. K. S.], Dartmouth Medical School, Hanover, New Hampshire 03755-3844; and Department of Radiologic Health Sciences, Colorado State University, Fort Collins, Colorado 80523 [C. A. W.]

Several heterocyclic amines, found in cooked food, are powerful mutagens in the Ames Salmonella mutagenicity test system. One of these, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) is one of the most mutagenic chemicals tested in this assay. In primary cultures of chick and rat hepatocytes, MeIQ, by itself, induced cytochrome P450 from the IA subfamily but was a weak inducer compared to 3-methylcholanthrene. However, in both chick and rat hepatocytes in culture, MeIQ decreased the amount of 3-methylcholanthrene-induced ethoxyresorufin deethylase activity, which is catalyzed by cytochrome P450 IA. The protein moiety of cytochrome P450 IA was decreased at MeIQ concentrations of 2.5 µg/ml or greater in chick hepatocytes and 25 µg/ml in rat hepatocytes. In hepatic microsomes from methylcholanthrene-treated chicks and rats, MeIQ was a competitive inhibitor of both ethoxyresorufin deethylase activity, a reaction catalyzed mainly by rodent cytochrome P450 IA1, and uroporphyrinogen oxidation, a reaction catalyzed by rodent P450 IA2. In cultured chick hepatocytes, MeIQ also decreased cytochrome P450-mediated oxidation of uroporphyrinogen by intact cells. The ability of MeIQ to inhibit as well as to induce cytochrome P450s of the IA subfamily may be important in assessing the mutagenic and carcinogenic effects of MeIQ in mammals.

¹ This work was supported by VA Medical Research funds and grants from R. J. Reynolds Tobacco Co. and NIH (CA 20512 to P. R. S.; CA 36447 to C. A. W.).

² To whom requests for reprints should be addressed, at Research 151, VA Medical Center, White River Junction, VT 05009.

Received 8/ 9/91. Accepted 4/23/92.

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