2-Amino-3,4-dimethylimidazo[4,5-f]quinoline induces and inhibits cytochrome P450 from the IA subfamily in chick and rat hepatocytes

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, Me...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1992-07, Vol.52 (13), p.3615-3621
Main Authors: SINCLAIR, J. F, SCHAEFFER, B. K, WOOD, S. G, LAMBRECHT, L. K, GORMAN, N, BEMENT, W. J, SMITH, E. L, SINCLAIR, P. R, WALDREN, C. A
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Carcinogenesis, carcinogens and anticarcinogens
Cells, Cultured
Chemical agents
Chick Embryo
Cytochrome P-450 CYP1A1
Cytochrome P-450 Enzyme System - analysis
Liver - drug effects
Liver - enzymology
Male
Medical sciences
Mutagens
Oxidoreductases - analysis
Quinolines - toxicity
Rats
Rats, Inbred F344
Tumors
Uroporphyrinogens - metabolism
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Summary: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 micrograms/ml or greater in chick hepatocytes and 25 micrograms/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.
ISSN:0008-5472
1538-7445