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Specificity of Rabbit Cytochrome P-450 Isozymes Involved in the Metabolic Activation of the Food Derived Mutagen 2-Amino-3-methylimidazo[4,5-] quinoline

Department of Clinical Pharmacology, School of Medicine, Flinders University of South Australia, Bedford Park, 5042, Australia [M. E. M., W. B., I. S.], and Laboratory of Experimental Carcinogenesis, NIH, Bethesda, Maryland 20205 [E. S.]

The involvement of rabbit liver cytochromes P-450 in the activation of the food derived heterocyclic amine mutagen, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), was assessed using the Ames/Salmonella test. The number of revertants induced by IQ per µg of control rabbit liver microsomes was 1872 ± 50 (SD, n = 3), and this increased to 3690 ± 239 when microsomes from 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) animals were used as the metabolic activation source. Microsomes from phenobarbital, rifampicin, and acetone pretreated rabbits were less efficient than controls at activating IQ to a mutagen. Cytochrome P-450 Forms 4 and 6, which are induced by TCDD, were found to be efficient activators of IQ to a mutagen in reconstitution experiments. Form 4 was 7.7-fold more active than Form 6 and produced 1702 revertants/0.125 pmol with a 20-min preincubation step in the Ames test. Anti-Form 4 IgG inhibited the activation of IQ in control and TCDD induced microsomes by 78 and 79%, respectively. The contents of cytochrome P-450 Form 4, determined by Western blot analysis, in control and phenobarbital, acetone, rifampicin, and TCDD pretreated microsomes were 0.55 ± 0.19, 0.63 ± 0.34, 0.5 ± 0.27, 0.28 ± 0.16, and 2.19 ± 0.43 (n = 3) nmol/mg protein, respectively. A highly significant statistical correlation existed between the capacity of the above microsomes to activate IQ to a mutagen and their cytochrome P-450 Form 4 content (r = 0.96; r² = 0.92). The content of cytochrome P-450 Form 6 in the above microsomes was also highly correlated with their capacity to activate IQ (r = 0.92; r² = 0.85). Based on these results and the tissue distribution of cytochrome P-450 Forms 4 and 6, the former obviously contributes most toward the activation of IQ in the liver, whereas Form 6 would be expected to be primarily involved in this process in extrahepatic tissues.

¹ To whom requests for reprints should be addressed, at Department of Clinical Pharmacology, Flinders Medical Centre, Bedford Park, 5042 Australia.

Received 12/15/87. Revised 5/ 9/88. Accepted 5/19/88.

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