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Metabolism of Food-derived Heterocyclic Amines in Human and Rabbit Tissues by P4503A Proteins in the Presence of Flavonoids¹

Departments of Clinical Pharmacology [R. A. McK., W. M. B., Z. A-A., M. E. McM.] and Histopathology [P. de la M. H.], School of Medicine, Flinders University of South Australia, Bedford Park, SA 5042, Australia

The ability of human and rabbit gastrointestinal-tract microsomes to metabolize the heterocyclic amine 2-amino-3,4-dimethylimidazo[4,5-f]-quinoline (MeIQ) to a mutagen was determined with the Ames test. When human jejunal and ileal microsomes were used as the metabolic activation source, MeIQ produced 1675 and 388 revertants/mg of microsomal protein, respectively, and this increased to 29,230 and 17,963 revertants/mg of microsomal protein, respectively, in the presence of 100 µM -naphthoflavone. MeIQ in the presence of control rabbit duodenal, jejunal, and ileal microsomes produced 2304 ± 1018, 988 ± 386, and 444 ± 134 (mean ± SD, four samples) revertants/mg of microsomal protein, respectively. In the presence of -naphthoflavone (100 µM), these activities increased >7-fold. P4503A proteins were detectable on Western blots of microsomes prepared from both human and rabbit small intestine. Further, rifampicin-induced rabbit hepatic-microsomal activation of MeIQ was completely inhibited at low concentrations of -naphthoflavone, but at higher concentrations (i.e., 100 µM) this returned to control levels. Flavone also caused a marked stimulation of MeIQ activation in human and rabbit gastrointestinal-tract microsomes. The aforementioned data suggest that flavonoids markedly increase the ability of P4503A isozymes to activate heterocyclic amines to mutagens in the Ames test.