Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: Implications for drug-drug interaction

Our laboratory has previously shown that dietary administration of indole-3 -carbinol (I3C) to male Fischer 344 rats has the very unusual property of i nducing hepatic levels of a number of cytochrome P450s (CYPs), especially C YP1A1, while markedly inhibiting the levels of flavin-containing monooxygen ase (FMO) 1 protein and its catalytic activity. We hypothesized that rats f ed I3C or 3,3'-diindolylmethane (DIM), one of its major acid condensation p roducts formed in vivo, should exhibit a marked shift in the metabolic prof iles of drugs or xenobiotics that are substrates for both monooxygenase sys tems. Male rats were fed AIN-76A powdered diets containing 0, 1000, or 2500 ppm I3C or DIM for 4 weeks. Dietary I3C and DIM reduced FMO1 protein level s (8% reduction with I3C and 84% with DIM at 1000 ppm, and 90% reduction wi th I3C and 97% with DIM at 2500 ppm) in hepatic microsomes. The ratio of FM O (N-oxygenation)- to CYP (N-demethylation)-mediated metabolism of N,N-dime thylaniline decreased in liver microsomes from I3C- or DIM-fed rats from ne ar unity to 0.02 at the highest dietary doses. FMO-mediated N-oxygenation ( nicotine N-1'-oxide) was decreased, whereas CYP-mediated (nornicotine and n icotine Delta (1,5)-iminium ion) metabolism of nicotine was unchanged in li ver microsomes from rats fed I3C or DIM. Similarly, the ratio of FMO to CYP metabolites of tamoxifen decreased due to a reduction in N-oxygenation. Th is study demonstrates alteration of FMO- and CYP-mediated drug metabolism i n vitro by dietary I3C or DIM and suggests the potential for altered toxici ty of tamoxifen and nicotine in vivo.