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 inducing hepatic levels of a number of cytochrome P450s (CYPs), especially CYP1A1, while markedly inhibiting the levels of flavin-containing monooxygenase (FMO) 1 protein and its catalytic activity. We hypothesized that rats fed I3C or 3,3'-diindolylmethane (DIM), one of its major acid condensation products formed in vivo, should exhibit a marked shift in the metabolic profiles of drugs or xenobiotics that are substrates for both monooxygenase systems. 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 levels (8% reduction with I3C and 84% with DIM at 1000 ppm, and 90% reduction with I3C and 97% with DIM at 2500 ppm) in hepatic microsomes. The ratio of FMO (N-oxygenation)- to CYP (N-demethylation)-mediated metabolism of N,N-dimethylaniline decreased in liver microsomes from I3C- or DIM-fed rats from near unity to 0.02 at the highest dietary doses. FMO-mediated N-oxygenation (nicotine N-1'-oxide) was decreased, whereas CYP-mediated (nornicotine and nicotine delta (1,5)-iminium ion) metabolism of nicotine was unchanged in liver 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. This study demonstrates alteration of FMO- and CYP-mediated drug metabolism in vitro by dietary I3C or DIM and suggests the potential for altered toxicity of tamoxifen and nicotine in vivo.
Katchamart
S
S
Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA.
Stresser
D M
DM
Dehal
S S
SS
Kupfer
D
D
Williams
D E
DE
D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation; D004347:Drug Interactions; D004790:Enzyme Induction; D007211:Indoles / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009538:Nicotine / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013629:Tamoxifen / Q000378:metabolism
D000814:Aniline Compounds; D007211:Indoles; D013629:Tamoxifen; D009538:Nicotine; C015157:N,N-dimethylaniline; D003577:Cytochrome P-450 Enzyme System; C016517:indole-3-carbinol; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)