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Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interaction.
Drug Metab Dispos. 2000 Aug; 28(8):930-6.DM

Abstract

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.

Authors+Show Affiliations

Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, Oregon, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10901703

Citation

Katchamart, S, et al. "Concurrent Flavin-containing Monooxygenase Down-regulation and Cytochrome P-450 Induction By Dietary Indoles in Rat: Implications for Drug-drug Interaction." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 28, no. 8, 2000, pp. 930-6.
Katchamart S, Stresser DM, Dehal SS, et al. Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metab Dispos. 2000;28(8):930-6.
Katchamart, S., Stresser, D. M., Dehal, S. S., Kupfer, D., & Williams, D. E. (2000). Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interaction. Drug Metabolism and Disposition: the Biological Fate of Chemicals, 28(8), 930-6.
Katchamart S, et al. Concurrent Flavin-containing Monooxygenase Down-regulation and Cytochrome P-450 Induction By Dietary Indoles in Rat: Implications for Drug-drug Interaction. Drug Metab Dispos. 2000;28(8):930-6. PubMed PMID: 10901703.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concurrent flavin-containing monooxygenase down-regulation and cytochrome P-450 induction by dietary indoles in rat: implications for drug-drug interaction. AU - Katchamart,S, AU - Stresser,D M, AU - Dehal,S S, AU - Kupfer,D, AU - Williams,D E, PY - 2000/7/20/pubmed PY - 2000/9/19/medline PY - 2000/7/20/entrez SP - 930 EP - 6 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 28 IS - 8 N2 - 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. SN - 0090-9556 UR - https://www.unboundmedicine.com/medline/citation/10901703/Concurrent_flavin_containing_monooxygenase_down_regulation_and_cytochrome_P_450_induction_by_dietary_indoles_in_rat:_implications_for_drug_drug_interaction_ L2 - http://dmd.aspetjournals.org/cgi/pmidlookup?view=long&pmid=10901703 DB - PRIME DP - Unbound Medicine ER -