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 ofN,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 Δ 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.
Footnotes
-
Send reprint requests to: Dr. David E. Williams, Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331-6602. E-mail:David.Williams{at}orst.edu
-
↵1 A portion of this work was presented at the Society of Toxicology annual meeting, 1999, New Orleans, LA (abstract 1068).
-
This work was supported by U.S. Public Health Service Grants HL38650 (D.E.W.) and ES00834 (D.K.).
- Abbreviations used are::
- I3C
- indole-3-carbinol
- CYP
- cytochrome P450
- FMO
- flavin-containing monooxygenase
- DIM
- 3,3′-diindolylmethane
- DMA
- N,N-dimethylaniline
- ICZ
- indole[3,2-b]carbazole
- Received January 28, 2000.
- Accepted April 14, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
Log in using your username and password
Pay Per Article - You may access this article (from the computer you are currently using) for 1 day for US$35.00
Regain Access - You can regain access to a recent Pay per Article purchase if your access period has not yet expired.