Dietary indole-3-carbinol inhibits FMO activity and the expression of flavin-containing monooxygenase form 1 in rat liver and intestine.
Indole-3-carbinol (I3C), a naturally occurring component of cruciferous vegetables, has been shown to be an effective cancer chemopreventative agent in a number of animal models, and is currently being evaluated in human clinical trials. One proposed mechanism of action for I3C involves binding of I3C acid condensation products (formed in the stomach) to the Ah receptor, with resultant induction of both Phase I and Phase II enzymes. We have previously shown that dietary administration of I3C to male Fischer 344 rats markedly induces hepatic levels of CYP1A1, and to a lesser degree CYP1A2, CYP2B1/2, and CYP3A1/2. We now report that such treatment concurrently inhibits both the activity and expression of flavin-containing monooxygenase (FMO) form 1 in rat liver and intestine. This inhibition demonstrates both a time and dose dependency, resulting in an 8-fold reduction in expression of FMO1 in liver, and almost total ablation of FMO1 in intestinal tissues at the highest dietary I3C levels examined. There are many examples of xenobiotics that are metabolized by both the CYP and FMO monooxygenase systems. In many cases these enzyme systems produce different metabolites, which often have strikingly disparate toxicological and/or therapeutic properties. Therefore, the marked shift in the ratio of FMO/CYP levels in the livers (and other tissues) of rats fed I3C may result in significant alterations in the metabolism, disposition, and toxicity of xenobiotics. Testing for a similar phenomenon in humans would seem advisable before wide-spread administration.
Larsen-Su
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Toxicology Program, Oregon State University, Corvallis 97331-6602, USA.
Williams
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D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A; D004032:Diet; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D010105:Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344
D016588:Anticarcinogenic Agents; D007211:Indoles; C016517:indole-3-carbinol; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A