DIETARY INDOLE-3-CARBINOL INHIBITS FMO ACTIVITY AND THE EXPRESSION OFFLAVIN-CONTAINING MONOOXYGENASE FORM-1 IN RAT-LIVER AND INTESTINE

Indole-3-carbinol (I3C), a naturally occurring component of cruciferou s vegetables, has been shown to be an effective cancer chemopreventati ve agent in a number of animal models, and is currently being evaluate d in human clinical trials. One proposed mechanism of action for I3C i nvolves binding of I3C acid condensation products (formed in the stoma ch) to the Ah receptor, with resultant induction of both Phase I and P hase II enzymes. We have previously shown that dietary administration of I3C to male Fischer 344 rats markedly induces hepatic levels of CYP 1A1, and to a lesser degree CYP1A2, CYP2B1/2, and CYP3A1/2, We now rep ort that such treatment concurrently inhibits both the activity and ex pression of flavin-containing monooxygenase (FMO) form 1 in rat liver and intestine, This inhibition demonstrates both a time and dose depen dency, resulting in an 8-fold reduction in expression of FMO1 in liver , and almost total ablation of FMO1 in intestinal tissues at the highe st dietary I3C levels examined, There are many examples of xenobiotics that are metabolized by both the CYP and FMO monooxygenase systems, I n many cases these enzyme systems produce different metabolites, which often have strikingly disparate toxicological and/or therapeutic prop erties, Therefore, the marked shift in the ratio of FMO/CYP levels in the livers (and other tissues) of rats fed I3C may result in significa nt alterations in the metabolism, disposition, and toxicity of xenobio tics, Testing for a similar phenomenon in humans would seem advisable before wide-spread administration.