Graduate Thesis Or Dissertation
 

Indole-3-carbinol and 3,3'-diindolylmethane : relative potency as modulators of drug metabolism and carcinogenesis

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  • Indole-3-carbinol (I3C), the most abundant metabolite of glucobrassicins, is found in cruciferous vegetables such as broccoli, Brussels sprouts, cabbage and cauliflower. I3C has been shown to have anticarcinogenic activity against many chemical carcinogens in multiple target organs in animal models. However, the anticarcinogenic activity of I3C is considered indirect since I3C is converted irreversibly to its dimer and other condensation products under the low pH conditions of the stomach. 3,3'-Diindolylmethane (DIM), a primary breakdown product of I3C, also shows anticarcinogenic activity in a manner similar to I3C. Our laboratory has shown that I3C dramatically induces CYP1A (cytochrome P4501A) and inhibits FMO1 (flavin-containing monooxygenase form 1) expression in rat liver and intestine. We also showed that I3C induced hepatic CYP1A1/1A2 in male guinea pig, mouse and rabbit. There was no significant difference in FMO1 protein between control and I3C treated groups in these three species. The simultaneous induction of CYP and repression of FMO may alter the metabolism, disposition and toxicity of drugs and/or xenobiotics that are substrates of both monooxygenases such as N, N-dimethylaniline, nicotine and tamoxifen. In liver microsomes from rats fed I3C or DIM, the ratio of FMO to CYP metabolites of the three chosen compounds decreased, mostly due to a reduction of N-oxide FMO-dependent formation. Major concerns associated with human dietary I3C supplementation are its estrogenic effect as seen in trout and its ability to induce cytochrome P450s involved in bioactivation. Evidence presented here also demonstrated a dose response of vitellogenin induction after 2 weeks of dietary I3C or DIM in rainbow trout. In immature female rat, I3C and DIM significantly induced uterine peroxidase, hepatic CYP1A1/1A2 and CYP2B1/2B2. All our results suggested that I3C and/or DIM, in combination with other drugs that are substrates for both monooxygenases, could alter the therapeutic effects or toxicity of drugs. Also the estrogenic activity in rainbow trout and immature female rat should be considered when assessing risk for the use of I3C and DIM as chemopreventive agents or dietary supplements.
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