CHEMOPREVENTIVE AGENTS AND HUMAN CYTOCHROME P450 IN VIVO

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The development of cancer frequently involves an environmental component(s) and for this reason a prevention strategy is a particularly attractive approach for reducing cancer risk. To this end, various putative chemopreventive agents are either under preclinical investigation, development as drugs, or clinical evaluation. The rationale of certain of these agents is based on the notion that most environmental (pro)carcinogens are inactive per se and require metabolic activation, and that the balance between this process and subsequent elimination is important in an individual's susceptibility to the cancer process. Accordingly, decreasing an appropriate Phase I activating enzyme and/or increasing an important Phase II detoxifying enzyme could reduce cancer risk. However, because such modulation is not likely to be limited to a single enzyme or system, the selectivity of the interaction may be less than previously thought or desired. The cytochrome P450 (CYP) system is particularly important in this regard because it is often critical in procarcinogen activation, and these enzymes are also very important in the metabolism of drugs. Accordingly, the administration of a chemopreventive agent may not only alter cancer risk but also drug efficacy. The goal of the proposed research, therefore, is to determine the effects of selected chemopreventive agents on the in vivo activity of specific CYP enzymes in healthy human subjects. The agents to be studied are oltipraz, phenethylisothiocyanate and S-allylcysteine, which have either just become, or are about to be available for clinical investigation. The proposed experimental approach will be based on a conventional drug interaction study design using selected in vivo probes, reflective of the activity of individual CYP isoforms, in order to determine the inhibitory and/or inductive effects of single and repeated doses of the chemopreventive agent on the probes metabolism. The CYP isoforms of interest and the associated in vivo probes will be CYP1A2 (caffeine), CYP2A6 (coumarin), CYP2C9 (tolbutamide), CYP2C19 (mephenytoin), CYP2D6 (debrisoquine), CYP2E1(chlorzoxazone) and CYP3A(midazolam). The resulting data will provide, for the first time, information about such interactions in vivo in humans - the ultimate model -rather than in animals and/or in in vitro preparations. Moreover, the information will be of value in the further development and evaluation of the efficacy/ toxicity of these new chemopreventive agent.