CYTOCHROME P450 MEDIATED METABOLISM, DIET, AND THE GASTROINTESTINAL TRACT

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The oral bioavailability of drugs if determined by their absorption from the gastro-intestinal tract and first-pass metabolism occurring in either the intestinal epithelium and/or the liver. The often marked interindividual variability in plasma concentrations and associated clinical response is frequently determined by these factors. Extensive study has been made of the hepatic component of this effect, but other determinants are largely undefined. For example, CYP3A-mediated metabolism during absorption by the intestinal epithelium and efflux from this tissue associated with P- glycoprotein. Such processes as well as metabolism in the liver may be potentially modulated by dietary-related factors and/or intestinal disease. Accordingly, studies will address some of these determinants that are important in the clinical use of drugs or may be significant in the chemoprevention of cancer resulting from dietary and environmental procarcinogens. In the latter instance, it is though that enzymes like CYP1A, CYP2E1 and CYP3A activate the procarcinogen. Since the chemoprotective effect of vegetables against cancer is well-recognized, it is hypothesized that certain phytochemical may inhibit these enzymes. This will be tested by investigating the ability of cruciferous vegetables and garlic-related products to inhibit the metabolism of in vivo probes of the individual CYP isoforms in humans. Subsequently, studies will be extended to examine the effects of representative pure chemical constituents that are under development as chemoprotective agents (oltipraz, phenethyl isothiocyanate, S-allyl cysteine). The effect of diet of CYP2E1 and CYP3A activities will also be examined in racial groups with different disposition characteristics from Caucasians, as identified in Project 1. In particular, Japanese and Mexican-Americans that routinely eat a "western" diet compared to "native" diet. The mechanism(s) whereby dietary salt affects the plasma concentration-time profile of certain CYP3A/P-glycoprotein substrates will also be examined in both humans and animal models. Finally, the effect of intestinal disease such as celiac disease and tropical sprue on the oral bioavailability of drugs will be determined, since such inflammatory diseases are associated with major disturbances in the structure and functioning of the intestinal epithelium.