REGULATION OF P-450 III CYTOCHROMES IN LIVER & INTESTINE

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Cytochromes P-450 belonging to the P-450III gene family are major Phase I enzymes present in the liver and intestinal mucosa of rats and man. There are large interindividual differences in the expression of P-450III cytochromes and it is likely that this explains, atleast in part, the interpatient variation in oral bioavailability that is characteristic of P-450III substrates such as cyclosporine A, nifedipine, ethinyl estradiol and erythromycin. Studies performed to date suggest that the regulation of the liver and intestinal P-450III cytochromes is qualitively different. The goal of the proposed research is to continue identification of the environmental and genetic factors which influence the catalytic activity of P-450III cytochromes in human liver and intestine by 1). assaying characteristics of these and 5 other human cytochromes P-450 in live r and in duodenal mucosal biopsies obtained from patients with known medication and medical histories 2). validating noninvasive assays of the catalytic activity of P-450III cytochromes in liver (intravenous erythromycin breath test and urinary excretion of 6 Beta hydroxy cortisol) and intestine (oral erythromycin breath test) by testing patients undergoing liver and/or intestinal biopsies 3). identifying the P-450III genes expressed in intestinal mucosa by using the polymerase chain reaction and isozyme-specific synthetic oligonucleotide primers 4). determining if the wide range of compounds known to induce P-450III cytochromes in rat liver also induce P-450III mRNA, protein, catalytic activity and rate of denovo synthesis in rat intestine and 5) culturing explants of rat and human small bowel mucosa to define a valid in vitro model for regulation studies. The data obtained from the continuing basic investigation of the P-450III cytochromes in rat and man are essential to understanding the important roles they are likely to play in health and disease.