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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Pharmacology A Study Section (PHRA)
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University of Michigan Ann Arbor
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