Hepatic cytochromes P-450 belonging to the P-450IIIA gene subfamily are induced by some polyhalogenated biphenyls and are involved in the bioactivation of some ubiquitous mycotoxins and porphyrogenic compounds. It has recently been shown that there are significant interindividual differences in the liver content and catalytic activities of the P-450IIIA enzymes. It logically follows that the health outcome of an individual exposed to any variety of natural and man-made toxins may depend, at least in part, on the activity profile of P-450IIIA cytochromes in the liver which, in turn, appears to reflect a complex interplay of genetic and environmental factors. Study of the health implications and regulation of P-450IIIA enzymes will require safe and noninvasive tests capable of selectively measuring the catalytic activities of P-450IIIA cytochromes in people. We have recently reported that the ability to demethylate a test dose of erythromycin, measured by a convenient breath test, appears to selectively quantitate at least some liver P-450IIIA enzymes in patients. The activity of P-450IIIA cytochromes may also be reflected by urinary excretion of the R10 and dehydro metabolites of warfarin, and by urinary excretion of metabolites of some endogenous hormones (6-beta cortisol and catechol estrogens). Warfarin, cortisol, and estrogens may have advantages over erythromycin as probes of P-450IIA cytochromes, and each probe may be metabolized by independently regulated members of the P- 450IIA subfamily in liver, kidney, intestine, or lung. The proposed research will: 1) identify which human liver P-450s, including the four known P-450IIIA subfamily members, are capable of producing the assayed metabolites from each probe, 2) identify which of the P-450s identified in (1) are also present in kidney and lung, where their activity might confound interpretation of urine assays (warfarin, 6-beta cortisol,,and two hydroxy estradiol) and the erythromycin breath test, respectively, or in intestine, where they may significantly contribute to the metabolism of orally administered substrates (erythromycin and warfarin), and 3) administer the probes to a variety of human populations, including subjects maintained in a controlled environment for 3 weeks, patients with possible inherited defects in P-450IIIA genes or their regulation, and individuals from the Michigan PCB (Great Lakes Fisherman) and PBB (rural farmers) cohorts to assess their potential role as biomarkers for exposure to these agents. The data obtained from these studies will not only determine which of the probes investigated have greatest potential as clinical and epidemiological tools, but will help define the criteria for ideal P-450 probes in the future.
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