The ability to remain healthy in an environment filled with potential toxins may rely in large part on the profile of cytochromes P-450 present in the liver which, at any given moment, reflects a complicated interplay of environmental and genetic factors. The goal of the proposed project is to define the environmental and genetic factors involved in the regulation of HLp, a form of cytochrome P-450 present in human liver which is immunologically and functionally similar to cytochromes found in the livers of rats (P450p) and rabbits (LM3c). Preliminary data suggests that the environmenal factors which regulate the hepatic concentration of HLp in patients may be similar to those regulating the homologous rat and rabbit forms and therefore HLp may be inducible by commonly used medications and by such ubiquitous environmental contaminents as polychlorinated biphenyls and organochlorine pesticides. The environmental and genetic factors which influence hepatic HLp concentrations will be determined by a). quantitating HLp protein and catalytic activity in microsomes prepared from liver specimens obtained from patients treated with a variety of medications, b). quantitating HLp gene expression (at the translational level) in established cultures of human hepatocytes and human hepatoma cells treated with compounds suspected of inducing HLp and c). by developing noninvasive tests of HLp activity and testing many patient populations including monozygotic and dizygotic twins. The data obtained in these studies are essential to understanding the possible physiologic roles of HLp, and the role HLp may play in disease states resulting from drug treatment or exposure to environmental substances.
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