Effects of Arsenic on Cytochromes P450

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Arsenite, a contaminant of water supplies in China, Mexico, Chile, Korea and the Northeastern and Western regions of the United States, is well-known to cause liver damage, cardiovascular disease, kidney problems, neuropathy and cancer in humans. The long-term objectives of this proposal are to identify the forms to CYP susceptible to arsenite and to delineate the mechanism by which arsenite decreases the induction of several forms of CYP, proteins involved in the elimination to toxic chemicals and therapeutic drugs. We have found that, in primary cultures of hepatocytes from species as diverse as humans, rats and chickens, arsenite causes major decreases in the protein moieties of several CYPs, with little to no decrease in their mRNAs. Thus, the mechanism by which arsenite decreases the protein moieties of these CYPs may provide information on mechanisms by which CYPs can be regulated post-transcriptionally. Hypotheses. The hypotheses to be investigated in this proposal are that 1) arsenite-mediated decreases in CYPs may increase the toxicity of many chemicals through decreased metabolism. This affect to decrease CYPs may also increase the risk of cancer by decreasing CYP-mediated formation of metabolites that promote differentiation or inhibit tumor growth; 2) the post-transcriptional mechanisms by which arsenite decrease formation of CYPs may involve both an increase in the degradation of the apoprotein moiety, and a decrease in translation of each CYP mRNA. Specific Aims: 1)To investigate the effect of acute versus long-term exposure to arsenite on a) expression of CYPs in primary cultures of human hepatocytes and b) metabolism of retinoic acid. 2) To investigate, in primary cultures of human and rat hepatocytes, the effect of arsenite on degradation of newly synthesized apoproteins of CYPs 1A1, 3A4 and 3A23. 3) To investigate, in primary cultures of human and rat hepatocytes, the effect of arsenite on translation of the mRNAs of CYPs 1A1, 3A4 and 3A23.