Effects of Arsenic on Cytochromes P450

描述（由申请人提供）：亚砷酸盐，一种供水污染物 在中国、墨西哥、智利、韩国以及东北和西部地区， 美国，是众所周知的导致肝损伤，心血管疾病， 肾脏问题、神经病变和癌症。的长期目标 该提案旨在确定易受亚砷酸盐影响的形式， 描述亚砷酸盐降低几种诱导的机制， 各种形式的蛋白质，参与消除有毒化学物质， 治疗药物我们发现，在肝细胞的原代培养物中， 在人类、老鼠和鸡等多种多样的物种中， 几种CYP的蛋白质部分减少，几乎没有减少 在它们的mRNA中。因此，亚砷酸盐降低蛋白质的机制 这些CYP的部分可以提供CYP可以 在转录后被调控。假设。假设是 在这个提议中研究的是：1）亚砷酸盐介导的CYP降低 可能会通过降低新陈代谢增加许多化学品的毒性。这 影响降低CYP也可能增加癌症的风险， CYP介导的促进分化或抑制分化的代谢物形成 肿瘤生长; 2）转录后机制，砷减少 CYP的形成可能涉及两种降解的增加， 脱辅基蛋白部分，以及每个mRNA翻译的减少。具体 目的：1）研究急性与长期暴露于 a）人肝细胞原代培养物中CYP表达， B）视黄酸代谢。2)为了研究，在原代培养的人类 和大鼠肝细胞，亚砷酸盐对新合成的 CYP 1A 1、3A 4和3A 23的脱辅基蛋白。3)为了研究，在原代培养中 人和大鼠肝细胞，亚砷酸盐对翻译的影响， CYP 1A 1、3A 4和3A 23的mRNA。

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.