Effects of Arsenic on Cytochromes P450

描述(申请人提供)：亚砷酸盐，自来水污染物 在中国、墨西哥、智利、韩国和东北和西部地区 美国，众所周知会导致肝脏损伤，心血管疾病， 人类的肾脏问题、神经病变和癌症。的长期目标 这项建议是为了确定对亚砷酸盐敏感的CYP的形式和 描述亚砷酸盐减少几种 CYP的形式、参与消除有毒化学物质的蛋白质和 治疗药物。我们发现，在原代培养的肝细胞中， 物种多样，如人类、老鼠和鸡，亚砷酸盐是主要原因 几种环磷酰胺的蛋白质含量下降，几乎没有下降 在它们的mRNA中。因此，亚砷酸盐降低蛋白质的机制 这些细胞周期蛋白的部分可以提供有关细胞周期蛋白的机制的信息 被转录后调控。假设。假设是 在本方案中研究的是1)亚砷酸盐介导的细胞色素P450的减少 可能会通过降低新陈代谢来增加许多化学品的毒性。这 影响降低细胞色素P450也可能通过降低而增加患癌症的风险 CYP介导的促进分化或抑制分化的代谢物的形成 肿瘤生长；2)亚砷酸盐减少的转录后机制 细胞色素P450的形成可能与细胞的降解增加有关 脱脂蛋白部分，以及每个CYP mRNA的翻译减少。特定的 目的：1)研究急性暴露与长期暴露对健康的影响 亚砷酸盐对人肝细胞原代培养细胞色素P450表达的影响 B)维甲酸的代谢。2)研究在人类原代培养中 和大鼠肝细胞，亚砷酸盐对新合成的降解作用的影响 细胞色素P450 1A1、3A4和3A23的脱辅基蛋白。3)在原代培养中进行调查 在人和大鼠肝细胞中，亚砷酸盐对翻译的影响 Cyps 1A1、3A4和3A23的mRNAs。

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.