Effects of Arsenic on Cytochromes P450

砷对细胞色素 P450 的影响

• 批准号: 6704772
• 负责人: JACQUELINE A SINCLAIR
• 金额: $ 32.48万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-22 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6704772
• 关键词: arsenic; cytochrome P450; cytotoxicity; environmental toxicology; genetic transcription; genetic translation; hemoprotein; human tissue; laboratory rat; liver cells; messenger RNA; oxidation; protein degradation; retinoate; tissue /cell culture

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.

描述（由申请人提供）：砷，污染物的污染物 在中国，墨西哥，智利，韩国以及东北地区和西部地区 美国众所周知会造成肝脏损害，心血管疾病， 人类的肾脏问题，神经病和癌症。长期目标 该提议是为了确定易受砷的CYP的形式， 描述砷减少几种诱导的机制 CYP的形式，涉及消除有毒化学物质的蛋白质和 治疗药物。我们发现，在原发性培养肝细胞中 像人类，大鼠和鸡一样多样化的物种，砷会引起重大 几个CYP的蛋白质部分减少，几乎没有减少 在他们的mRNA中。因此，砷降低蛋白质的机制 这些CYP的部分可能会提供有关CYP可以使用的机制的信息 在转录后受到调节。假设。假设是 在此提案中调查的是1）CYPS中砷介导的降低 可以通过降低代谢来增加许多化学物质的毒性。这 降低CYP的影响也可能通过减少来增加癌症的风险 CYP介导的代谢产物的形成，促进分化或抑制 肿瘤生长； 2）砷减少的转录后机制 CYP的形成可能涉及降解的降解 载脂蛋白部分，每个CYP mRNA的翻译减少。具体的 目的：1）研究急性与长期暴露的影响 砷对人类肝细胞的原发性培养物的表达A）表达 b）视黄酸的代谢。 2）在人类的主要文化中进行调查 和大鼠肝细胞，砷对新合成的降解的影响 CYPS 1A1、3A4和3A23的载蛋白。 3）调查，在初级文化中 人和大鼠肝细胞的作用，砷对翻译的影响 CYPS 1A1、3A4和3A23的mRNA。