EFFECTS OF ARSENIC ON CYTOCHROME P450

在美国东北部和西部地区，几乎一半的超级基金地点以及许多公共和私人供水中都发现了高水平的砷。饮用水中高水平的砷会增加患皮肤癌、膀胱癌、肺癌和肾癌的风险。该实验室和其他实验室以前的工作已经证明，砷可以对特定的细胞色素P450(Cyps)产生实质性影响，这些细胞色素P450主要负责药物和其他异物通过肝脏、肺和其他器官的代谢。特别是，砷暴露降低了化学物质对细胞周期蛋白的诱导，这些化学物质随后被这些细胞周期蛋白代谢。我们推测，砷诱导的CYP介导的异种代谢的改变可能会对人类和其他生物对其他有毒化学物质的反应产生重大影响，这些有毒化学物质可能发生在超级基金站点，其中包含砷与其他金属和有机污染物的组合。据推测，这会增加其他有毒化学品的生物积累，因此这些效应可能会导致砷引起的癌症和血管疾病，和/或增强其他化学品的毒性。本项目的总体目标是确定砷(III)和其他选定金属对特定肝脏细胞色素P450的影响。我们以前的研究表明，在培养的肝细胞中，低浓度的砷显著降低了几种主要细胞周期蛋白的诱导。这些砷介导的减少并不是由于血红素加氧酶的诱导、血红素的耗竭或氧化损伤，如先前假设的那样。我们假设这些影响主要发生在转录后水平。我们的具体目标将是：1)确定在完整的啮齿动物中，急性和长期暴露于砷(III)对细胞色素P450的诱导的影响，以及砷调节多氯联苯和药物积累和消除的能力；以及2)在培养的肝细胞中，确定亚砷酸盐通过转录后机制特异性地减少大鼠和鸡的细胞色素P450 23和鸡细胞色素P450 1的合成。这些研究可能提供对砷和其他有毒金属的影响的洞察，以及接触其他有毒物质的影响，这些以前没有被认识到。由于大多数超级基金站点和其他废物站点包含复杂的毒素混合物，并且这些站点中超过60%包含有毒金属，因此了解它们的组合时的影响对于我们全面评估这些制剂的健康影响将是重要的。

Arsenic is found at high levels in almost half of all Superfund sites as well as many public and private water supplies in the northeastern and western regions of the United States. High levels of arsenic in drinking water are associated with an increased risk of skin, bladder, lung, and kidney cancer. Previous work in this and other laboratories has demonstrated that arsenic can have substantial effects on specific cytochrome P450s (CYPs) that are principally responsible for metabolism of drugs and other xenobiotics by the liver, lung and other organs. In particular, arsenic exposure decreases the induction of CYPs by chemicals that are subsequently metabolized by these CYPs. We hypothesize that arsenic-induced alterations in CYP mediated xenobiotic metabolism may have a significant impact on the response of humans and other organisms to other toxic chemicals, which might occur in Superfund sites containing arsenic in combination with other metals and organic contaminants. This is postulated to increase the bioaccumulation of other toxic chemicals, and therefore these effects may contribute to arsenic- induced cancer and vascular disease and/or enhance the toxicity of other chemicals. The overall goal of this project is to determine the effects of arsenic (III) and other selected metals on specific liver CYPs. Our previous studies have demonstrated in hepatocytes in culture that low concentrations of arsenic significantly decrease induction of several major CYPs. These arsenic mediated decreases are not due to the induction of heme oxygenase, depletion of heme, or oxidative damage as had been previously postulated. We hypothesize that these effects occur mainly at the post-transcriptional level. Our specific aims will be to: 1) determine in intact rodents the effects of acute and chronic exposure to arsenic (III) on induction of CYPs, and the ability of arsenic to modulate accumulation and elimination of polychlorinated biphenyls and drugs; and 2) determine, in cultured hepatocytes, the post-transcriptional mechanisms by which arsenite specifically decreases synthesis of rat CYPA23 and chick CYP2H1. These studies may provide insight into effects of arsenic and other toxic metals, in combination with exposures to other toxic agents, that have not previously been appreciated. Since most Superfund sites and other waste sites contain complex mixtures of toxins, and over 60% of these sites contain toxic metals, understanding their effects when present in combinations will be important for our overall evaluation of the health effects of these agents.