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发现了高水平的砷。饮用水中高含量的砷与皮肤癌、膀胱癌、肺癌和肾癌的风险增加有关。本实验室和其他实验室先前的工作已经证明，砷可以对特定的细胞色素P450（CYP）产生实质性影响，CYP主要负责肝脏、肺和其他器官对药物和其他外源性物质的代谢。特别是，砷暴露减少诱导CYP的化学物质，随后代谢这些CYP。我们推测，砷诱导的改变，在砷介导的异生物质代谢可能有显着的影响，人类和其他生物体的反应，其他有毒化学物质，这可能会发生在超级基金网站含有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累积，因此这些影响可能会导致砷诱发的癌症和血管疾病，和/或增强其他化学品的毒性。该项目的总体目标是确定砷（III）和其他选定的金属对特定肝脏CYP的影响。我们以前的研究表明，在培养的肝细胞中，低浓度的砷显着降低几个主要CYP的诱导。这些砷介导的减少并不像之前假设的那样是由于血红素加氧酶的诱导、血红素的消耗或氧化损伤。我们推测，这些影响主要发生在转录后水平。我们的具体目标将是：1）确定在完整的啮齿类动物的急性和慢性暴露于砷（III）对诱导的CYP的影响，和砷的能力，以调节积累和消除的多氯联苯和药物;和2）确定，在培养的肝细胞中，转录后机制，砷特异性地减少大鼠CYPA 23和鸡CYP 2 H1的合成。这些研究可能会提供洞察砷和其他有毒金属的影响，结合暴露于其他有毒物质，这是以前没有意识到的。由于大多数超级基金场地和其他废物场地含有复杂的毒素混合物，超过60%的这些场地含有有毒金属，因此了解它们在组合时的影响对于我们全面评估这些物质对健康的影响至关重要。

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.