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所在地以及许多公共和私人供水系统中都发现了高浓度的砷。饮用水中砷含量过高会增加患皮肤癌、膀胱癌、肺癌和肾癌的风险。该实验室和其他实验室先前的工作已经证明，砷可以对特定的细胞色素p450 （CYPs）产生实质性影响，CYPs主要负责肝脏、肺和其他器官的药物和其他外源药物的代谢。特别是，砷暴露减少了随后被这些CYPs代谢的化学物质对CYPs的诱导。我们假设砷诱导的CYP介导的外源代谢的改变可能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，这些化学物质可能发生在含有砷的超级基金场所，与其他金属和有机污染物结合。这被认为会增加其他有毒化学物质的生物积累，因此这些影响可能导致砷诱发的癌症和血管疾病和/或增强其他化学物质的毒性。该项目的总体目标是确定砷（III）和其他选定金属对特定肝脏CYPs的影响。我们之前的研究表明，在培养的肝细胞中，低浓度的砷显著降低了几种主要CYPs的诱导。这些砷介导的减少不是由于血红素加氧酶的诱导、血红素的消耗或氧化损伤，如以前所假设的那样。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)在完整的啮齿动物中确定急性和慢性暴露于砷（III）对诱导CYPs的影响，以及砷调节多氯联苯和药物积累和消除的能力；2)在培养的肝细胞中，确定亚砷酸盐特异性降低大鼠CYPA23和鸡CYP2H1合成的转录后机制。这些研究可能有助于深入了解砷和其他有毒金属与其他有毒物质的接触所产生的影响，这在以前是不为人知的。由于大多数超级基金场址和其他废物场址含有复杂的毒素混合物，其中60%以上的场址含有有毒金属，因此了解它们以组合形式存在时的影响对我们全面评估这些物质对健康的影响非常重要。

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.