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.
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