Superfund Research Program
Effects of Arsenic on Cytochrome P450
Project Leader: Jacqueline F. Sinclair (Dartmouth Medical School)
Grant Number: P42ES007373
Funding Period: 1995 - 2005
Toxic metals are present in combination with a wide variety of organic compounds at Superfund and other toxic waste sites, and people exposed at these sites are also exposed to other toxins and drugs in their normal activities. The purpose of this study is to determine the effect of the toxic metal, arsenite, on the Cytochromes P450 (CYPs). The CYPs are a group of enzymes found in the liver that convert organic chemicals to less toxic, more easily excreted compounds. Modifications in the concentrations of CYPs by exposure to arsenite at concentrations that may be found in the environment could alter the metabolism of many toxic chemicals. Using primary cultures of chick and rat hepatocytes (liver cells) as our model systems, researchers previously found that exposure to arsenite at environmental concentrations decreased the induction of all forms of CYP examined. Arsenite did not affect the CYP protein once it had been synthesized, nor did it affect the availability of heme, the cofactor of the CYPs. Since arsenite did not decrease the messenger RNAs (mRNAs) of many of the CYPs examined, project investigators concluded that there is a post-transcriptional mechanism by which arsenite decreased some CYPs.
This has contributed to knowledge of the mechanism by which arsenic causes toxicity. In the most recent studies, researchers have found that arsenite decreases basal and induced expression of CYP3A4 in primary cultures of human hepatocytes. This CYP is involved in the metabolism of many therapeutic drugs as well as other chemicals. Thus, results have implications for human health, since decreases in CYPs would alter detoxification of chemicals by the liver. Project investigators continue to investigate, in cultured hepatocytes, the post-transcriptional mechanism by which arsenite decreases CYPs, and will determine, in intact rodents, the effect of acute and chronic exposure to arsenite on induction of CYPs by polychlorinated biphenyls.