Superfund Research Program
Effects of Arsenic on Cytochrome P450
Project Leader: Jacqueline F. Sinclair (Dartmouth Medical School)
Grant Number: P42ES007373
Funding Period: 1995 - 2005
Project Summary (2000-2005)
The overall goal of this project is to determine the effects of arsenic and other selected metals on specific liver cytochrome P450s (CYPS). Previous studies have demonstrated 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. These effects are believed to occur mainly at the post-transcriptional level. Researchers are investigating in intact rodents the effects of acute and chronic exposure to arsenic on induction of CYPS, and the ability of arsenic to modulate accumulation and elimination of polychlorinated biphenyls and drugs. The scientists are determining, in cultured hepatocytes, the post-transcriptional mechanisms by which arsenite specifically decreases synthesis of rat CYP3A23 and chick CYP2HI. These studies are providing insight into the effects of arsenic and other toxic metals in combination with exposures to other toxic agents.