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 scientists continue to study the effects of heavy metals on the expression and function of a family of proteins (CYPs) present in the liver. These are the primary proteins involved in drug metabolism and detoxification. Many of these proteins increase after exposure to chemicals which must be detoxified, a phenomenon called induction. Using cultured hepatocytes the researchers have found that arsenite, at levels in the range of the current drinking water standard (50 ppm), causes concentration-dependent decreases in induction of several important CYPs. These findings suggest that exposure to low levels of arsenic can alter detoxification of other chemicals. For example, decreases in CYP1A, which metabolizes PCBs, some pesticides and herbicides, might increase accumulation of these chemicals in the body. Decreases in CYP3A, a major drug-metabolizing protein in humans, could alter responses to therapeutic drugs.
One major focus this year bas been to elucidate the mechanism by which arsenic decreases CYPs. It had been suggested that arsenic decreased the heme prosthetic group of CYP either through induction of the heme degrading protein, heme oxygenase, or by increasing oxidative breakdown of CYP protein and/or heme. The researchers found that increases in heme oxygenase are not responsible for the decreases in CYPs. Furthermore, several anti-oxidants did not prevent arsenite-mediated decreases in CYP induction, suggesting that oxidative damage is not responsible for the effects of arsenite on CYP. These results suggest a novel mechanism by which low, non-toxic concentrations of arsenite can decrease CYPs.