Superfund Research Program
Effects of Arsenic on Cytochrome P450
Project Leader: Jacqueline F. Sinclair (Dartmouth Medical School)
Grant Number: P42ES007373
Funding Period: 1995 - 2005
This year, investigators have been studying the effects of arsenic, a dose-dependent hepatotoxin, on cytochrome P450. The effect of arsenite on induction of CYP2H, CYP2B, CYP3A and CYP1A, which are the major forms of cytochrome P450, were investigated in primary cultures of chicken and rat liver cells. Arsenite treatment of liver cells decreased all four forms of P450 at doses that were not overtly toxic to the cells. Arsenite exerted its effects principally during late stages in the biochemical synthesis of these proteins. Arsenite also increased another enzyme, heme oxygenase, which breaks down heme. A dramatic increase in this protein was observed when the liver cells were exposed to the combination of arsenite and barbiturate drugs. These results suggest that people exposed to certain drugs and low doses of arsenic may be at an even greater risk for decreased elimination of drugs and other xenobiotics as compared to those exposed to arsenic alone. This project's research findings, that very low doses of arsenite decrease induction of at least four forms of cytochrome P450 without apparent toxicity to liver cells, suggests that exposure to doses of arsenite lower than the current EPA allowable limit for water (50 ppb) may affect the breakdown and elimination of toxic chemicals that are substrates of the susceptible forms of P450. The effects of lead on the terminal steps of heme synthesis are also being examined. It has been found that, contrary to previous findings in experiments using blood cells, lead does not inhibit ferochelatase activity in liver cells, nor does it affect iron availability. Further work is planned to compare metal exposures to blood and liver cells under these conditions.