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 investigators are determining the mechanism by which arsenic decreases the formation of several forms of cytochrome P450 (CYP) enzymes in the liver, and to investigate the impact of these decreases in CYP on the metabolism and elimination of toxic chemicals and therapeutic drugs. The CYPs are a family of proteins primarily responsible for the liver metabolism of many endogenous and exogenous chemicals, such as lipids, steroids, cholesterol, PCBs, pesticides, and organic solvents. Exposure to organic toxic chemicals can result in increased synthesis of the CYPs involved in their metabolism, a response that may have evolved in order to afford protection from such chemicals. Arsenic was one of the earliest liver toxins to be identified in humans, and is associated with biliary occlusion, fibrosis and cirrhosis in the liver. Exposure to high levels of arsenic has been associated with an increased incidence of human cancers including those found in liver, lung, bladder and kidney. However, arsenic alone does not cause these types of cancers in experimental animals, suggesting that arsenic itself is not a direct-acting carcinogen. Moreover, it is still not known whether continual exposure to lower levels of arsenic will have any metabolic consequences that can jeopardize the health of humans. Project researchers have found in cultured liver cells that acute exposure to arsenite decreases synthesis of several forms of CYP. If this occurs in humans, it could alter the metabolism and elimination of toxic chemicals that are substrates of such CYPs, and thereby indirectly affect human health. For example, a chemical may accumulate to potentially toxic levels in the presence of arsenite due to decreased induction of the CYP responsible for its detoxification. Polychlorinated biphenyls (PCBs) are contaminants in the environment and at some Superfund Sites that can have estrogenic and carcinogenic potential. PCBs are metabolized by CYPs and often induce the CYPs involved in their own metabolism. In studies of cultured rat hepatocytes, arsenite caused major decreases in induction of CYP3A by phenobarbital. In humans, CYP3A is involved in the metabolism of a number of drugs. Therefore, a major decrease in CYP3A could have serious clinical implications such as increased toxicity if the parent drug is toxic, or decreased effectiveness if the metabolite is the active form of the drug. These studies may provide additional insight into the mechanisms by which arsenic contributes to the cancer process and other diseases in humans.