Superfund Research Program
Low Levels of Arsenite Found to Decrease Hepatic Cytochrome P450 Activity
The heavy metal, arsenic, is well recognized for its links to major forms of disease such as cancer and vascular disease; however, new evidence suggests that this toxic metal is also capable of producing much more subtle health effects. As part of an ongoing effort to understand the effects of arsenic on cytochrome P450 activity, scientists within the Dartmouth College Superfund Basic Research Program recently determined that low doses of arsenite, the partially reduced inorganic form of arsenic, are capable of decreasing the induction of cytochrome P450 enzymes - an important finding because this class of enzymes is necessary for the metabolism of endogenous hormones, as well as pharmaceutical agents, environmental contaminants and other xenobiotics.
These findings were obtained in recent experiments that were conducted in primary cultures of chicken and rat hepatocytes to test the effects of arsenite on the induction of CYP2H, CYP2B, CYP3A, and CYP1A, which are major inducible forms of cytochrome P450. In these studies arsenite was added to the cells simultaneously with chemicals that induce these specific forms of cytochrome P450. Treatment of the cells was found to decrease induction of all four forms of cytochrome P450 at arsenite doses that were not overtly toxic to the hepatocytes. The heavy metal exerted its effects principally during the late stages of biochemical synthesis of the inducible P450 enzymes.
Arsenite treatment was also found to increase the activity of another enzyme, heme oxygenase, confirming studies by other investigators. This enzyme breaks down the heme molecule, which is a major component of cytochrome P450 enzymes. However, the mechanism behind arsenite's effects on diminished cytochrome P450 activity is not totally explained by the increased activity of heme oxygenase. Current experiments are aimed at determining whether arsenite can reduce cytochrome P450 activity indirectly by initiating oxidative damage to the heme molecule, or by altering translation of the mRNAs for these forms of cytochrome P450.
One of the forms of cytochrome P450 which is decreased by arsenite, namely CYP3A, is a major barbiturate-inducible form of cytochrome P450 in humans and is involved in the metabolism of numerous drugs. These results suggest that people exposed simultaneously to certain drugs and low doses of arsenic may be at risk for decreased elimination of the drugs.
This research is significant because it contributes to an understanding of the events that occur at biochemical and molecular levels to produce arsenic related health effects, and also shows that arsenic's effects are not just limited to high doses and major forms of disease. Low doses of arsenite may potentially interfere with the liver's enzymatic defenses against some environmental chemicals and with its ability to metabolize and eliminate certain pharmaceutical agents. Currently, there is special interest in determining arsenic's mechanisms of action and its spectrum of biological activity to aid in a more accurate estimation of the risks this metal poses to humans. This is crucial for setting appropriate standards for drinking water and environmental and occupational exposures that protect human health and which are scientifically justified on the one hand, without causing excessive financial burdens on society on the other hand.
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To learn more about this research, please refer to the following sources:
- Jacobs JM, Roussel RR, Roberts M, Marek D, Wood SG, Walton HS, Dwyer B, Sinclair PR, Sinclair JF. 1998. Effect of arsenite on induction of CYP1A and CYP2H in primary cultures of chick hepatocytes. Toxicol Appl Pharmacol 150(2):376-382. PMID:9653069
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