University of Washington: Details

Summary

Many toxicants commonly found at Superfund sites are capable of inducing oxidative stress in animals and humans. These toxic agents may act synergistically when mixtures of such chemicals are present, and the ability of organisms to survive and adapt to such mixed exposures may depend upon their ability to utilize cellular antioxidants and antioxidant enzymes to combat this stress. A very important enzyme involved in antioxidant defense is glutamate-cysteine ligase (GLCL), the rate limiting enzyme for the synthesis of the cellular antioxidant glutathione (GSH). The primary goal of this project is to investigate the genetic and biochemical bases of GLCL regulation in mice and humans. Researchers are identifying which factors control GLCL expression and activity, in order to develop murine models of GLCL overexpression and GLCL insufficiency. Project investigators are also assessing the frequency of the genetic polymorphisms in GLCL genes in humans affected with diseases or conditions associated with oxidative stress. This information will be useful in determining the functional significance of this enzyme in defense against toxicants, and its utility as a biomarker of exposure and/or susceptibility to toxicants commonly found at hazardous waste sites that may act individually or synergistically to induce oxidant stress. Ultimately, this information will help minimize uncertainties in risk evaluation for people and animals exposed to low doses of contaminants at Superfund sites.