Project Summary (2000-2005)

The overall goal of this project is to investigate specific metal-protein interactions that appear to be associated with pathways leading to subsequent toxic events. Eight of the 22 agents of greatest concern at Superfund sites are toxic metals. The mechanisms by which these metals elicit their adverse biological effects are still poorly understood, particularly the effects of low dose, chronic exposures like most human exposures near these sites. Researchers are focusing on the protein interactions of arsenic, nickel and chromium. All three of these metals are human carcinogens, and all three have a high affinity for, or react with, the thiol of cysteines, yet they are not readily detoxified by metallothionein. Project investigators hypothesize that these cysteine interactions in key target proteins may mediate or contribute to their mechanisms of action as toxins and carcinogens. Model protein and peptide systems represent potential targets in three important protein classes: the DNA binding domain of glucocorticoid receptor (a hormone-mediated transcription factor), the heme domain of cytochrome P450BM-3 (a xenobiotic-metabolizing enzyme) and sub-domains of XPA (a DNA repair protein). Researchers are determining the molecular basis for the effects of toxic metals on the functional properties of these model proteins. Understanding the molecular mechanisms by which arsenic, chromium and nickel act as human carcinogens is important in evaluating their overall health effects in exposed populations. In addition, these studies are providing evidence of specific protein adducts that could serve as potential biomarkers both for toxic metal exposure and for biological effects.