Despite the fact that 3 million children are affected by lead poisoning each year in the United States, efforts to treat these children and to eliminate lead from the environment have been inadequate. Although chelating agents are currently available for the treatment of lead poisoning, they have been shown to have severe side effects. Lead poisoning is stated as a multifaceted problem since disruption of a variety of biochemical processes is responsible for toxicity rather than a single mechanism. Even though oxidative stress appears to play a major role, the molecular mechanisms of lead toxicity are not completely known. Our previous studies demonstrated that treatment with thiols (N-acetylcystein, alpha-lipoic acid and captopril) significantly reversed lead-induced alterations in oxidative stress parameters, in both in vivo and in vitro models. However, none of these antioxidants showed any significant chelating action for lead. In order to improve the chelating abilities of thiol antioxidants in the treatment of lead poisoning, we propose to use their unnatural enantiomers because their natural, biologically-active enantiomers are quickly metabolized, whereas their unnatural ones are not. This is due to the fact that enzymes in living systems are usually stereoselective. Therefore, this continuation of our NIH (1R15ES 09497-01) proposal will explore chelating actions of the unnatural thiol enantiomers, particularly D-NAC and D-Cysteine in lead poisoning. This research will produce more effective and safe therapeutic agents for chelation by exploiting biological dependence on stereochemistry. In addition, the proposal may offer insights into our understanding of the mechanisms of enantiomeric selectivity of thiols in general.
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