Variability in glutathione-dependent detoxication in vivo and its relevance to detoxication of chemical mixtures.

Glutathione (GSH) has multiple functions in detoxication and its depletion has been associated with an increased risk of chemical toxicity. Because GSH can be depleted by different agents, combinations of compounds in chemical mixtures are likely to enhance risk over that seen with individual chemicals. Our studies have focussed on factors affecting the status of GSH in humans. In addition, we have utilized animals models and cell culture systems to understand the role of GSH in protection against chemical injury. Results of these studies show that, while large variations in sulfur amino acid content occur in the human diet, these variations are not correlated simply with GSH levels in vivo as reflected in the blood plasma pool. However, plasma levels of GSH do vary with gender, age, race and dietary habits, and these factors could affect the risk of toxicity in individuals exposed to chemical mixtures. In animal studies, we found that extracellular pools of GSH, including the blood plasma, lung-lining fluid and small intestinal lumen can be very important in protection against chemically induced injury. These pools can function to detoxify chemicals extracellularly, supply GSH and its precursors to cells and protect the extracellular surface of the plasma membrane from damage. Finally, endogenous gene-activated mechanisms of cell death which produce the characteristic morphology of apoptosis are susceptible to thiol-disulfide redox regulation. Perturbations in GSH status induced by chemical mixtures could alter this regulation and lower the threshold for chemically induced cell death by apoptosis. Thus, in vivo GSH status could be an important determinant of toxicity from chemical mixtures and may be useful as a biomarker for such risk.