VARIABILITY IN GLUTATHIONE-DEPENDENT DETOXICATION IN-VIVO AND ITS RELEVANCE TO DETOXICATION OF CHEMICAL-MIXTURES

Glutathione (GSH) has multiple functions in detoxication and its deple tion has been associated with an increased risk of chemical toxicity. Because GSH can be depleted by different agents, combinations of compo unds in chemical mixtures are likely to enhance risk over that seen wi th individual chemicals. Our studies have focussed on factors affectin g the status of GSH in humans. In addition, we have utilized animal mo dels and cell culture systems to understand the role of GSH in protect ion 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 a s reflected in the blood plasma pool. However, plasma levels of GSH do vary with gender, age, race and dietary habits, and these factors cou ld affect the risk of toxicity in individuals exposed to chemical mixt ures. In animal studies, we found that extracellular pools of GSH, inc luding 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, suppl y GSH and its precursors to cells and protect the extracellular surfac e of the plasma membrane from damage. Finally, endogenous gene-activat ed mechanisms of cell death which produce the characteristic morpholog y of apoptosis are susceptible to thiol-disulfide redox regulation. Pe rturbations in GSH status induced by chemical mixtures could alter thi s regulation and lower the threshold for chemically induced cell death by apoptosis. Thus, in vivo GSH status could be an important determin ant of toxicity from chemical mixtures and may be useful as a biomarke r for such risk.