Depletion of Glutathione by Chemicals and Fasting

The efflux of liver GSH and metabolism of the resulting plasma GSH and GSSG appears to help ensure a continuous supply of plasma cysteine. Interorgan GSH has a half-life of 1-2 min, with the brush border membrane of the kidneys providing 

Depletion of cellular GSH has been widely studied with hundreds of chemicals including APAP and bromobenzene. These studies demonstrated very clearly that bioactivation followed by GSH adduct formation causes depletion of cytosolic glutathione and oxidative stress as indicated by indicators including enhanced levels of GSSG, lipid peroxidation, and loss of membrane integrity. 

Fasting enhances the toxicity of many chemicals. One of the earliest studies of this phenomenon compared the effects of fasting and various diets on chloroform-induced hepatotoxicity. Increased hepatotoxicity in association with fasting occurs with chemicals that are capable of depleting GSH, including carbon tetrachloride, 1,1-dichloroethylene, APAP, bromobenzene, and many others. Because fasting decreases the hepatic concentration of GSH in mice and rats, such a decrease could account for the enhanced toxicity of many of these chemicals in fasted animals. In several instances, as a result of a depletion of GSH in the liver after pretreatment with diethyl maleate, APAP, bromobenzene, carbon tetrachloride, and anthracy-clines, showed increased hepatotoxicity. 

Protection against this effect was achieved by transfection of cells with PHGPx gene. Overexpression of PHGPx has been shown to suppress cell death that is due to oxidative damage. 

Mitochondrial oxidative stress and mitochondrial GSH defense affects transcription factor activation. Oxidant stress in mitochondria not only can promote the loss of mitochondrial GSH and mitochondrial functions, but also can promote extramito-chondrial activation of NF-kB and therefore may affect nuclear gene expression. Mitochondria are targets of cytokines leading to the overproduction of reactive oxygen species induced by ceramide, a lipid intermediate of cytokine action and closely associated with apoptosis. Chronic ethanol intake depletes liver mitochondrial glutathione due to an ethanol-induced defect in the transport of GSH from cytosol into the mitochondrial matirix. This sensitizes liver cells to the prooxidant effects of cytokines and prooxidants generated by the oxidative metabolism of ethanol. 

---