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Glutathione depletion: its effects on other antioxidant systems and hepatocellular damage
M Comporti1, E Maellaro, B Del Bello
1Istituto di Patologia Generale dell'Università di Siena, Italy.
Abstract:
1. The mechanisms of the liver damage produced by three glutathione (GSH)-depleting agents, bromobenzene, allyl alcohol and diethyl maleate, were investigated. 2. With each toxin liver necrosis was accompanied by lipid peroxidation that developed only after severe depletion of GSH. 3. Changes in antioxidant systems by alpha-tocopherol (vitamin E) and ascorbic acid were studied. A decrease in the hepatic level of vitamin E, and a change in the redox state of vitamin C (increase in oxidized over reduced form) were evident whenever extensive lipid peroxidation developed. However, in the case of bromobenzene intoxication these alterations preceded lipid peroxidation, and may be an index of oxidative stress leading to subsequent membrane damage. 4. Experiments carried out with vitamin E-deficient or supplemented diets indicated that pathological phenomena occurring as a consequence of GSH depletion depend on hepatic levels of vitamin E. In vitamin E-deficient animals, lipid peroxidation and liver necrosis appeared earlier than in animals fed the control diet. In animals fed a vitamin E-supplemented diet, bromobenzene and allyl alcohol had only limited toxicity, and diethyl maleate none, in spite of similar hepatic GSH depletion. Thus, vitamin E may largely modulate the expression of toxicity by GSH-depleting agents.
Insights
Glutathione depletion causes liver damage, with vitamin E significantly influencing toxicity. Supplementing vitamin E reduces liver damage from these agents, highlighting its protective role against oxidative stress.
Area of Science:
- Hepatology
- Toxicology
- Biochemistry
Background:
- Hepatotoxicity can result from glutathione (GSH) depletion.
- Antioxidants like vitamin E and vitamin C play roles in cellular protection.
- Understanding the interplay between GSH depletion and antioxidant status is crucial for liver health.
Purpose of the Study:
- To investigate the mechanisms of liver damage induced by GSH-depleting agents.
- To elucidate the role of vitamin E and vitamin C in mediating or protecting against this damage.
- To determine if hepatic vitamin E levels modulate the toxicity of GSH-depleting agents.
Main Methods:
- Investigated liver damage from bromobenzene, allyl alcohol, and diethyl maleate.
- Monitored hepatic glutathione (GSH) levels and lipid peroxidation.
- Assessed changes in hepatic vitamin E and ascorbic acid (vitamin C) redox state.
- Utilized vitamin E-deficient, control, and supplemented diets in animal models.
Main Results:
- Liver necrosis correlated with lipid peroxidation, occurring after severe GSH depletion.
- Vitamin E levels decreased and vitamin C became more oxidized during lipid peroxidation.
- In bromobenzene intoxication, these antioxidant changes preceded lipid peroxidation.
- Vitamin E deficiency exacerbated liver damage, while vitamin E supplementation reduced toxicity.
Conclusions:
- Vitamin E levels significantly modulate the toxicity of GSH-depleting agents.
- Vitamin E plays a critical protective role against oxidative stress and subsequent liver damage.
- Antioxidant status, particularly vitamin E, is a key determinant in the expression of hepatotoxicity.