Oxidative Stress and the Glutathione System

Mitochondrial respiration and microsomal redox reactions continuously produce reactive oxygen species within hepatocytes. Molecular oxygen⁰² usually undergoes tetravalent reduction to water (during aerobic metabolism). Small quantities of oxygen, however, undergo univalent and divalent reactions, to yield superoxide and hydrogen peroxide.^[238] Besides hepatic parenchyma, other types of cells within the liver produce reactive radicals. For example, Kupffer cells, endothelial cells, polymorphonuclear leukocytes, and macrophages, when activated, produce significant quantities of reduced oxygen species and nitro-radicals.^{[144] [239] [240] [241]}

The liver has various defense mechanisms for preserving intracellular oxidants within a safe range, below the micromolar level.^{[147] [242]} These defenses involve (1) thiol-rich peptides, such as glutathione (γ-glutamyl-cysteine-glycine); (2) micronutrients, such as vitamin E and vitamin C; (3) metal-sequestering proteins, such as ferritin; (4) enzymes for detoxifying reactive oxygen species, such as catalase and superoxide dismutase; and (5) enzymes that detoxify lipid peroxides, such as glutathione peroxidase. Of the antioxidant defenses, the single most important one is glutathione.^{[233] [243] [244] [245] [246] [247]}

Glutathione is an essential cofactor for many antioxidant pathways, including glutathione peroxidase and thiol/disulfide exchange reactions. Glutathione peroxidase detoxifies organic peroxides and free radicals and has a higher affinity for hydrogen peroxide than does catalase. Glutathione S-transferase forms conjugates between electrophilic substances and the free thiol of reduced glutathione (GSH). GSH also takes part in nonenzymatic reactions, yielding products such as oxidized glutathione (GSSG) and mixed disulfides of glutathione and protein. Hepatocytes, which are the main site of glutathione synthesis, contain high cytoplasmic concentrations of glutathione, ranging from 5 to 10 mmol/L.^[147] Mitochondria actively take up glutathione; disruption of this transport (e.g., secondary to chronic ethanol exposure) leads to mitochondrial damage.^[233]

Under normal conditions, most glutathione exists as GSH. GSH plays a critical role in preserving the redox capacity of the cell. Oxidative stresses deplete GSH, converting it to GSSG. Glutathione reductase reverses this reaction, regenerating GSH and restoring the redox state. Synthesis of NADPH, the cofactor for glutathione reductase, requires ATP. Therefore, the capacity of hepatocytes to withstand oxidative stress is dependent on hepatocellular energy production.^[243]

Adverse conditions (malnutrition, ischemia and reperfusion, toxic radical production) can rapidly exhaust glutathione substrate, making hepatocytes highly susceptible to oxidative injury. In this setting, it may be important to treat patients with thiol-rich agents, such as

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