Cytoprotection the second major determinant of toxic potential

The progression to cell damage after the production of primary or secondary cyto-toxic mediators is not inevitable, nor is it irreversible. A battery of chemical and enzymic cytoprotectants prevails within the liver. These cytoprotectants combat the endogenous production of potential cytotoxins (such as reactive oxygen species [ROS] and cytokines) and reverse their adverse effects (by the repair of oxidized proteins, damaged membranes and methylated DNA). The cytoprotectants include the antioxidant vitamins A, C and D, reduced glutathione (GSH) and numerous chemicals, proteins and enzymes with complementary functions in maintaining redox status with its normal reductive bias. Particularly important are the enzymes detoxifying ROS, e.g. superoxide dismutase, catalase and the glutathione-depen-dent enzymes. The latter include glutathione peroxidase, which reduces hydrogen peroxide in mitochondria where catalase is absent, and the glutathione transferases which catalyse the detoxication of electrophiles with GSH. Within normal liver, the activity of these multiple, interacting, cytoprotective pathways retains a bias towards continued cellular homeostasis. This prevails despite the deleterious influence of dietary restrictions and minor bacterial/viral infections, and the customary presence of toxic insults of short-term duration and/or mild severity (e.g. ROS produced in mitochondria, peroxisomes and the endoplasmic reticulum, and by activated Kupffer cells). However, the balance will tip towards liver damage if the impairment of cytoprotection is severe and the load of intoxicants exceeds cyto-protective capacity in either the short or long term. Clearly, multiple defects in the cytoprotective armoury coupled with a tendency to an excessive toxin production (or secondary response) will predispose individuals to damage. Genetic variants recognized in detoxication pathways are being increasingly associated with such predisposition.

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