ABSTRACT
Cytotoxicity induced by xenobiotics and hormonal changes is a complex event, comprising primary and secondary mechanisms whose joint operation may lead to irreversible molecular changes associated with cell death. In this respect, alcoholic liver cell necrosis may be conditioned either by the generation of ethanol-derived acetaldehyde leading to covalent binding to biomolecules and derangement of key metabolic functions, the production of hypoxic damage secondary to elevated O2 uptake, impairment of membrane functions upon reduction in membrane fluidity, and/or by the development of oxidative stress. The latter mechanism is involved in the hepatotoxic effects of lindane, involving both early direct actions related to the biotransformation of the insecticide and late adaptive changes derived from cytochrome P-450 induction. Thyroid calorigenesis involving an accelerated rate of O2 consumption in the liver determines an increased oxidative stress status due to higher rates of O2 and/or H2O2 production by microsomal, mitochondrial, and peroxisomal electron transport systems, with diminished antioxidant defenses. Hyperthyroidism-induced liver oxidative stress may be associated with cell injury, altered hepatic functions, and potentiation of toxicity by xenobiotics. Liver oxidative stress may be secondarily exacerbated by neutrophil infiltration and/or alterations in Kupffer cell function. These phagocytes release chemical mediators and respiratory burst-related reactive O2 species upon stimulation in the liver, which are potentially toxic for parenchymal cells. As the different factors underlying oxidative stress and the interrelationships between oxidative stress and other cytotoxic mechanisms become better defined preventive and protective interventions will become more clear.