No abstract

An overt increased liver lipid peroxidation associated with Liver lipid peroxidation, nonheme iron, antioxidants, alcohol-dependent liver disease 4,5 had been described in the and protein oxidation were investigated in experimental intragastric rat feeding model. The high blood alcohol levels alcohol-induced liver disease in the rat. Wistar male rats achieved in this model as well as the rich unsaturated fat were intragastrically and continuously infused for 4 diet appear important in determining the susceptibility to weeks with a high-fat diet plus an ethanol or an isocafree-radical-related reactions and to alcohol-dependent liver loric amount of dextrose, maintaining a high blood alcodisease. 6-8 However, membranous lipids are not the sole tarhol level (200-300 mg%). This model induced fatty liver, gets of an ethanol-induced oxidative stress in the liver. It is spotty necrosis, and focal inflammation. This pathology well documented that cellular proteins may also be disturbed was associated with an enhanced lipid peroxidation and by free radicals. Remmer et al. 9 reported that the primary a decrease in the major antioxidant factors. Hepatic atarget of the oxygen-radical attack promoted by ethanol is tocopherol and glutathione concentrations were signifirepresented by cellular proteins and not by lipids. Key metacantly decreased in ethanol-fed rats. Glutathione peroxibolic enzymes may be involved among the proteins damaged dase (GPx) was also decreased, whereas glutathione by free-radical attack. Fucci et al. 10 showed that microsomal S-transferase (GST) was unaffected. The nonheme iron mixed function oxidation reactions involving cytochrome level was significantly decreased. Protein oxidation was P450 inactivate 10 enzymes playing a key role in metabolism. assessed through three parameters: protein thiols, proAmong these enzymes, glutamine synthetase (GS) is a key tein carbonyl groups, and the activity of glutamine synenzyme in nitrogen metabolism and is highly sensitive to thetase (GS), a centrilobular enzyme particularly susfree-radical attack. Its exclusive localization in the periveceptible to free-radical-mediated damage. Ethanol-fed nous area of the liver lobule 11 could favor its oxidative modifirats had decreased protein thiol concentrations and recation through reactive oxygen species generated by CYP duced GS activity, together with increased protein car-2E1, which is markedly induced in the perivenous cells by bonyls. A significant correlation between GS activity ethanol treatment in the intragastric feeding model.12 and the pathological score was observed. This study conThe present study was undertaken to determine the ethafirms the ethanol-related increase in lipid peroxidation nol effects on lipid peroxidation and on some cellular antioxiand shows that ethanol impairs the hepatic antioxidant dants represented by a-tocopherol, a main chain-breaking potential. Furthermore, evidence of oxidative protein membranous antioxidant, as well as by glutathione and gludamage is given, including decreased a...

An ethanol-induced oxidative stress is not restricted to the liver, where ethanol is actively oxidized, but can affect various extrahepatic tissues as shown by experimental data obtained in the rat during acute or chronic ethanol intoxication. Most of these data concern the central nervous system, the heart and the testes. An acute ethanol load has been reported to enhance lipid peroxidation in the cerebellum. This is accompanied by an increase in the cytosolic concentration of low-molecular-weight iron derivatives which may contribute to the generation of aggressive free radicals. The ethanol-induced decrease in the main antioxidant systems (superoxide dismutase, alpha-tocopherol, ascorbate and selenium) is a likely contributor to the cerebellar oxidative stress. Most of these disturbances can be prevented by allopurinol administration. Some experimental data support also the occurrence of pro- and anti-oxidant disturbances in the cerebellum and in other regions of the central nervous system after chronic ethanol administration. Chronic ethanol administration enhances lipid peroxidation in the heart. The increased conversion of xanthine dehydrogenase into xanthine oxidase as well as the activation of peroxisomal acyl CoA-oxidase linked to ethanol administration could contribute to the oxidative stress. Chronic ethanol administration elicits in the testes an enhancement in mitochondrial lipid peroxidation and a decrease in the glutathione level, which appear to be correlated to the gross testicular atrophy observed. Vitamin A supplementation attenuates the changes in lipid peroxidation, glutathione and testicular morphology. Whether the reported disturbances are involved in the pathogenesis of the tissue disorders observed in alcoholic patients remains unanswered.(ABSTRACT TRUNCATED AT 250 WORDS)

To elucidate the mechanisms through which 2-mercaptoacetate administration inhibits fatty acid oxidation in the liver, the respiration rates induced by different substrates were studied polarographically in rat hepatic mitochondria isolated 3 h after 2-mercaptoacetate administration. Palmitoyl-L-carnitine oxidation was almost completely inhibited in either the absence or presence of malonate. Octanoate oxidation was also inhibited, and the intramitochondrial acyl-CoA content was markedly increased. The oxidation rate of pyruvate and 2-oxoglutarate on the one hand and of 3-hydroxybutyrate, succinate and glutamate on the other was either normal or only slightly decreased. In the presence of 2,4-dinitrophenol, the extent of the inhibition of palmitoyl-L-carnitine oxidation was unchanged. All these results are consistent with the hypothesis that the 2-mercaptoacetate inhibition of fatty acid oxidation is due to an inhibition of the beta-oxidation pathway itself. Finally, the mitochondrial defect responsible for this inhibition was shown to be an inhibition of palmitoyl-CoA dehydrogenase activity (EC 1.3.99.3).