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...

We previously reported that ethanol elicits an increased protein oxidation in the liver of rats receiving chronic ethanol by continuous intragastric infusion (TsukamotoFrench method). This accumulation of oxidized proteins could result from a decrease in the cytosolic proteolysis, related specifically to alkaline protease and its major components, the proteasomes. Because several studies suggest that intracellular proteolysis depends on the severity of oxidative stress, we investigated the cytosolic proteolytic activity under two chronic ethanol treatment paradigms associated with varying degrees of oxidative stress.

The N-methyl-D-aspartate receptor/nitric oxide synthase (NOS)/guanylate cyclase pathway, which plays a crucial role in synaptic plasticity in the brain, is modulated by ethanol. We studied the effect of ethanol in vitro on NOS in rat cerebellum and showed that ethanol (25-200 mM) inactivated NOS in a dose-dependent manner. This inactivation was prevented by the biopterin cofactor tetrahydrobiopterin (BH4) as well as by L-arginine, a NOS substrate, but not by NADPH. These results suggest that ethanol reduces NOS activity by modulating the conformation of the enzyme and thereby its stability, probably by interacting with the binding sites of BH4 and/or of L-arginine. Our data also suggest that inactivation of NOS may contribute to the decrease in the cGMP level, and thus may play a role in the pharmacological actions of ethanol in vivo.

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