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A significant decrease in myocardial creatine kinase (CK) activity is apparent 2 hr after an acute ethanol load (2.3 g/kg, i.p.) in the rat. A lower dose (1.15 g/kg, i.p.), as well as ethanol addition in vitro up to 50 mM, do not affect this activity. Pretreatment with allopurinol (146 mumols/kg, i.p.) given at 16 hr and at 30 min before ethanol (2.3 g/kg) or with desferrioxamine (152 mumols/kg, i.p.) 30 min before ethanol failed to prevent the ethanol-induced decrease in CK activity. By contrast, propranolol (17 mumols/kg, i.p.), administered 30 min before ethanol elicited an enhanced CK activity in both control and ethanol-treated rats. This finding is likely related to the beta-blocking action and/or antioxidant properties of propranolol. Chronic ethanol intake (18% in calories) for 4 weeks also induced a decrease in myocardial CK activity, which could play a role in the pathogenesis of alcoholic cardiomyopathy.

Lipoperoxidation, a degradative process of membranous polyunsaturated fatty acids, has been suggested to represent an important mechanism in the pathogenesis of ethanol toxicity on the liver and possibly also on the brain. Catalysis by transition metals, especially iron, is involved in the biosynthesis of free radicals contributing to lipid peroxidation. Although the exact nature of the redox-active iron implicated in this catalysis is still unknown, it has been well established that lipid peroxidation can be prevented in vitro by iron chelators such as desferrioxamine. Deprivation of redox-active iron through desferrioxamine inhibits by about 50% the microsomal oxidation of ethanol in vitro and reduces very significantly in vivo the overall ethanol elimination rate in rats. Administration of desferrioxamine together with ethanol also reduces the ethanol-induced disturbances in the antioxidant defense mechanisms of the hepatocyte. It also reduces in mice both the severity of physical dependence on ethanol and lethality following the acute administration of a narcotic dose of ethanol. Chronic overloading of rats with iron results, on the opposite, in an increased rate of ethanol elimination, although alcohol dehydrogenase and catalase activities are reduced and cytochrome P-450 depleted in the liver of such iron-overloaded animals. The magnitude of the ethanol-induced increase in lipid peroxidation and decrease in the major membranous antioxidant, alpha-tocopherol, is exacerbated in iron-overloaded rats. Several disturbances of iron metabolism have been reported in human alcoholics. Their contribution to ethanol toxicity appears very likely in the case of hepatic siderosis associated with alcohol abuse. Ethanol could however disturb iron metabolism even in the absence of gross abnormalities of the total iron stores. It is suggested that ethanol intoxication could increase cellular redox-active iron, thus contributing to an enhanced steady-state concentration of reactive-free radicals. This oxidative stress would lead to lipoperoxidative damage and cellular injury.

Crude synaptic membrane fluidity (checked by fluorescence polarization) together with (Na+ + K+) ATPase activity were examined 18 hours after a single oral ethanol administration (5 g/kg bwt.) to naive rats and to rats previously intubated with ethanol repeatedly during 4 days. The sensibility of both parameters to different concentrations of ethanol added in vitro (0.175 M-1.400 M) was also determined. Although no changes in the basal intrinsic fluidity were found, (Na+ + K+)ATPase activity increased slightly in both conditions. The fluidizing as well as the ATPase inhibiting effects following the addition of ethanol in vitro were markedly increased 18 hours after ethanol administration to naive rats. This hypersensitization was no longer apparent in rats pretreated with ethanol during 4 days. The acute ethanol-induced hypersensitization found in naive rats appears not to be related to an unspecific stress or to changes in body temperature. The disappearance of this hypersensitization in short-term alcohol-intoxicated animals may represent the first stage of tolerance acquisition.

After acute ethanol administration (2.3 g/kg) peroxisomal and extra-peroxisomal catalase activities were affected in opposite directions. As long as ethanol was present, peroxisomal catalase activity was enhanced, but unaffected by amino-triazole (AT) injection. Extra-peroxisomal catalase activity was decreased during the 24hr following ethanol administration and was also inhibited after AT injection. Whereas mitochondrial manganese-dependent superoxide dismutase (Mn-SOD) was unaffected, the cytosolic Cu,Zn-SOD activity was decreased. The time-course of this decrease suggests that acute ethanol administration affects primarily extra-peroxisomal catalase activity, thus rendering cytosolic superoxide dismutase more exposed to oxygen derivatives.

When studied at different times following ethanol intubation, the effects of pyrazole, administered to rats prior to ethanol, affects differently the alcohol-induced disturbances in hepatic [1-14C] palmitate oxidation. This peculiar time-course of the pyrazole induced effects supports the relationship between active ethanol oxidation and inhibition of hepatic fatty acid oxidation, but also emphasizes the caution which must be taken when using pyrazole to study "in vivo" the mechanisms involved in the alcohol induced fatty liver.

In starved rats, ethanol administered acutely enhances tryptophan oxygenase (TO) and tyrosine aminotransferase (TAT) activities. Ethanol also inhibits the early phase of the cortisol-mediated TO and TAT induction. Ethanol administered at the same time as tryptophan does not modify the tryptophan-mediated TO and TAT induction. In cortisol-pretreated rats, ethanol enhances the subsequent TO and TAT induction whereas no additive effects are observed when ethanol is injected together with tryptophan. These results suggest that ethanol mimics the effects of tryptophan on TO and TAT activities. In fed animals, ethanol alone does not result in increased TO and TAT activities, but inhibits their cortisol induction. It increases TO activities when given together with a tryptophan dose which, when given alone, does not enhance these activities. It is suggested that the observed inhibitory effects of ethanol on cortisol-mediated TO and TAT induction in starved and fed animals are related to a defective cortisol transport in the liver cells.

Manganese superoxide dismutase (Mn-SOD) studied during ethanol vapor inhalation shows no changes during the inhalation period (4 days) and a transient increase 12 hours after ethanol withdrawal. A significant decrease in cytosolic Cu-Zn-SOD is found at the end of the inhalation period and was sustained during 48 hours following ethanol withdrawal. It is suggested that this decrease in Cu-Zn-SOD activity might be related to an inactivation of the enzyme linked to the increase in hydroxyl radical production related to ethanol metabolism. Cytosolic catalase is reduced at the end of the ethanol inhalation period. This decrease could be related to an enhanced superoxide radical concentration linked to the reduced Cu-Zn-SOD activity.

Two hours after an acute ethanol load (50 mmol/kg, i.p.), brain mitochondrial superoxide production was unchanged. This is contrary to our previous findings concerning liver mitochondria. On the other hand, the ethanol treatment caused a marked inhibition of respiration stimulated by phosphate plus ADP (with succinate or pyruvate plus malate as substrates) (state 3) in the brain mitochondria, whereas it did not exert any modification on the hepatic mitochondrial electron transport chain.