Oxidative stress, metabolism of ethanol and alcohol-related diseases

Alcohol-induced oxidative stress is linked to the metabolism of ethanol. Th ree metabolic pathways of ethanol have been described in the human body so far. They involve the following enzymes: alcohol dehydrogenase, microsoma[ ethanol oxidation system (MEOS) and catalase. Each of these pathways could produce free radicals which affect the antioxidant system. Ethanol per se, hyperlactacidemia and elevated NADH increase xanthine oxidase activity, whi ch results in the production of superoxide. Lipid peroxidation and superoxi de production correlate with the amount of cytochrome P450 2E1. MEOS aggrav ates the oxidative stress directly as well as indirectly by impairing the d efense systems. Hydroxyethyl radicals are probably involved in the alkylati on of hepatic proteins. Nitric oxide (NO) is one of the key factors contrib uting to the vessel wall homeostasis, an important mediator of the vascular tone and neuronal transduction, and has cytotoxic effects. Stable metaboli tes - nitrites and nitrates - were increased in alcohol ics (34.3 +/- 2.6 v s. 22.7 +/- 1.2 mu mol/l, p < 0.001). High NO concentration could be discus sed for its excitotoxicity and may be linked to cytotoxicity in neurons, gl ia and myelin. Formation of NO has been linked to an increased preference f or and tolerance to alcohol in recent studies. Increased NO biosynthesis al so via inducible NO synthase (NOS, chronic stimulation) may contribute to p latelet and endothelial dysfunctions. Comparison of chronically ethanol-fed rats and controls demonstrates that exposure to ethanol causes a decrease in NADPH diaphorase activity (neuronal NOS) in neurons and fibers of the ce rebellar cortex and superior colliculus (stratum griseum superficiale and i ntermedium) in rats. These changes in the highly organized structure contri bute to the motor disturbances, which are associated with alcohol abuse. An tiphospholipid antibodies (APA) in alcoholic patients seem to reflect membr ane lesions, impairment of immunological reactivity, liver disease progress ion, and they correlate significantly with the disease severity. The low-de nsity lipoprotein (LDL) oxidation is supposed to be one of the most importa nt pathogenic mechanisms of atherogenesis, and antibodies against oxidized LDL (oxLDL) are some kind of epiphenomenon of this process. We studied IgG oxLDL and four APA (anticardiolipin, antiphosphatidylserine, antiphosphatid ylethanotamine and antiphosphatidylcholine antibodies). The IgG oxtDL (406. 4 +/- 52.5 vs. 499.9 +/- 52.5 mU/ml) was not affected in alcoholic patients , but oxLDL was higher (71.6 +/- 4.1 vs. 44.2 +/- 2.7 <mu>mol/l, p < 0.001) . The prevalence of studied APA in alcoholics with mildly affected liver fu nction was higher than in controls, but not significantly. On the contrary, changes of autoantibodies to IgG oxLDL revealed a wide range of IgG oxLDL titers in a healthy population. These parameters do not appear to be very p romising for the evaluation of the risk of atherosclerosis. Free radicals i ncrease the oxidative modification of LDL. This is one of the most importan t mechanisms, which increases cardiovascular risk in chronic alcoholic pati ents. important enzymatic antioxidant systems - superoxide dismutase and gl utathione peroxidase - are decreased in alcoholics. We did not find any cha nges of serum retinol and tocopherol concentrations in alcoholics, and bloo d and plasma selenium and copper levels were unchanged as well. Only the zi nc concentration was decreased in plasma. It could be related to the impair ment of the immune system in alcoholics. Measurement of these parameters in blood compartments does not seem to indicate a possible organ, e.g. liver deficiency. Copyright (C) 2001 National Science council. ROC and S. Karger AG. Basel.