Elsevier

Life Sciences

Volume 81, Issue 3, 27 June 2007, Pages 177-187
Life Sciences

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Alcohol-induced oxidative stress

https://doi.org/10.1016/j.lfs.2007.05.005Get rights and content

Abstract

Alcohol-induced oxidative stress is linked to the metabolism of ethanol involving both microsomal and mitochondrial systems. Ethanol metabolism is directly involved in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These form an environment favourable to oxidative stress. Ethanol treatment results in the depletion of GSH levels and decreases antioxidant activity. It elevates malondialdehyde (MDA), hydroxyethyl radical (HER), and hydroxynonenal (HNE) protein adducts. These cause the modification of all biological structures and consequently result in serious malfunction of cells and tissues.

Introduction

Oxygen is indispensable to mammalian life. By four-electron transfer, oxygen is reduced to water and the energy liberated is stored as chemical energy. Yet reduction of the ubiquitous oxygen can be incomplete and reactive oxygen species (ROS) are generated. Both reactive oxygen as well as nitrogen species (ROS/RNS) have dual actions from a biological point of view. On the one hand, they present a major problem by oxidizing important structures and macromolecules in the cells and on the other hand, they act as a part of defence and signaling mechanisms (Poulsen et al., 2000).

In 1894 Henry John Horstman Fenton, a British chemist, reported that the combination of FeSO4 and H2O2 causes the oxidation of tartaric acid, giving a violet colour on the addition of caustic alkali. We now know that reactive oxygen species (ROS) and reactive nitrogen species (RNS) are implicated in various physiological processes, as well as in different pathological events such as DNA mutations, carcinogenesis, aging, atherosclerosis, radiation damage, inflammation, ischemia-reperfusion injury, diabetes mellitus, neurodegenerative diseases, and toxic injuries, including acute and chronic alcohol toxicity. A role of free radicals in the development of alcoholic liver damage has been suspected since the early 1960's (Albano, 2002).

Ethanol being soluble both in water and lipids can diffuse rapidly through the mucous membrane of the oesophagous and stomach. After its absorption ethanol appears in both expired air and in urine. It is not stored in the body, as whatever is ingested is oxidized. It is metabolized entirely in the liver (Antia and Abraham, 1997, Eastwood and Passmore, 1986).

Section snippets

Ethanol metabolism

Alcohol-induced oxidative stress is linked to the metabolism of ethanol. Three metabolic pathways of ethanol have so far been described in the human body, which involve the following enzymes: alcohol dehydrogenase, microsomal ethanol oxidation system (MEOS) and catalase. Each of these pathways could produce free radicals that affect the antioxidant system. The classical pathway of ethanol metabolism, which is catalysed by alcohol dehydrogenase to form acetaldehyde results in the formation of

Role of mitochondria

One of the earliest effects of ethanol consumption on the liver is a change in the structure of mitochondria. The mitochondria are often enlarged and distorted, appearing either as swollen or elongated structures, with the cristae often disrupted or without normal organization (Kiessling and Tobe, 1964). In the rat model, these structural changes in the mitochondria are accompanied by the development of fatty liver (Rubin et al., 1972), suggesting the possibility that hepatic energy metabolism

Role of Kupffer cells

Both microsomal and mitochondrial systems are known to involve oxidative stress. The stimulation of Kupffer cells causes cytokines and chemokines release, hepatocyte hyper-metabolism and activation of hepatic stellate cell (Crabb, 1999). Kupffer cell activation by endotoxin is involved in alcohol-induced liver injury. Ethanol causes tolerance in the early phase after its consumption, while sensitization is observed later. Both tolerance and sensitization are induced by gut-derived endotoxin.

Cytochrome (CYP 2E1)

Ethanol induces the CYP2E1 form of cytochrome P450 enzyme, which metabolizes and activates many toxicological substrates, including ethanol, to more toxic products. Ethanol ingestion causes an increase in free radical generation in the liver by induction of microsomal cytochrome P-450, conversion of xanthine dehydrogenase into xanthine oxidase in cytosol and increases one electron reduction in mitochondria (Skrzydlewska et al., 2002, Bai and Cederbaum, 2006). Levels of CYP2E1 are elevated under

Reactive oxygen species

Reactive oxygen species (ROS) are small, highly reactive, oxygen-containing molecules that can react with and damage complex cellular molecules, particularly in the liver (Wu and Cederbaum, 2003). Ethanol metabolism is directly involved in not only the production of reactive oxygen species (ROS), but also related in the formation of an environment favourable to oxidative stress such as hypoxia, endotoxaemia and cytokine release (Sergent et al., 2001). Further, alcohol can alter the levels of

Reduced glutathione (GSH)

Reduced glutathione (GSH) is a critical cellular antioxidant, and is important in limiting the toxicity of ethanol as well as many other toxic chemicals. Removal of GSH causes a loss of viability in the CYP2E1-expressing cells. This is associated with mitochondrial damage and a decrease in mitochondrial membrane potential. Surprisingly, CYP2E1-expressing cells elevate GSH levels, due to the transcriptional activation of glutamate cysteine ligase. CYP2E1-dependent oxidative stress, mitochondrial

Lipid metabolism

Levels of free fatty acids and fatty acid ethyl esters are elevated in liver, kidney, brain, and heart of rats treated with ethanol. These are the possible mediators in the production of alcohol dependent syndromes (Calabrese et al., 1995). Fatty acid ethyl esters are non-oxidative products of ethanol metabolism. Fatty acid ethyl esters bind with lipoproteins and albumin in human plasma and are carried to the different parts of the body where they induce organ damage (Bird et al., 1997).

Effects on proteins

Thiol-containing proteins appear to be targets of free radicals. Damage to cellular proteins occurs with chronic ethanol intake (Abraham et al., 2002). Oxidative modification of hepatic mitochondrial protein thiols due to chronic alcohol consumption leads to altered thiol redox status. This in turn compromises the mitochondrial membrane polarization, which is essential for ATP synthesis by mitochondria.

Chronic ethanol feeding significantly increased both cytosolic and mitochondrial

Hydroxyethyl radical

Administration of ethanol elicits the generation of the 1-hydroxyethyl radical. Its reactivity contributes to alcohol-induced immunological disturbances (Nordmann and Rouach, 1996). Two of the most abundant aldehydes formed during chronic ethanol consumption are malondialdehyde and acetaldehyde. They can react synergistically with proteins to generate a new hybrid adduct, called malondialdehyde-acetaldehyde protein adduct (MAAs) (Tuma et al., 2001, Xu et al., 1997). These MAA-modified proteins

Nitric oxide

Nitric oxide (NO) production may play a dual role, mediating protective effects at lower concentrations and tissue damage by over production. It acts as an important mediator of the vascular tone and neuronal transduction, and has cytotoxic effects. Stable metabolites–nitrites and nitrates–are increased in alcoholics (Zima et al., 2001). Formation of NO has been linked to an increased tolerance to alcohol (Zima et al., 2001). NO is synthesized from the amino acid arginine by a five electron

Superoxide dismutase

There are many enzymes in vivo that can potentially produce O2•− radicals, including xanthine oxidase (McCord and Fridovich, 1968), NADPH oxidases (Badwey and Karnovsky, 1980) and CYP2E1 (Knecht et al., 1993). Mitochondrial antioxidant enzyme, manganese superoxide dismutase (Mn-SOD) is induced consistently in experimental animals after acute and chronic ethanol administration (Koch et al., 2004). Chronic ethanol feeding caused an up-regulation of the enzyme at the mRNA level, which seems to be

Oxidant–antioxidant system biomarker

Oxidative stress can be observed in heavy drinkers without severe liver disease (Trotti et al., 2001). The stimulation of hepatic cytochrome P-450 monooxygenase activity was accompanied by enhanced microsomal malondialdehyde formation and a decreased level of the antioxidant, α-tocopherol. Thus, the level of malondialdehyde and α-tocopherol in the serum may be recommended as biological markers of ethanol-provoked oxidative stress (Das et al., 2003, Wisniewska-Knypl and Wronska-Nofer, 1994). The

Conclusion

The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders. Ethanol per se, hyperlactacidemia and elevated NADH increase xanthine oxidase activity, which results in the production of superoxide. Lipid peroxidation and superoxide production correlate with the amount of cytochrome P450 2E1 (Mantle and Preedy, 1999, Zima et al., 2001). The induction of CYP 2E1 in the microsomes results in the generation of hydroxyethyl

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