Ethanol stimulates the production of reactive oxygen species at mitochondrial complexes I and III

Bailey, Shannon M.; Pietsch, Emma; Cunningham, Carol C.

doi:10.1016/s0891-5849(99)00138-0

Cited by 198 publications

(142 citation statements)

References 33 publications

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“…Examples include valproic acid [33], amiodarone [34][35][36], Wilson's disease [8], Alpers' syndrome [37] and (to some extent) alcohol [7]. These too have similarly pleiomorphic potential, extending from acute hepatitis to cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

“…It has been described in non-alcoholic steatohepatitis (NASH) [5,6], alcoholic liver disease [7,8] and Wilson's disease [9] to name just a few, but its role in drug-induced liver injury has generally been overlooked (except when accompanied by severe microvesicular steatosis). A recent retrospective study of druginduced liver fatalities was performed using the WHO database [1].…”

Section: The Role Of Mitochondrial Dysfunctionmentioning

confidence: 99%

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Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Julie

Kende

et al. 2008

Diabetologia

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Section: Discussionmentioning

confidence: 99%

Section: The Role Of Mitochondrial Dysfunctionmentioning

confidence: 99%

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Julie

Kende

et al. 2008

Diabetologia

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“…55 Long-term ethanol treatment enhances mitochondrial ROS production, causing leakage between complex I and III of the electron transport chain. 12 Long-term ethanol consumption also affects mitochondrial oxidative phosphorylation in the liver and suppresses the synthesis of certain subunits of the respiratory complexes. 56 Decreased levels of ATP as a result of a low rate of ATP synthesis have been observed in animals fed ethanol on a long-term basis.…”

Section: Discussionmentioning

confidence: 99%

Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase

et al. 2003

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Because alcoholic liver disease has been linked to oxidative stress, we investigated the effect of a compromised antioxidant defense system, Cu, Zn-superoxide dismutase (Sod1) deficiency, on alcohol-induced liver injury. C57BL/129SV wild-type (Sod1 ؉/؉ ) and Sod1 knockout (Sod1 ؊/؊ ) mice were fed dextrose or ethanol (10% of total calories) liquid diets for 3 weeks. Histologic evaluation of liver specimens of Sod1 ؊/؊ mice fed ethanol showed the development of liver injury ranging from mild to extensive centrilobular necrosis and inflammation. Sod1 ؉/؉ mice fed ethanol showed mild steatosis; both Sod1 ؉/؉ and Sod1 ؊/؊ mice fed the dextrose diet had normal histology. Alanine transaminase levels were significantly elevated only in Sod1 ؊/؊ mice fed ethanol. Cytochrome P450 2E1 (CYP2e1) activity was elevated about 2-fold by ethanol in Sod1 ؉/؉ and Sod1 ؊/؊ mice. Ethanol consumption increased levels of protein carbonyls and lipid peroxidation aldehydic products in the liver of Sod1 ؊/؊ mice. Hepatic adenosine triphosphate (ATP) content was reduced dramatically in Sod1 ؊/؊ mice fed ethanol in association with a decrease in the mitochondrial reduced glutathione (GSH) level and activity of MnSOD. Immunohistochemical determination of 3-nitrotyrosine (3NT) residues in liver sections of the Sod1 knockout mice treated with ethanol showed a significant increase of 3NT staining in the centrilobular areas. In conclusion, a rather moderate ethanol consumption promoted oxidative stress in Sod1 ؊/؊ mice, with increased formation of peroxynitrite, protein carbonyls, and lipid peroxidation and decreased mitochondrial GSH and MnSOD. We speculate that the increased oxidative stress causes mitochondrial damage and reduction of ATP content, leading to alcoholic liver injury. This model may be useful in further mechanistic studies on alcohol-induced liver injury. (HEPATOLOGY 2003;38:1136-1145

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“…7 The major sites of ROS formation in the electron transport chain are the NADH dehydrogenase complex and the cytochrome bc1 complex. 16,17 The rate of ROS formation increases with higher Δp and, therefore, it depends on the respiratory conditions, notably on the substrate and O 2 supply and the electron transport rate. 12 Conditions that increase the supply of mitochondrial NAD(P)H and enhance the reducing pressure on the electron transport chain without increasing the rate of respiration promote the formation of O 2 .…”

Section: Ethanol Mitochondrial Energy Metabolism and Oxidative Stressmentioning

confidence: 99%

Alcohol and mitochondria: A dysfunctional relationship

2002

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Mitochondria are intimately involved in the generation of and defense against reactive oxygen species (ROS). Mitochondria are themselves targets of oxidative stress and also contribute to mechanisms by which oxidative stress-related signals control cell fate. Ethanol promotes oxidative stress, both by increasing ROS formation and by decreasing cellular defense mechanisms. These effects of ethanol are prominent in the liver, the major site of ethanol metabolism in the body. The question remains to what extent this contributes to ethanol-dependent tissue damage or the susceptibility of cells to other stressors. In this review, we consider how mitochondrial actions of ethanol influence oxidative stress management of liver cells. Mitochondrial electron transport constitutes the major intracellular source of ROS, and ethanol treatment imposes conditions that promote ROS formation by mitochondria, the effects of which may be enhanced by a decrease in mitochondrial oxidative stress defenses. A significant target of ethanol-related increases in oxidative stress is mitochondrial DNA. Ethanol-induced damage to mitochondrial DNA, if not adequately repaired, impairs mitochondrial function, which further increases oxidative stress in the cell, leading to a vicious cycle of accumulating cell damage that is more apparent with advancing age. Uncontrolled mitochondrial formation of ROS promotes the inappropriate activation of the mitochondrial permeability transition, increasing the sensitivity of cells to other proapoptotic or damage signals. In combination with ethanol-induced defects in mitochondrial function, these alterations may promote both apoptotic and necrotic cell death in response to otherwise benign or beneficial challenges and contribute to the onset or progression of alcohol-induced liver diseases.Chronic excessive alcohol consumption causes injury to the liver and other tissues, but, despite intensive study, the factors that relate ethanol intake to the onset and progression of liver disease remain controversial. There is considerable evidence from both human and animal studies that alcohol consumption enhances oxidative stress, in liver as well as in other tissues. However, opinions are divided as to why oxidative stress develops, how it affects liver function, and what its relevance is for liver pathology. 1-6 Mitochondria are recognized as the major intracellular source of reactive oxygen species (ROS), which is generated as a by-product of their major metabolic activity of cellular respiration. 7 Mitochondrial constituents are themselves targets of ROS, and the mitochondrial management of oxidative stress has consequences both for cellular energy metabolism and for the processes that control the onset and progression of the cell death response, whether it results in apoptosis or necrosis. Hence, an understanding of how these complementary functions of mitochondria are affected by alcohol consumption may provide important insights into the mechanisms associated with liver damage. In this review, we wil...

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Ethanol stimulates the production of reactive oxygen species at mitochondrial complexes I and III

Cited by 198 publications

References 33 publications

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone

Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase

Alcohol and mitochondria: A dysfunctional relationship

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