Chronic Ethanol Consumption Alters the Glutathione/Glutathione Peroxidase‐1 System and Protein Oxidation Status in Rat Liver

Bailey, Shannon M.; Patel, Vinood B.; Young, Tracey; Asayama, Kohtaro; Cunningham, Carol C.

doi:10.1111/j.1530-0277.2001.tb02273.x

Cited by 151 publications

(67 citation statements)

References 56 publications

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“…34,35 The observed decreased GSH/GSSG ratio 15 is consistent with increased activity of glutathione reductase. 36 Because glutathione reductase is also a flavoprotein, 37 its presumed increased activity would predictably decrease the availability of FAD and NADPH for the MTHFR reaction. Furthermore, SAM is required to stabilize the binding of FAD to the active site of MTHFR.…”

Section: Discussionmentioning

confidence: 99%

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Villanueva

Halsted

2004

Hepatology

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Alcoholic liver disease is associated with abnormal hepatic methionine metabolism, including increased levels of homocysteine and S-adenosylhomocysteine (SAH) and reduced levels of Sadenosylmethionine (SAM) and glutathione (GSH). The concept that abnormal methionine metabolism is involved in the pathogenesis of alcoholic liver disease was strengthened by our previous findings in a micropig model where combining dietary folate deficiency with chronic ethanol feeding produced maximal changes in these metabolites together with early onset of microscopic steatohepatitis and an eightfold increase in plasma aspartate aminotransferase. The goal of the present study was to determine potential mechanisms for abnormal levels of these methionine metabolites by analyzing the transcripts and activities of transmethylation enzymes in the livers of the same micropigs. Ethanol feeding or folate deficiency, separately or in combination, decreased transcript levels of methylenetetrahydrofolate reductase (MTHFR), methionine adenosyltransferase (MAT1A), glycine-N-methyltransferase (GNMT) and S-adenosylhomocysteine hydrolase (SAHH). Ethanol feeding alone reduced the activities of methionine synthase (MS) and MATIII and increased the activity of GNMT. Each diet, separately or in combination, decreased the activities of MTHFR and SAHH. In conclusion, the observed abnormal levels of methionine metabolites in this animal model of accelerated alcoholic liver injury can be ascribed to specific effects of ethanol with or without folate deficiency on the expressions and activities of hepatic enzymes that regulate transmethylation reactions. These novel effects on transmethylation reactions may be implicated in the pathogenesis of alcoholic liver disease. ( A bnormal hepatic methionine metabolism can result from chronic exposure to ethanol or from folate deficiency. Hyperhomocysteinemia has been described in chronic alcoholics, 1,2 and decreased liver S-adenosylmethionine (SAM) levels were found in experimental animals and cultured hepatocytes exposed to ethanol. [3][4][5][6] Folate deficiency also results in abnormal methionine metabolism, because 5-methyltetrahydrofolate (5-MTHF) is substrate for the methionine synthase (MS) reaction that converts homocysteine to methionine, the substrate for SAM (Fig. 1). Furthermore, folate deficiency is frequently associated with alcoholic liver disease, in part, because chronic exposure to ethanol reduces the intestinal transport of folic acid and increases folate excretion in the urine. [7][8][9] Previous data support the concept that changes in methionine metabolism are involved in the development of alcoholic liver disease. Studies in rats and micropigs have demonstrated MS activity is reduced during chronic ethanol exposure. 10 -13 Rats that were fed ethanol by gastric tube demonstrated decreased methionine adenosyltransferase MAT1-III activity with decreased SAM and SAM/ S-adenosylhomocysteine (SAH) ratio in association with increased DNA strand breaks. 5 A MAT1A knockout mouse model developed he...

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Section: Discussionmentioning

confidence: 99%

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Villanueva

Halsted

2004

Hepatology

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“…Importantly, it is proposed that loss of mitochondrial GSH sensitizes hepatocytes from alcohol-fed animals to TNFα induced cell death [78,79], specifically when mitochondria are "loaded" with free cholesterol [80]. In contrast, several studies have shown that mitochondrial GSH depletion may not be a consistent outcome following chronic alcohol consumption as studies have shown increased mitochondrial GSH in response to alcohol consumption [81][82][83][84]. Similarly, Cederbaum and colleagues have shown increased GSH in HepG2 cells over-expressing CYP450 2E1 due to upregulation of glutamate cysteine ligase [85].…”

Section: Mitochondria Dysfunction In Fatty Liver Diseases -Bioenergetmentioning

confidence: 99%

“…Indeed, cirrhotics possessing two copies of the low-activity, valine-SOD2 variant and high-activity, proline-GPx1 variant are protected from cancer. Furthermore, chronic alcohol consumption is known to increase SOD2 activity [130,131] and decrease mitochondria GPx1 activity [81]. Thus, an imbalance resulting in increased hydrogen peroxide formation and decreased detoxification may be a critical event for the initiation and progression of alcohol induced liver injury.…”

Section: Genetic Factors Determining the Pathobiology Of Fatty Liver mentioning

confidence: 99%

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Mantena

King

Andringa

et al. 2008

Free Radical Biology and Medicine

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388

302

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Fatty liver disease associated with chronic alcohol consumption or obesity/type 2 diabetes has emerged as a serious public health problem. Steatosis, accumulation of triglyceride in hepatocytes, is now recognized as a critical "first-hit" in the pathogenesis of liver disease. It is proposed that steatosis "primes" the liver to progress to more severe liver pathologies when individuals are exposed to subsequent metabolic and/or environmental stressors or "second-hits". Genetic risk factors can also influence the susceptibility and severity of fatty liver disease. Furthermore, oxidative stress, disrupted nitric oxide (NO) signaling, and mitochondrial dysfunctional are proposed to be key molecular events that accelerate or worsen steatosis and initiate progression to steatohepatitis and fibrosis. This review article will discuss the following topics regarding the pathobiology and molecular mechanisms responsible for fatty liver disease: 1) the "two-hit" or "multi-hit" hypothesis; 2) the role of mitochondrial bioenergetic defects and oxidant stress; 3) interplay between NO and mitochondria in fatty liver disease; 4) genetic risk factors and oxidative stress responsive genes; and 5) the feasibility of antioxidants for treatment.

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“…Alcohol and lead toxicity may lead to diseases of various nature including increases in fatty acids [29], ROS [30,31], blood pressure [32] and hepatotoxicity/liver cirrhosis [33] etc. Further studies by Bailey et al [34] suggested that the chronic ethanol related increase in hepatocyte ROS may be linked to depressed activity of H 2 O 2 scavenging enzyme glutathione peroxidase. Davies [35] and later Berlett and Stadtman [36] found that proteins may be readily oxidized by various ROS through direct oxidative attack on specific aminoacid residues and that this result in the generation of carbonyl groups and subsequent destruction of protein.…”

Section: Discussionmentioning

confidence: 99%

Garlic Oil and Vitamin E Prevent the Adverse Effects of Lead Acetate and Ethanol Separately as well as in Combination in the Drinking Water of Rats

Sajitha

Jose

Andrews

et al. 2010

Indian J Clin Biochem

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Daily feeding of drinking water containing lead acetate (160 mg/l) or 10% alcohol by volume or a combination of both to rats for a month produced certain deleterious effects through oxidative stress. Both heavy metal lead and alcohol are capable of doing such damages. The deleterious alterations observed were in the parameters of blood, serum and tissues, viz; Hb, Pb, proteins, lipids, lipid per oxidation, Vitamins C and E levels and enzyme activities of AST, ALT, and catalase. Simultaneous feeding of either of the two antioxidants garlic oil (GO) and vitamin E at equal doses of 100 mg/kg/day, to the rats counteracted the deleterious effects of the above two chemicals significantly. The maximum damage was brought about by feeding of drinking water containing both lead acetate and alcohol. The protective effects of GO and Vitamin E were not significantly different. The mechanism of actions of the Vitamin E and GO is probably due to their efficiency as detoxifying agents and antioxidants, to scavenging free radicals as well as an independent action of GO on the removal of lead salt as lead sulfide.

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Chronic Ethanol Consumption Alters the Glutathione/Glutathione Peroxidase‐1 System and Protein Oxidation Status in Rat Liver

Abstract: This study demonstrates that chronic ethanol-induced alterations in the glutathione/GSHPx-1 antioxidant system might promote oxidative modification of liver proteins, namely those of the mitochondrion, which could contribute to the adverse effects of ethanol on the liver.

Cited by 151 publications

References 56 publications

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Hepatic transmethylation reactions in micropigs with alcoholic liver disease

Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases

Garlic Oil and Vitamin E Prevent the Adverse Effects of Lead Acetate and Ethanol Separately as well as in Combination in the Drinking Water of Rats

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