<scp>l</scp>‐Buthionine (<i>S,R</i>) Sulfoximine Depletes Hepatic Glutathione But Protects Against Ethanol‐Induced Liver Injury

Donohue, Terrence M.; Curry-McCoy, Tiana V.; Todero, Sandra L.; White, Ronda L.; Kharbanda, Kusum K.; Nanji, Amin A.; Osna, Natalia A.

doi:10.1111/j.1530-0277.2007.00393.x

Cited by 28 publications

(39 citation statements)

References 26 publications

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“…Besides inhibiting GCL, BSO accelerates Cyp2e1-dependent metabolism (8). Cyp2e1 oxidizes acetaminophen to its active metabolite, N-acetyl-p-benzoquinoneimine, which is cytotoxic due to DNA and protein adduct formation.…”

Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1

Taguchi

Maher²,

Suzuki³

et al. 2010

Molecular and Cellular Biology

199

195

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Keap1 regulates Nrf2 activity in response to xenobiotic and oxidative stresses. Nrf2 is an essential regulator of cytoprotective genes. Keap1-null mice are lethal by weaning age due to malnutrition caused by severe hyperkeratosis of the upper digestive tract. Analysis of Keap1::Nrf2 double mutant mice revealed that currently recognizable phenotypes of Keap1-null mice are all attributable to constitutive activation of Nrf2. We previously reported that hepatocyte-specific Keap1 knockout (Keap1 flox/؊ ::Albumin-Cre) mice are viable and more resistant to acute toxicity of acetaminophen (APAP). In the current study, we found that the floxed Keap1 allele is hypomorphic and that Keap1 expression was decreased in all examined tissues of Keap1 flox/؊ mice. Taking advantage of the hypomorphic phenotype of Keap1 flox/؊ mice, we examined the effects of graded reduction of Keap1 expression in adult mice. When challenged with APAP, Keap1 flox/؊ mice were more protected from mortality than wild-type and even Keap1 flox/؊ ::Albumin-Cre mice. In contrast, a decrease in Keap1 levels to less than 50% resulted in increased mortality in a study of 2-year-old mice. These results support our contention that the benefits of Nrf2 activation in acute toxicity are hormetic and that constitutive Nrf2 activation beyond a certain threshold is rather disadvantageous to long-term survival.

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Section: Discussionmentioning

confidence: 99%

Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1

Taguchi

Maher²,

Suzuki³

et al. 2010

Molecular and Cellular Biology

199

195

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“…Animal experiments have revealed that proteasome activity declines in animals that have higher (i.e. > 40 mmol/L) serum ethanol concentrations [40] . The lysosomal system, on the other hand, appears to be impaired by lower serum ethanol levels, as recently reported in livers of female ethanol-fed rats [41] .…”

Section: Suppression Of Autophagymentioning

confidence: 99%

Autophagy and ethanol-induced liver injury

Donohue¹

2009

WJG

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The majority of ethanol metabolism occurs in the liver. Consequently, this organ sustains the greatest damage from ethanol abuse. Ethanol consumption disturbs the delicate balance of protein homeostasis in the liver, causing intracellular protein accumulation due to a disruption of hepatic protein catabolism. Evidence indicates that ethanol or its metabolism impairs trafficking events in the liver, including the process of macroautophagy, which is the engulfment and degradation of cytoplasmic constituents by the lysosomal system. Autophagy is an essential, ongoing cellular process that is highly regulated by nutrients, endocrine factors and signaling pathways. A great number of the genes and gene products that govern the autophagic response have been characterized and the major metabolic and signaling pathways that activate or suppress autophagy have been identified. This review describes the process of autophagy, its regulation and the possible mechanisms by which ethanol disrupts the process of autophagic degradation. The implications of autophagic suppression are discussed in relation to the pathogenesis of alcohol-induced liver injury.

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“…Both serum ethanol levels (11 mg ⁄ dl in wild type and 36 mg ⁄ dl in SOD null) were well below the legally intoxicating level (80 mg ⁄ dl) in humans. This was largely because the highest level of ethanol in the diet was about 32% lower than that given to mice in a previous study (Donohue et al, 2007b). Ethanol administration caused a 3-to 3.5-fold increase in serum ALT levels in SOD ) ⁄ ) mice compared with their pair-fed controls and with wild-type ethanol-fed mice (Fig.…”

Section: Indicators Of Intoxication Ethanol Metabolism and Liver Damentioning

confidence: 75%

“…In this study, the final concentration of total ethanol calories was 20%. This was less than the 29.2.% we previously gave to ethanol-fed C57B1 ⁄ 6 mice (Donohue et al, 2007b) because we anticipated that SOD null mice would have enhanced sensitivity to oxidative stress, as reported previously (Kessova and Cederbaum, 2007) and we wanted to avoid mortality in these animals. We anticipated that, compared with wild-type animals, ethanol feeding, which itself enhances oxidative stress in wild-type animals would exacerbate hepatic protein modification, cause a rise in lysosomal leakage, and decrease proteasome activity in SOD null mice, even at the rather low levels of dietary ethanol used here.…”

Section: Discussionmentioning

confidence: 91%

“…The latter was demonstrated by the absence of a significant rise in lipid peroxides and no other prominent signs of hepatotoxicity in these animals. Ethanol consumption normally causes oxidative damage, even in animals equipped to neutralize oxidants (Donohue et al, 2007b). Thus, it is likely that the absence of these changes in wild-type mice was due to the lower ethanol concentration in the diet (graded doses from 5 to 20%, compared with the usual 29.2% of total calories) combined with the relatively short duration (24 days) of chronic ethanol feeding.…”

Section: Discussionmentioning

confidence: 99%

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Chronic Ethanol Consumption Results in Atypical Liver Injury in Copper/Zinc Superoxide Dismutase Deficient Mice

Curry-McCoy

Osna

Nanji

et al. 2010

Alcoholism Clin & Exp Res

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Ethanol-fed SOD(-/-) mice exhibited lower alcohol dehydrogenase activity and lack of CYP2E1 inducibility, thereby causing decreased ethanol metabolism compared with wild-type mice. These and other atypical responses to ethanol, including the absence of ethanol-induced steatosis and enhanced glutathione levels, appear to be linked to enhanced oxidative stress due to lack of antioxidant enzyme capacity.

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l‐Buthionine (S,R) Sulfoximine Depletes Hepatic Glutathione But Protects Against Ethanol‐Induced Liver Injury

Cited by 28 publications

References 26 publications

Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1

Genetic Analysis of Cytoprotective Functions Supported by Graded Expression of Keap1

Autophagy and ethanol-induced liver injury

Chronic Ethanol Consumption Results in Atypical Liver Injury in Copper/Zinc Superoxide Dismutase Deficient Mice

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