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

Authors

  • Terrence M. Donohue Jr,

    1. Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska
    2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
    3. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska
    4. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
    5. Department of Environmental Toxicology, University of Nebraska Medical Center, Omaha, Nebraska
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  • Tiana V. Curry-McCoy,

    1. Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska
    2. Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska
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  • Sandra L. Todero,

    1. Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska
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  • Ronda L. White,

    1. Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska
    2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
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  • Kusum K. Kharbanda,

    1. Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska
    2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
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  • Amin A. Nanji,

    1. Department of Pathology and Laboratory Medicine, Dalhousie University School of Medicine, Halifax, Nova Scotia
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  • Natalia A. Osna

    1. Liver Study Unit, U.S. Department of Veterans Affairs Medical Center, University of Nebraska Medical Center, Omaha, Nebraska
    2. Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska
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  • This work was supported by Grant AA09384 from the National Institute on Alcohol Abuse and Alcoholism and by Medical Research Funds from the Department of Veterans Affairs.

Reprint requests: Terrence M. Donohue, Jr., PhD, Liver Study Unit, Omaha VA Medical Center, 4101 Woolworth Avenue, Omaha, NE 68105; E-mail: tdonohue@unmc.edu

Abstract

Background: l-Buthionine (S,R) sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and has been used as an effective means of depleting glutathione from cells and tissues. Here we investigated whether treatment with BSO enhanced ethanol-induced liver injury in mice.

Methods: Female C57Bl/6 mice were pair fed with control and ethanol-containing liquid diets in which ethanol was 29.2% of total calories. During the final 7 days of pair feeding, groups of control-fed and ethanol-fed mice were given 0, 5 or 7.6 mM BSO in the liquid diets.

Results: Compared with controls, ethanol given alone decreased total liver glutathione. This effect was exacerbated in mice given ethanol with 7.6 mM BSO, causing a 72% decline in hepatic glutathione. While ethanol alone caused no decrease in mitochondrial glutathione, inclusion of 7.6 mM BSO caused a 2-fold decline compared with untreated controls. l-Buthionine (S,R) sulfoximine did not affect ethanol consumption, but serum ethanol levels in BSO-treated mice were nearly 6-fold lower than in mice given ethanol alone. The latter decline in serum ethanol was associated with a significant elevation in the specific activities of cytochrome P450 2E1 and alcohol dehydrogenase in livers of BSO-treated animals. Ethanol consumption caused a 3.5-fold elevation in serum alanine aminotransferase levels but the enzyme fell to control levels when BSO was included in the diet. l-Buthionine (S,R) sulfoximine administration also attenuated ethanol-induced steatosis, prevented the leakage of lysosomal cathepsins into the cytosol, and prevented the ethanol-elicited decline in proteasome activity.

Conclusions: l-Buthionine (S,R) sulfoximine, administered with ethanol, significantly depleted hepatic glutathione, compared with controls. However, despite the decrease in hepatic antioxidant levels, liver injury by ethanol was alleviated, due, in part, to a BSO-elicited acceleration of ethanol metabolism.

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