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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Insulin and Glucagon Regulation of GlutathioneS-Transferase Expression in Primary Cultured Rat Hepatocytes

Sang K. Kim, Kimberley J. Woodcroft and Raymond F. Novak
Journal of Pharmacology and Experimental Therapeutics April 2003, 305 (1) 353-361; DOI: https://doi.org/10.1124/jpet.102.045153
Sang K. Kim
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Kimberley J. Woodcroft
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Raymond F. Novak
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Abstract

Diabetes is a major cause of morbidity and mortality, and complications resulting from diabetes have been attributed in part to increased oxidative stress. Glutathione S-transferases (GSTs) constitute a major protective mechanism against oxidative stress. Studies of the expression and activity of GSTs during diabetes are inconclusive, with both increased and decreased GST expression being reported in vivo. Insulin and glucagon effects on GST expression and the signaling pathway involved in the glucagon regulation of GST expression were examined in primary cultured rat hepatocytes. The addition of insulin resulted in the elevation of alpha-class GST protein levels, whereas alpha- and pi-class GST protein levels were markedly decreased in hepatocytes cultured with glucagon. In contrast, mu-class GST protein expression was unaffected by insulin or glucagon treatment. Insulin concentrations ≥1 nM resulted in increased GST activities and alpha-class GST protein levels, whereas glucagon concentrations ≥20 nM decreased alpha- and pi-class protein levels and activity. Treatment of cells with 8-bromo-cAMP or dibutyryl-cAMP also resulted in decreased alpha- and pi-class GST protein levels. Pretreatment withN-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide (H89), a selective inhibitor of protein kinase A, before glucagon addition markedly attenuated the glucagon effect. This study demonstrates that insulin and glucagon regulate, in an opposing manner, the expression of alpha-class GSTs and that glucagon completely inhibits pi-class GST expression in vitro, suggesting that hepatic GST expression may be decreased during diabetes. Furthermore, the present study implicates cAMP and protein kinase A in mediating the inhibitory effect of glucagon on GST expression.

Footnotes

  • This work was supported by National Institutes of Health Grant ES03656 to R.F.N. and by the Cell Culture and Imaging and Cytometry Core Facilities of EHS Center Grant P30 ES06639 from the National Institute of Environmental Health Sciences.

  • DOI: 10.1124/jpet.102.045153

  • Abbreviations:
    GSTs
    glutathioneS-transferases
    H89
    N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline sulfonamide
    PI3-kinase
    phosphatidylinositol 3-kinase
    Br-cAMP
    8-bromo-cAMP
    DB-cAMP
    dibutyryl-cAMP
    PKA
    protein kinase A
    LDH
    lactate dehydrogenase
    CDNB
    1-chloro-2,4-dinitrobenzene
    DCNB
    1,2-dichloro-4-nitrobenzene
    NBD
    7-chloro-4-nitrobenzo-2-oxa-1,3-diazole
    EA
    ethacrynic acid
    ARE
    antioxidant response element
    MAP
    mitogen-activated protein
    PBS
    phosphate-buffered saline
    PBS-T
    0.05% Tween 20 in PBS
    • Received October 4, 2002.
    • Accepted December 16, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 1
1 Apr 2003
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Insulin and Glucagon Regulation of GlutathioneS-Transferase Expression in Primary Cultured Rat Hepatocytes

Sang K. Kim, Kimberley J. Woodcroft and Raymond F. Novak
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 353-361; DOI: https://doi.org/10.1124/jpet.102.045153

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Insulin and Glucagon Regulation of GlutathioneS-Transferase Expression in Primary Cultured Rat Hepatocytes

Sang K. Kim, Kimberley J. Woodcroft and Raymond F. Novak
Journal of Pharmacology and Experimental Therapeutics April 1, 2003, 305 (1) 353-361; DOI: https://doi.org/10.1124/jpet.102.045153
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