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Research ArticleArticle

PI3K Inhibitors Reverse the Suppressive Actions of Insulin on CYP2E1 Expression by Activating Stress-Response Pathways in Primary Rat Hepatocytes

Jaspreet S. Sidhu, Fei Liu, Sean M. Boyle and Curtis J. Omiecinski
Molecular Pharmacology May 2001, 59 (5) 1138-1146; DOI: https://doi.org/10.1124/mol.59.5.1138
Jaspreet S. Sidhu
Department of Environmental Health, University of Washington, Seattle, Washington
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Fei Liu
Department of Environmental Health, University of Washington, Seattle, Washington
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Sean M. Boyle
Department of Environmental Health, University of Washington, Seattle, Washington
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Curtis J. Omiecinski
Department of Environmental Health, University of Washington, Seattle, Washington
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Abstract

Insulin-associated signaling pathways are critical in the regulation of hepatic physiology. Recent inhibitor-based studies have implicated a mechanistic role for phosphatidylinositol 3′ kinase (PI3K) in the insulin-mediated suppression of CYP2E1 mRNA levels in hepatocytes. We investigated the dose dependence for this response and for the effects of insulin and extracellular matrix on PI3K signaling and CYP2E1 mRNA expression levels using a highly defined rat primary hepatocyte culture system. The PI3K inhibitors wortmannin and LY294002 stimulated stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) and p38 mitogen-activated protein kinase (MAPK) phosphorylation in a rapid and concentration-dependent manner that paralleled the inhibition of protein kinase B (PKB) phosphorylation. Although PI3K inhibitors reversed the suppressive effects of insulin on CYP2E1 expression, these effects only occurred at concentrations well in excess of those required to achieve complete inhibition of PKB phosphorylation. These same concentrations produced cytotoxic responses as evidenced by perturbed cellular morphology and elevated release of lactate dehydrogenase. Wortmannin-mediated activation of the SAPK/JNK and p38 MAPK pathways also resulted in the mobilization of activator protein-1 complex to the nuclear compartment. We conclude that the suppression of CYP2E1 mRNA expression by insulin is not directly associated with PI3K-dependent pathway activation, but rather is linked to a cytotoxic response stemming from acute challenge with PI3K inhibitors.

Footnotes

    • Received November 14, 2000.
    • Accepted January 31, 2001.
  • Send reprint requests to: Curtis J. Omiecinski, Ph.D, Department of Environmental Health, University of Washington, 4225 Roosevelt Way NE, #100, Seattle, WA 98105-6099. E-mail:cjo{at}u.washington.edu

  • This study was supported by the National Institute of General Medical Sciences (GM32281). C.J.O. is a Burroughs Wellcome Fund Toxicology Scholar.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 59 (5)
Molecular Pharmacology
Vol. 59, Issue 5
1 May 2001
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Research ArticleArticle

PI3K Inhibitors Reverse the Suppressive Actions of Insulin on CYP2E1 Expression by Activating Stress-Response Pathways in Primary Rat Hepatocytes

Jaspreet S. Sidhu, Fei Liu, Sean M. Boyle and Curtis J. Omiecinski
Molecular Pharmacology May 1, 2001, 59 (5) 1138-1146; DOI: https://doi.org/10.1124/mol.59.5.1138

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Research ArticleArticle

PI3K Inhibitors Reverse the Suppressive Actions of Insulin on CYP2E1 Expression by Activating Stress-Response Pathways in Primary Rat Hepatocytes

Jaspreet S. Sidhu, Fei Liu, Sean M. Boyle and Curtis J. Omiecinski
Molecular Pharmacology May 1, 2001, 59 (5) 1138-1146; DOI: https://doi.org/10.1124/mol.59.5.1138
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