Constitutive androstane receptor mediates the induction of drug metabolism in mouse models of type 1 diabetes

Authors

  • Bingning Dong,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
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  • Mohammed Qatanani,

    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
    Current affiliation:
    1. Division of Endocrinology, Diabetes, and Metabolism and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA
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  • David D. Moore

    Corresponding author
    1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
    • Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030
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    • fax: 713-798-3017.


  • Potential conflicts of interest: none.

Abstract

Untreated type 1 diabetes increases hepatic drug metabolism in both human patients and rodent models. We used knockout mice to test the role of the nuclear xenobiotic receptors constitutive androstane receptor (CAR) and pregnane and xenobiotic receptor (PXR) in this process. Streptozotocin-induced diabetes resulted in increased expression of drug metabolizing cytochrome P450s and also increased the clearance of the cytochrome P450 substrate zoxazolamine. This induction was completely absent in Car−/− mice, but was not affected by the loss of PXR. Among the many effects of diabetes on the liver, we identified bile acid elevation and activated adenosine monophosphate-activated protein kinase as potential CAR-activating stimuli. Expression of the CAR coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α was also increased in mouse models of type 1 diabetes. Conclusion: The CAR-dependent induction of drug metabolism in newly diagnosed or poorly managed type 1 diabetes has the potential for significant impact on the efficacy or toxicity of therapeutic agents. (HEPATOLOGY 2009.)

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