Premium
Constitutive androstane receptor mediates the induction of drug metabolism in mouse models of type 1 diabetes
Author(s) -
Dong Bingning,
Qatanani Mohammed,
Moore David D.
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23025
Subject(s) - constitutive androstane receptor , pregnane x receptor , coactivator , medicine , endocrinology , nuclear receptor , drug metabolism , cytochrome p450 , pharmacology , peroxisome proliferator activated receptor , receptor , drug , biology , chemistry , metabolism , biochemistry , transcription factor , gene
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. (H EPATOLOGY 2009.)