Dong Bingning, Qatanani Mohammed, Moore David D
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Hepatology. 2009 Aug;50(2):622-9. doi: 10.1002/hep.23025.
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)-1alpha was also increased in mouse models of type 1 diabetes.
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.
未经治疗的1型糖尿病会增加人类患者和啮齿动物模型的肝脏药物代谢。我们使用基因敲除小鼠来测试核异生素受体组成型雄烷受体（CAR）和孕烷及异生素受体（PXR）在此过程中的作用。链脲佐菌素诱导的糖尿病导致药物代谢细胞色素P450的表达增加，同时也增加了细胞色素P450底物唑拉西泮的清除率。这种诱导在Car(-/-)小鼠中完全不存在，但不受PXR缺失的影响。在糖尿病对肝脏的众多影响中，我们确定胆汁酸升高和激活的腺苷单磷酸激活蛋白激酶是潜在的CAR激活刺激因素。在1型糖尿病小鼠模型中，CAR共激活因子过氧化物酶体增殖物激活受体γ共激活因子（PGC）-1α的表达也增加。
新诊断或管理不善的1型糖尿病中CAR依赖的药物代谢诱导可能对治疗药物的疗效或毒性产生重大影响。
