Haines Corinne, Chatham Lynsey R, Vardy Audrey, Elcombe Clifford R, Foster John R, Lake Brian G
a Concept Life Sciences (formerly CXR Biosciences Ltd.) , Dundee , UK.
b Regulatory Science Associates , Renfreshire , UK.
Xenobiotica. 2019 Feb;49(2):227-238. doi: 10.1080/00498254.2018.1437300. Epub 2018 Mar 26.
The hepatic and thyroid gland effects of the constitutive androstane receptor (CAR) activator sodium phenobarbital (NaPB) and the pregnane X receptor (PXR) activator pregnenolone-16α-carbonitrile (PCN) were examined in male Sprague-Dawley wild-type (WT) and knockout (KO) rats lacking both hepatic CAR and PXR receptors (CAR KO/PXR KO rats). The treatment of WT rats for 7 d with 500 ppm NaPB in the diet and 100 mg/kg/d PCN by gavage resulted in increased relative liver weight, hepatocyte hypertrophy, increased hepatocyte replicative DNA synthesis (RDS) and induction of cytochrome P450 CYP2B and CYP3A subfamily enzymes. NaPB and PCN also induced thyroid gland follicular cell RDS and hepatic microsomal UDP-glucuronosyltransferase activity towards thyroxine as substrate. These effects were not observed in the liver and thyroid gland of CAR KO/PXR KO rats. Male C57BL/6 J (WT) and CAR KO/PXR KO mice were given 1000 ppm NaPB in the diet for 7 d. In WT, but not in CAR KO/PXR KO, mice NaPB treatment resulted in liver hypertrophy and induction of hepatocyte RDS and Cyp2b enzymes. These results suggest that the CAR KO/PXR KO rat and mouse models are useful experimental models for mode of action studies with rodent CAR activators.
在雄性斯普拉格-道利野生型（WT）大鼠以及缺乏肝脏组成型雄烷受体（CAR）和孕烷X受体（PXR）的基因敲除（KO）大鼠（CAR KO/PXR KO大鼠）中，研究了CAR激动剂苯巴比妥钠（NaPB）和PXR激动剂孕烯醇酮-16α-腈（PCN）对肝脏和甲状腺的影响。用饮食中500 ppm的NaPB和经口灌胃100 mg/kg/d的PCN对WT大鼠进行7天的处理，导致肝脏相对重量增加、肝细胞肥大、肝细胞复制性DNA合成（RDS）增加以及细胞色素P450 CYP2B和CYP3A亚家族酶的诱导。NaPB和PCN还诱导甲状腺滤泡细胞RDS以及以甲状腺素为底物的肝脏微粒体UDP-葡萄糖醛酸基转移酶活性。在CAR KO/PXR KO大鼠的肝脏和甲状腺中未观察到这些效应。给雄性C57BL/6 J（WT）和CAR KO/PXR KO小鼠喂食饮食中1000 ppm的NaPB，持续7天。在WT小鼠而非CAR KO/PXR KO小鼠中，NaPB处理导致肝脏肥大以及肝细胞RDS和Cyp2b酶的诱导。这些结果表明，CAR KO/PXR KO大鼠和小鼠模型是用于研究啮齿动物CAR激动剂作用模式的有用实验模型。
