Qatanani Mohammed, Zhang Jun, Moore David D
Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
Endocrinology. 2005 Mar;146(3):995-1002. doi: 10.1210/en.2004-1350. Epub 2004 Nov 24.
The induction of hepatic drug metabolizing enzymes alters not only the metabolism of the xenobiotic substances that induce them but also the metabolism of various endogenous hormones. The xenobiotic receptor constitutive androstane receptor (CAR) (NR1I3) mediates the well-studied induction of CYP2B genes and other drug-metabolizing enzymes by phenobarbital (PB), an antiepileptic drug that has been shown to alter thyroid hormone (TH) levels. Here we show that CAR is required for PB-mediated disruption of TH homeostasis and the induction of thyroid follicular cell proliferation. Treatment with PB or the more potent and more effective CAR ligand 1, 4-bis-[2-(3, 5,-dichloropyridyloxy)] benzene resulted in universal induction of thyroid hormone glucuronidation and sulfation pathways in a CAR-dependent manner. This resulted in a decrease in serum T4 concentration and a concomitant increase in serum TSH levels. CAR activation also decreased serum T3 levels in mice in which T3 production was blocked. The increase in serum TSH levels resulted in the stimulation of thyroid-follicular cell proliferation. These results highlight the central role of the xenosensor CAR in drug-hormone interactions.
肝脏药物代谢酶的诱导不仅会改变诱导它们的外源性物质的代谢，还会改变各种内源性激素的代谢。外源性受体组成型雄烷受体（CAR）（NR1I3）介导了苯巴比妥（PB）对CYP2B基因和其他药物代谢酶的诱导作用，该抗癫痫药物已被证明会改变甲状腺激素（TH）水平。在此，我们表明CAR是PB介导的TH稳态破坏和甲状腺滤泡细胞增殖诱导所必需的。用PB或更有效且更强效的CAR配体1,4-双-[2-(3,5-二氯吡啶氧基)]苯进行处理，会以CAR依赖的方式普遍诱导甲状腺激素葡萄糖醛酸化和硫酸化途径。这导致血清T4浓度降低，同时血清TSH水平升高。在T3生成受阻的小鼠中，CAR激活也会降低血清T3水平。血清TSH水平的升高导致甲状腺滤泡细胞增殖受到刺激。这些结果突出了外源性传感器CAR在药物-激素相互作用中的核心作用。
