Reduction of thyroid hormones triggers down-regulation of hepatic CYP2B through nuclear receptors CAR and TR in a rat model of acute stroke

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• 作者：Yuntao Bing ; Siying Zhu ; Kun Jiang ; Guicheng Dong ; Jie Li ; Zheqiong Yang ; Jing Yang ; Jiang Yue
• 关键词：ACTH ; adrenocorticotropic hormone ; ALT ; alanine aminotransferase ; AST ; aspartate aminotransferase ; CAR ; constitutive androstane receptor ; ChIP ; chromatin immunoprecipitation ; CYPs ; cytochrome P450 ; CPR ; cytochrome P450 reductase ; DR4 ; a direct repeat separated by 4 base pairs ; FT3 ; free triiodthyronine ; FT4 ; free thyroxine ; GH ; growth hormone ; I/R ; ischemia/reperfusion ; IL ; interleukin ; MCAO ; middle cerebral artery occlusion ; NCoR ; nuclear receptor corepressor ; NRs ; nuclear receptors ; NTIS ; nont
• 刊名：Biochemical Pharmacology
• 出版年：15 February, 2014
• 年：2014
• 卷：87
• 期：4
• 页码：636-649
• 全文大小：3393 K

文摘

Stroke is a neurological condition and may cause changes in hepatic drug-metabolizing enzymes. Hepatic CYP2B is involved in the metabolism of a variety of centrally active substances. The purpose of this study was to investigate the possible down-regulation mechanism of hepatic CYP2B after acute stroke. Using a rat model of acute stroke induced by middle cerebral artery occlusion, we studied the influence of brain ischemia/reperfusion (I/R) injury on CYP2B expression. Effects of 3,5,3鈥?triiodo-L-thyronine (T3) treatment on constitutive androstane receptor (CAR) and thyroid hormone receptors (TRs, including TR伪 and TR尾) proteins were detected in Huh7 cells. We found dramatic decreases in the levels of plasma free triiodthyronine, free thyroxine and hepatic CYP2B expression. Both CAR and retinoid X receptor alpha (RXR伪) were significantly dissociated from the phenobarbital-responsive enhancer module (PBREM) of the CYP2B1 promoter in the early stages of the acute stroke. The levels of the polymer of TRs, CAR, and RXR伪 were time-dependently decreased after brain I/R injury. T3 regulated the CAR expression at the transcriptional level, and facilitated the translocation of TR伪/尾 proteins as well as the binding of TRs, RXR伪, and CAR to PBREM region. The reduction of thyroid hormone levels after a brain I/R injury may be the initial trigger for the down-regulation of hepatic CYP2B1 via induction of the dissociation of CAR from the TRs and from the PBREM region. Our data suggest that patients with acute ischemic stroke may have a decreased CYP2B-mediated metabolism of exogenous and endogenous compounds because of the low level of thyroid hormones.