title: Reduction of thyroid hormones triggers down-regulation of hepatic CYP2B through nuclear receptors CAR and TR in a rat model of acute stroke.
abstract: 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'-triiodo-L-thyronine (T3) treatment on constitutive androstane receptor (CAR) and thyroid hormone receptors (TRs, including TRα and TRβ) 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 (RXRα) 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 RXRα were time-dependently decreased after brain I/R injury. T3 regulated the CAR expression at the transcriptional level, and facilitated the translocation of TRα/β proteins as well as the binding of TRs, RXRα, 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.
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China; Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Bing
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China; Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Siying
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China; Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Baotou Teachers' College, Inner Mongolia University of Science & Technology, Baotou 014030, China.
authors.forename: Guicheng
authors.initials: G
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Zheqiong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: yuejiang@whu.edu.cn.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D000090702:Constitutive Androstane Receptor; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D011988:Receptors, Thyroid Hormone / Q000502:physiology*; D020521:Stroke / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D013963:Thyroid Hormones / Q000172:deficiency* / Q000378:metabolism
chemical_list: D000090702:Constitutive Androstane Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D019362:Cytochrome P-450 CYP2B1
keywords: Acute stroke; Constitutive androstane receptor; Cytochrome P450 2B; Thyroid hormone; Thyroid hormone receptors