pregnane X receptor and constitutive androstane receptor modulate differently CYp3A-mediated metabolism in earlyand late-stage cholestasis

作     者：Daniela Gabbia Arianna Dalla Pozza Laura Albertoni Roberta Lazzari Giorgia Zigiotto Maria Carrara Vincenzo Baldo Tatjana Baldovin Annarosa Floreani Sara De Martin 

作者机构：Department of Pharmaceutical and Pharmacological SciencesUniversity of Padova Department of MedicineGeneral Pathology and Cytopathology UnitUniversity of Padova Department of CardiacThoracicand Vascular SciencesHygiene and Public Health UnitUniversity of Padova Department of SurgeryOncology and GastroenterologyUniversity of Padova 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2017年第23卷第42期

页      面：7519-7530页

核心收录：

学科分类：1002[医学-临床医学] 10[医学] 

基　　金：Supported by the University of Padova No.CPDA138721/13 

主　　题：Cholestasis CYP3A Drug metabolism Pregnane X receptor Constitutive androstane receptor 

摘      要：AIM To ascertain whether cholestasis affects the expression of two CYP3 A isoforms(CYP3 A1 and CYP3 A2) and of pregnane X receptor(PXR) and constitutive androstane receptor(CAR).METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3 A1 and CYP3 A2 were assessed by means of q RT-PCR and Western blot, respectively. Alterations in CYP3 A activity were measured by calculating the kinetic parameters of 4-OH and 1 -OH-midazolam hydroxylation, marker reactions for CYP3 A enzymes.RESULTS The m RNA and protein expression of CYP3 A1 increased significantly in mild cholestasis(P 0.01). At variance, m RNA and protein expression of CYP3 A2 didn t change in mild cholestasis, whereas the expression and activity of both CYP3 A1 and CYP3 A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.CONCLUSION Early-and late-stage cholestasis affects CYP3 Amediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3 Amediated liver detoxification.