Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2017; 23(42): 7519-7530
Published online Nov 14, 2017. doi: 10.3748/wjg.v23.i42.7519
Pregnane X receptor and constitutive androstane receptor modulate differently CYP3A-mediated metabolism in early- and late-stage cholestasis
Daniela Gabbia, Arianna Dalla Pozza, Laura Albertoni, Roberta Lazzari, Giorgia Zigiotto, Maria Carrara, Vincenzo Baldo, Tatjana Baldovin, Annarosa Floreani, Sara De Martin
Daniela Gabbia, Arianna Dalla Pozza, Giorgia Zigiotto, Maria Carrara, Sara De Martin, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
Laura Albertoni, Department of Medicine, General Pathology and Cytopathology Unit, University of Padova, Padova 35131, Italy
Roberta Lazzari, Vincenzo Baldo, Tatjana Baldovin, Department of Cardiac, Thoracic, and Vascular Sciences, Hygiene and Public Health Unit, University of Padova, Padova 35131, Italy
Annarosa Floreani, Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35131, Italy
Author contributions: Gabbia D, Dalla Pozza A, Albertoni L, Lazzari R and Zigiotto G performed the research; Baldovin T, Carrara M, Baldo V and De Martin S contributed new reagents/analytic tools; Gabbia D, Alberton L, Baldovin T, Carrara M, Floreani A and De Martin S analyzed the data; De Martin S designed and coordinated the research; Gabbia D, Floreani A and De Martin S wrote the paper.
Supported by the University of Padova, No. CPDA138721/13.
Institutional review board statement: The study was reviewed and approved by the Institutional Review board of the “Organismo Preposto al Benessere Animale (OPBA)” of the University of Padova.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Ethics Committee of University of Padova, and by the Italian Ministry for the care and use of laboratory animals [Prot. no. 24, 2015].
Conflict-of-interest statement: The authors have no conflict of interest to report.
Data sharing statement: Statistical analyses and dataset available from the corresponding author at sara.demartin@unipd.it.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sara De Martin, PharmD, PhD, Assistant Professor, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, Padova 35131, Italy. sara.demartin@unipd.it
Telephone: +39-49-8275776 Fax: +39-49-8275093
Received: August 4, 2017
Peer-review started: August 7, 2017
First decision: August 30, 2017
Revised: September 18, 2017
Accepted: October 17, 2017
Article in press: October 17, 2017
Published online: November 14, 2017
Processing time: 99 Days and 21.4 Hours
Core Tip

Core tip: We demonstrated that early- and late-stage cholestasis affects CYP3A-mediated metabolism differently, probably as consequence of the different activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). As a consequence, cholestatic patients may have an altered drug metabolism: in the early stage due to the induction of CYP3A enzymes; and in the late stage due to the high deposition of fibrotic liver and consequent hepatocyte loss. Secondly, since PXR activation is known to induce alternative hepatic export routes and detoxification enzymes, the induction of these cellular pathways with PXR and/or CAR agonists could be exploited as a therapeutic strategy for the management of cholestatic diseases.