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THE ROLE OF PREGNANE X RECEPTOR IN RITONAVIR-INDUCED LIVER INJURY

SHEHU, AMINA I (2015) THE ROLE OF PREGNANE X RECEPTOR IN RITONAVIR-INDUCED LIVER INJURY. Master's Thesis, University of Pittsburgh. (Unpublished)

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Abstract

Ritonavir (RTV) is a HIV protease inhibitor and an important component of anti-HIV therapy. Hepatotoxicity has been reported in ~10% of patients who receive RTV-containing regimens. However, the hepatotoxicity of RTV-containing regimens was significantly enhanced in subjects who were pretreated with rifampicin (RIF), a first-line anti-tuberculosis drug. RIF is also known as a ligand of human pregnane X receptor (PXR), a transcription factor that is highly expressed in the liver and regulates drug metabolism and many cellular functions. We hypothesize that RIF-mediated PXR activation potentiates RTV hepatotoxicity. We used a transgenic mouse model that expresses human PXR and human CYP3A4 (TgCYP3A4/hPXR). A CYP3A4 transgenic mouse model on the Pxr-null background (TgCYP3A4/Pxr-null) was used as the control. We found that pretreatment with RIF sensitized the TgCYP3A4/hPXR mice to RTV hepatotoxicity, and this sensitizing effect was abolished in the TgCYP3A4/Pxr-null mice. Furthermore, we found that PXR activation increased RTV bioactivation and unfolded protein response. In summary, PXR is a key modulator of RTV induced liver injury. The results from this study can be used to guide decisions on safety considerations regarding RTV-containing regimens in clinical practice.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
SHEHU, AMINA Iais21@pitt.eduAIS21
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Wen, Xiewex6@pitt.eduWEX6
Sant, VinayakVIS45@pitt.eduVIS45
Xiaochao, MaMXIAOCHA@pitt.eduMXIAOCHA
Date: 13 July 2015
Date Type: Publication
Defense Date: 22 June 2015
Approval Date: 13 July 2015
Submission Date: 29 June 2015
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 37
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: pregnane X receptor, Ritonavir, liver injury
Date Deposited: 13 Jul 2015 15:44
Last Modified: 13 Jul 2018 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/25515

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