SHEHU, AMINA I
(2015)
THE ROLE OF PREGNANE X RECEPTOR IN RITONAVIR-INDUCED LIVER INJURY.
Master's Thesis, University of Pittsburgh.
(Unpublished)
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
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| 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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