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Pregnane X receptor activation potentiates the hepatotoxicity of pharmacoenhancers

Shehu, Amina I. (2019) Pregnane X receptor activation potentiates the hepatotoxicity of pharmacoenhancers. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Ritonavir (RTV) is a first generation pharmacoenhancer used in anti-HIV therapy. Hepatotoxicity is one of the major safety concerns for HIV/AIDS patients receiving ritonavir (RTV)-containing antiretroviral regimens. In a recent series of clinical trials, the hepatotoxicity associated with RTV-containing regimens occurred in 100% of subjects who were pretreated with rifampicin (RIF) or efavirenz (EFV). Both RIF and EFV are potent ligands of human pregnane X receptor (PXR), a ligand-dependent transcription factor that upregulates Cytochrome P450 3A4 (CYP3A4) expression. Therefore, we hypothesize that drug mediated PXR activation potentiates RTV hepatotoxicity. Due to specie differences in PXR activation, humanized PXR and CYP3A4 mouse models were utilized. Pretreatment with both RIF and EFV potentiated RTV hepatotoxicity. Further studies showed that PXR mediated CYP3A4 induction increased RTV bioactivation in a humanized PXR/CYP3A4 mouse model which resulted in oxidative stress, endoplasmic reticulum stress and cellular injury.
The second part of this dissertation focused on cobicistat (COBI), the new second generation pharmacoenhancer and structural analog of RTV. Clinical trials comparing the safety of COBI to RTV showed a similar rate of liver injury adverse events between the COBI and RTV treatment arms suggesting a similarity in their adverse effect profile. Based on our initial findings that the PXR/CYP3A4 axis plays an essential role in RTV hepatotoxicity, we explored the role of PXR/CYP3A4 axis in COBI hepatotoxicity. Using our humanized mouse models, hepatocellular injury was observed in PXR/CYP3A4-humanized mice pretreated with RIF followed by COBI which was similar to the phenotype observed with RTV. In addition, pretreatment with a constitutive androstane receptor (CAR) activator (another nuclear receptor), significantly up- regulated CYP3A4 expression and potentiated COBI hepatotoxicity in a CYP3A4-transgenic mouse model deficient in PXR. Further studies illustrated that induction of CYP3A4 increased COBI metabolism and bioactivation resulting in oxidative stress, endoplasmic reticulum stress, and hepatocellular injury as observed with RTV.
Collectively, this work established the essential roles of hPXR and CAR ligands/activators that can induce CYP3A4 expression as risk factors for RTV/COBI hepatotoxicity. Our results can be used to develop novel strategies based upon PXR, CYP3A4, and their downstream pathways to ensure the safe use of RTV/COBI-containing regimens in the clinic.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shehu, Amina I.ais21@pitt.eduais21
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMa, Xiaochaomxiaocha@pitt.edu
Committee MemberXie, Wenwex6@pitt.edu
Committee MemberPoloyac, Samuel M.poloyac@pitt.edu
Committee MemberMcMahon, Deborahmcmahond@pitt.edu
Committee MemberFernandez, Christian A.chf63@pitt.edu
Date: 3 September 2019
Date Type: Publication
Defense Date: 11 July 2019
Approval Date: 3 September 2019
Submission Date: 30 August 2019
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 135
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: pregnane X receptor, ritonavir, cobicistat,constitutive androstane receptor,hepatotoxicity,CYP3A4
Date Deposited: 03 Sep 2019 12:19
Last Modified: 03 Sep 2019 12:19
URI: http://d-scholarship.pitt.edu/id/eprint/37430

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