Pregnane X receptor activation potentiates ritonavir hepatotoxicity
Amina I. Shehu, … , Frank J. Gonzalez, Xiaochao Ma
Amina I. Shehu, … , Frank J. Gonzalez, Xiaochao Ma
Published April 30, 2019
Citation Information: J Clin Invest. 2019;129(7):2898-2903. https://doi.org/10.1172/JCI128274.
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Concise Communication AIDS/HIV Hepatology

Pregnane X receptor activation potentiates ritonavir hepatotoxicity

Abstract

Ritonavir (RTV) is on the World Health Organization’s list of essential medicines for antiretroviral therapy, but can cause hepatotoxicity by unknown mechanisms. Multiple clinical studies found that hepatotoxicity occurred in 100% of participants who were pretreated with rifampicin or efavirenz followed by RTV-containing regimens. Both rifampicin and efavirenz are activators of the pregnane X receptor (PXR), a transcription factor with marked interspecies differences in ligand-dependent activation. Using PXR-humanized mouse models, we recapitulated the RTV hepatotoxicity observed in the clinic. PXR was found to modulate RTV hepatotoxicity through CYP3A4-dependent pathways involved in RTV bioactivation, oxidative stress, and endoplasmic reticulum stress. In summary, the current work demonstrated the essential roles of human PXR and CYP3A4 in RTV hepatotoxicity, which can be applied to guide the safe use of RTV-containing regimens in the clinic.

Authors

Amina I. Shehu, Jie Lu, Pengcheng Wang, Junjie Zhu, Yue Wang, Da Yang, Deborah McMahon, Wen Xie, Frank J. Gonzalez, Xiaochao Ma

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Figure 1

Role of human PXR in the hepatotoxicity cause by pretreatment with RIF followed by RTV.

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Role of human PXR in the hepatotoxicity cause by pretreatment with RIF f...
(A) Schematic showing the adverse drug interactions between RIF and RTV in humans that led to the early termination of clinical studies. (B–F) Evaluation of liver damage in WT and hPXR/CYP3A4 mice pretreated with RIF for 7 days followed by RTV. (B and C) Activities of ALT and AST in the serum of WT mice. (D) Genotyping results of hPXR/CYP3A4 mice, which are positive for human PXR and CYP3A4, but negative for mouse Pxr and Cyp3a. (E and F) Activities of ALT and AST in the serum of hPXR/CYP3A4 mice. All data are shown as mean ± SEM (n = 3–4). Statistical significance was determined by 1-way ANOVA with Tukey’s post hoc test. ****P < 0.0001 for RIF+RTV group vs. control, RTV, and RIF groups.