Pregnane X receptor activation potentiates ritonavir hepatotoxicity

• Published in: The Journal of clinical investigation Vol. 129; no. 7; pp. 2898 - 2903
• Main Authors: Shehu, Amina I, Lu, Jie, Wang, Pengcheng, Zhu, Junjie, Wang, Yue, Yang, Da, McMahon, Deborah, Xie, Wen, Gonzalez, Frank J, Ma, Xiaochao
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.07.2019
• Subjects: Acquired immune deficiency syndrome; AIDS; Animal genetic engineering; Animal models; Animals; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Antiviral drugs; Atazanavir; Biomedical research; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Clinical trials; Concise Communication; Cytochrome P-450; Cytochrome P-450 CYP3A - genetics; Cytochrome P-450 CYP3A - metabolism; Dietary supplements; Disease Models, Animal; Efavirenz; Endoplasmic reticulum; Endoplasmic Reticulum Stress - drug effects; Endoplasmic Reticulum Stress - genetics; Health; Hepatotoxicity; Highly active antiretroviral therapy; HIV; Human immunodeficiency virus; Humans; Medical research; Metabolites; Mice; Oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Pregnane X Receptor - genetics; Pregnane X Receptor - metabolism; Public health; Receptor mechanisms; Rifampin; Ritonavir; Ritonavir - adverse effects; Ritonavir - pharmacology; Rodents; AIDS/HIV; Toxicology; Hepatology; Toxins/drugs/xenobiotics
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI128274

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 significant inter-species 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.