RT Journal Article
SR Electronic
T1 Efavirenz and Efavirenz-like Compounds Activate Human, Murine, and Macaque Hepatic IRE1α-XBP1
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.118.113647
DO 10.1124/mol.118.113647
A1 Carley J.S. Heck
A1 Allyson N. Hamlin
A1 Namandje N. Bumpus
YR 2018
UL http://molpharm.aspetjournals.org/content/early/2018/11/15/mol.118.113647.abstract
AB Efavirenz (EFV), a widely used antiretroviral drug, is associated with idiosyncratic hepatotoxicity and dyslipidemia. Here we demonstrate that EFV stimulates the activation in primary hepatocytes of key cell stress regulators: inositol requiring 1α (IRE1α) and X-box binding protein 1 (XBP1). Following EFV exposure, XBP1 splicing (indicating activation) was increased 35.7-fold in primary human hepatocytes. Paralleling this, XBP1 splicing and IRE1α phosphorylation (p-IRE1α, active IRE1α) were elevated 36.4-fold and 4.9-fold, respectively, in primary mouse hepatocytes. Of note, with EFV treatment, 47.2% of mouse hepatocytes were apoptotic; which was decreased to 23.9% in the presence of STF083010, an inhibitor of XBP1 splicing. Experiments performed using pregnane X receptor (PXR)-null mouse hepatocytes revealed that EFV-mediated XBP1 splicing and hepatocyte death were not dependent on PXR, which is a nuclear receptor transcription factor that plays a crucial role in the cellular response to xenobiotics. Interestingly, incubation with the primary metabolite of EFV, 8-hydroxyEFV (8-OHEFV), only resulted in 10.3-, and 2.9-fold increased XBP1 splicing in human and mouse hepatocytes and no change in levels of p-IRE1α in mouse hepatocytes. To further probe the structure-activity relationship of IRE1α-XBP1 activation by EFV, 16 EFV analogs were employed. Of these, an analog in which the EFV alkyne is replaced with an alkene and an analog in which the oxazinone oxygen is replaced by a carbon stimulated XBP1 splicing in human, mouse, and macaque hepatocytes. These data demonstrate that EFV and compounds sharing the EFV scaffold can activate IRE1α-XBP1 across humans, mice, and macaques.