Differential interactions of antiretroviral agents with LXR, ER and GR nuclear receptors: potential contributing factors to adverse events.

ABSTRACT: Antiretroviral (ARV) drugs activate pregnane X receptors and constitutive androstane receptors, increasing the risk of drug interactions due to altered drug metabolism and disposition. The closely related liver X receptors (LXR?/?), oestrogen receptors (ER?/?) and glucocorticoid receptor (GR) regulate many endogenous processes such as lipid/cholesterol homeostasis, cellular differentiation and inflammation. However, ARV drug activation of these nuclear receptors has not been thoroughly investigated.The ability of an ARV drug library to activate LXR?/?, ER?/? and GR was assessed using a combined in silico and in vitro approach encompassing computational docking and molecular descriptor filtering, cell-free time-resolved fluorescence resonance energy transfer co-activator assays to assess direct binding to ligand-binding domains (LBDs), cell-based reporter assays and target gene expression.Direct LBD interactions with LXR? and/or LXR? were predicted in silico and confirmed in vitro for darunavir, efavirenz, flavopiridol, maraviroc and tipranavir. Likewise, efavirenz was also predicted and confirmed as a ligand of ER?-LBD. Interestingly, atazanavir and ritonavir also activated LXR?/? in reporter assays, while tipranavir enhanced transcriptional activity of ER?. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir.There was good agreement between in silico predictions and in vitro results. However, some nuclear receptor interactions identified in vitro were probably due to allosteric effects or nuclear receptor cross-talk, rather than direct LBD binding. This study indicates that some of the adverse effects associated with ARV use may be mediated through 'off-target' effects involving nuclear receptor activation.

SUBMITTER: Svard J 

PROVIDER: S-EPMC3904266 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature