title: Differential interactions of antiretroviral agents with LXR, ER and GR nuclear receptors: potential contributing factors to adverse events.
abstract: OBJECTIVE
  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 (LXRα/β), oestrogen receptors (ERα/β) 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.
  
  
  METHODS
  The ability of an ARV drug library to activate LXRα/β, ERα/β 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.
  
  
  RESULTS
  Direct LBD interactions with LXRα and/or LXRβ 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 ERα-LBD. Interestingly, atazanavir and ritonavir also activated LXRα/β in reporter assays, while tipranavir enhanced transcriptional activity of ERα. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Svärd
authors.forename: F
authors.initials: F
authors.lastname: Blanco
authors.forename: D
authors.initials: D
authors.lastname: Nevin
authors.forename: D
authors.initials: D
authors.lastname: Fayne
authors.forename: F
authors.initials: F
authors.lastname: Mulcahy
authors.forename: M
authors.initials: M
authors.lastname: Hennessy
authors.forename: J P
authors.initials: JP
authors.lastname: Spiers
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002460:Cell Line; D003198:Computer Simulation; D003907:Dexamethasone / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D031541:Fluorescence Resonance Energy Transfer; D015870:Gene Expression / Q000187:drug effects; D015723:Gene Library; D006801:Humans; D000071518:Liver X Receptors; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D057093:Orphan Nuclear Receptors / Q000187:drug effects*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000187:drug effects*; D014162:Transfection; D014961:X-Ray Diffraction
chemical_list: D044966:Anti-Retroviral Agents; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D004958:Estradiol; D003907:Dexamethasone; D008156:Luciferases
keywords: HIV protease inhibitor; TR-FRET co-activator assay; antiretroviral drug; efavirenz; glucocorticoid receptor; ligand-binding domain; liver X receptor; luciferase reporter assay; molecular modelling; nuclear receptor; oestrogen receptor