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

Abstract：

BACKGROUND AND PURPOSE: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. EXPERIMENTAL APPROACH: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. KEY 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 AND IMPLICATIONS: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.

journal_name

Br J Pharmacol

journal_title

British journal of pharmacology

authors

Svärd J,Blanco F,Nevin D,Fayne D,Mulcahy F,Hennessy M,Spiers JP

doi

10.1111/bph.12480

subject

Has Abstract

pub_date

2014-01-01 00:00:00

pages

480-97

issue

eissn

0007-1188

issn

1476-5381

journal_volume

171

pub_type

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