Abstract
The farnesoid X receptor (FXR) belongs to the nuclear receptor family and is activated by bile acids. Multiple, chemically rather diverse, FXR agonists have been developed and several of these compounds are currently tested in clinical trials for NAFLD and cholestasis. Here, we investigated possible FXR-agonism or antagonism of existing FDA/EMA-approved drugs. By using our recently developed FRET-sensor, containing the ligand binding domain of FXR (FXR-LBD), 1280 FDA-approved drugs were screened for their ability to activate FXR in living cells using flow cytometry. Fifteen compounds induced the sensor for more than twenty percent above background. Real-time confocal microscopy confirmed that avermectin B1a, gliquidone, nicardipine, bepridil and triclosan activated the FRET sensor within two minutes. These compounds, including fluticasone, increased mRNA expression of FXR target genes OSTα and OSTβ in Huh7 cells, and in most cases also of MRP2, SHP and FGF19. Finally, avermectin B1a, gliquidone, nicardipine and bepridil significantly increased IBABP promoter activity in a luciferase reporter assay in a dose-dependent manner. In conclusion, six FDA/EMA-approved drugs currently used in the clinical practice exhibit moderate agonistic FXR activity. This may on the one hand explain (undesired) side-effects, but on the other hand may form an opportunity for polypharmacology.
Highlights
Bile acids are responsible for effective absorption of fats and fat-soluble vitamins, facilitate digestion and are important regulators of cholesterol, triglyceride homeostasis and inflammation[1,2,3]
The FRET sensor used in this study consists of an farnesoid X receptor (FXR) ligand binding domain (LBD), an LXXLL motif, a nuclear localization sequence and an α-helical motif present in coactivators required for the ligand-dependent binding of coactivators to nuclear receptors
We explored whether FDA/EMA-approved drugs designed for other targets activate FXR
Summary
Bile acids are responsible for effective absorption of fats and fat-soluble vitamins, facilitate digestion and are important regulators of cholesterol, triglyceride homeostasis and inflammation[1,2,3]. Several of these metabolic actions of bile acids involve the activation of the nuclear farnesoid X receptor (FXR). Fifteen drugs were considered positive for FXR activation (>20% above background levels) in the screen, and at least 6 drugs currently widely used in clinical practice bind and activate FXR This implies that these drugs affect multiple target proteins, which is a common phenomenon[22]. Polypharmacology, or drug activity on multiple targets, forms the underlying mechanism of many side-effects and the subsequent drug withdrawal from the market[23], but may open up the possibility for modulating multiple targets with one drug[24]
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