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Identification of novel pregnane X receptor (PXR) agonists by In silico and biological activity analyses and reversal of cigarette smoke-induced PXR downregulation
Journal article   Peer reviewed

Identification of novel pregnane X receptor (PXR) agonists by In silico and biological activity analyses and reversal of cigarette smoke-induced PXR downregulation

Rajan T. Reddy and Toru Nyunoya
Biochemical and biophysical research communications, Vol.555, pp.1-6
05/28/2021
DOI: 10.1016/j.bbrc.2021.02.145
PMID: 33812052

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Abstract

Cigarette smoke (CS) contains many toxins that collectively harm nearly every organ in the body, and smoking is a key risk factor for many chronic diseases. Aside from its toxic actions, CS may alter expression of the drug- and steroid-binding pregnane X receptor (PXR), which when activated upregulates expression of cytochrome P450 (CYP) enzymes, glutathione transferases (GSTs), and multidrug resistance protein 1 (MDR1), an adaptive metabolic array that mediates clearance of CS component toxins. We sought to identify new PXR agonists that may be useful for restoring PXR activity in conditions wherein it is suppressed, and their mechanisms of PXR binding and activation. PXR has a uniquely larger, hydrophobic, and highly flexible ligand-binding domain (LBD) vs. other nuclear receptors, enabling it to interact with structurally diverse molecules. We tested certain calcium channel blockers (CCBs) as a pharmacological subset of potential PXR ligands, analyzing by molecular docking methods, and identified a putative active site in the PXR LBD, along with the relevant bonds and bonding energies. We analyzed felodipine binding and agonist activity in detail, as it showed the lowest binding energy among CCBs tested. We found felodipine was a potent PXR agonist as measured by luciferase reporter assay, whereas CCBs with higher binding energies were less potent (amlodipine) or nearly inactive (manidipine), and it induced CYP3A4 expression in HepG2 cells, a known target of PXR agonism. Felodipine also both induced PXR mRNA in HepG2 hepatocytes and reduced CS extract-induced diminution of PXR levels, indicating it modulates PXR expression. The results illuminate mechanisms of ligand-induced PXR activation and identify felodipine as a novel PXR agonist. •Analyzed calcium channel blocker (CCB) interactions with pregnane X receptor (PXR).•Identified and characterized selective CCBs as novel PXR agonists.•Cigarette smoke (CS) downregulates PXR mRNA and protein levels.•CCB felodipine reverses such CS-induced downregulation.
 Calcium channel blocker Cigarette smoke Cytochrome p450 HepG2 Molecular modeling Nuclear receptor

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