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

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, enabl

SUBMITTER: Reddy RT 

PROVIDER: S-EPMC8085111 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature