Likewise, a PXR variant rs3814057 was discovered to be associated with increased susceptibility to TB. genes to initiate their transcription. The PXR is unique in that it has an indiscriminate ligand-binding domain name [1, 3]. Thus, PXR ligands vary widely from prescription drugs to herbs, dietary compounds, steroids, vitamins and environmental compounds/contaminants [1, 48]. Species differences of PXR activation have been well-characterized [1, 2, 4]. Like other nuclear receptors, PXR has a conserved DNA binding domain [9]. However , the ligand binding domain name of PXR differs remarkably amongst species [9, 10], which explains the differences in the activation of PXR and its target genes across species. The rifamycins are among of the most important classes of drugs in TB therapy and are ligands of human being PXR [1113]. PXR activation modulates drug metabolism, energy metabolism and immune response [2, 4, 14, 15], which can affect the efficacy and safety of TB therapy. In addition , polymorphisms ofPXRmay affect TB susceptibility [16]. In this review, we focus on the potential role of PXR in anti-TB drug metabolism, toxicity, efficacy, resistance, and TB susceptibility. == 1 . 1 . Functions of PXR == == 1 . 1 . 1 . Regulation of drug metabolizing enzymes and transporters == The fate of drugs is modulated by drug metabolizing enzymes (Phase I and II) and transporters. Phase I drug metabolizing enzymes consists mainly from the cytochrome P450 (CYP) family members [17]. They usually catalyze the conversion of parent compounds to more polar molecules through oxidation [17, 18]. Phase II enzymes are made up of transferases that add polar groups like Vortioxetine glucuronides to make the parent drug inactive and more water-soluble [18, 19]. Transporters together with phase I and II drug metabolizing enzymes coordinate the process of drug metabolism and disposition [20]. The PXR regulates drug metabolism and excretion through modulating the expression of drug metabolizing enzymes and transporters [1, 20]. The PXR regulates an ample number of the phase I enzymes including CYP3A4, CYP2B6 and CYP2C9 [1, 2124], which all play an important role in the metabolism of clinically used drugs. The PXR also regulates phase II enzymes and transporters, such as glutathione S-transferase (GST), sulfotransferase 2A1 (SULT2A1), UDP-glucoronosyl transferase 1A1 (UGT1A1), P-glycoprotien, multidrug resistance-associated protein 2 (MRP2), and organic anion transporting polypeptide 2 (OATP2) [2532]. Therefore , PXR activation significantly affects drug metabolism and disposition [33]. == 1 . 1 . 2 . Drug resistance == The human PXR has been implicated in the emergence of resistance to anti-cancer drugs. High expressions of PXR and its target genes CYP3A4 and P-glycoprotein were observed in a prostate cancer cell line that showed resistance to chemotherapy drugs [34]. High Vortioxetine expressions of PXR have also been observed in breast cancer, endometrial cancer and colon cancer, which were thought to be important for drug resistance in chemotherapy [3538]. == 1 . 1 Vortioxetine . 3. Energy metabolism == PXR activation suppresses gluconeogenesis through interaction with forkhead box protein O1 (FoxO1), cAMP response element-binding protein (CREB), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PCG1) and hepatocyte nuclear element 4 (HNF4) [3941]. In lipid metabolism, PXR activation inhibits fatty acid -oxidation and ketogenesis through the down regulation of carnitine palmitoyltransferase1 a (Cpt1a) and 3-hydroxy-3-methylglutarate-CoA synthase 2 (Hmgcs2), the two important enzymes in Mouse monoclonal to SRA fatty acid -oxidation and ketogenesis, respectively [42]. Furthermore, PXR upregulates the expression of stearoyl-CoA desaturase 1 (Scd1), a key enzyme in the synthesis.