The pregnane X receptor (PXR, NR1I2) is a xenobiotic-activated transcription factor with high levels of expression in the liver. It not only plays a key role in drug metabolism and elimination, but also promotes tumor growth, drug resistance, and metabolic diseases. It has been proposed as a therapeutic target for type II diabetes, metabolic syndrome, and inflammatory bowel disease, and PXR antagonists have recently been considered as a therapy for colon cancer. There are currently no PXR antagonists that can be used in a clinical setting. Nevertheless, due to the large and complex ligand-binding pocket (LBP) of the PXR, it is challenging to discover PXR antagonists at the orthosteric site. Alternative ligand binding sites of the PXR have also been proposed and are currently being studied. Recently, the AF-2 allosteric binding site of the PXR has been identified, with several compounds modulating the site discovered. Herein, we aimed to summarize our current knowledge of allosteric modulation of the PXR as well as our attempt to unlock novel allosteric sites. We describe the novel binding function 3 (BF-3) site of PXR, which is also common for other nuclear receptors. In addition, we also mention a novel allosteric site III based on in silico prediction. The identified allosteric sites of the PXR provide new insights into the development of safe and efficient allosteric modulators of the PXR receptor. We therefore propose that novel PXR allosteric sites might be promising targets for treating chronic metabolic diseases and some cancers.

• Klíčová slova
• AF-2 site, BF-3 site, CAR, PAM-antagonist, PXR, allosteric site, pregnane X receptor,
• MeSH
• alosterické místo MeSH
• diabetes mellitus 2. typu * MeSH
• furylfuramid MeSH
• lidé MeSH
• ligandy MeSH
• pregnanový X receptor MeSH
• receptory cytoplazmatické a nukleární MeSH
• steroidní receptory * metabolismus   MeSH
• xenobiotika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• furylfuramid MeSH
• ligandy MeSH
• pregnanový X receptor MeSH
• receptory cytoplazmatické a nukleární MeSH
• steroidní receptory * MeSH
• xenobiotika MeSH

Pregnane X Receptor (PXR) is a ligand-activated transcription factor which binds many structurally different molecules. The receptor is able to regulate the expression of a wide array of genes and is involved in cancer and different key physiological processes such as the metabolism of drugs/xenobiotics and endogenous compounds including lipids and carbohydrates, and inflammation. Algae, sponges, sea squirts, and other marine organisms are some of the species from which structurally new molecules have been isolated that have been subsequently identified in recent decades as ligands for PXR. The therapeutic potential of these natural compounds is promising in different areas and has recently resulted in the registration of trabectedin by the FDA as a novel antineoplastic drug. Apart from being potentially novel drugs, these compounds can also serve as models for the development of new molecules with improved activity. The aim of this review is to succinctly summarize the currently known natural molecules isolated from marine organisms with a proven ability to interact with PXR.

• Klíčová slova
• CYP450, PXR, cancer, gene regulation, inflammation, marine origin, natural compound,
• MeSH
• biologické přípravky chemie   izolace a purifikace   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• Porifera chemie   MeSH
• pregnanový X receptor metabolismus   MeSH
• regulace genové exprese účinky léků   MeSH
• Urochordata chemie   MeSH
• vodní organismy chemie   MeSH
• vyvíjení léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• biologické přípravky MeSH
• ligandy MeSH
• pregnanový X receptor MeSH

The pregnane X receptor (PXR) is a drug/xenobiotic-activated transcription factor of crucial importance for major cytochrome P450 xenobiotic-metabolizing enzymes (CYP) expression and regulation in the liver and the intestine. One of the major target genes regulated by PXR is the cytochrome P450 enzyme (CYP3A4), which is the most important human drug-metabolizing enzyme. In addition, PXR is supposed to be involved both in basal and/or inducible expression of many other CYPs, such as CYP2B6, CYP2C8, 2C9 and 2C19, CYP3A5, CYP3A7, and CYP2A6. Interestingly, the dynamics of PXR-mediated target genes regulation has not been systematically studied and we have only a few mechanistic mathematical and biologically based models describing gene expression dynamics after PXR activation in cellular models. Furthermore, few indirect mathematical PKPD models for prediction of CYP3A metabolic activity in vivo have been built based on compartmental models with respect to drug⁻drug interactions or hormonal crosstalk. Importantly, several negative feedback loops have been described in PXR regulation. Although current mathematical models propose these adaptive mechanisms, a comprehensive mathematical model based on sufficient experimental data is still missing. In the current review, we summarize and compare these models and address some issues that should be considered for the improvement of PXR-mediated gene regulation modelling as well as for our better understanding of the quantitative and spatial dynamics of CYPs expression.

• Klíčová slova
• Pregnane X receptor, gene regulation, mathematical models, simulation,
• MeSH
• genové regulační sítě * MeSH
• lidé MeSH
• pregnanový X receptor MeSH
• steroidní receptory genetika   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• teoretické modely * MeSH
• zpětná vazba fyziologická MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• pregnanový X receptor MeSH
• steroidní receptory MeSH
• systém (enzymů) cytochromů P-450 MeSH

Pregnane X receptor is a ligand-activated nuclear receptor (NR) that mainly controls inducible expression of xenobiotics handling genes including biotransformation enzymes and drug transporters. Nowadays it is clear that PXR is also involved in regulation of intermediate metabolism through trans-activation and trans-repression of genes controlling glucose, lipid, cholesterol, bile acid, and bilirubin homeostasis. In these processes PXR cross-talks with other NRs. Accumulating evidence suggests that the cross-talk is often mediated by competing for common coactivators or by disruption of coactivation and activity of other transcription factors by the ligand-activated PXR. In this respect mainly PXR-CAR and PXR-HNF4α interference have been reported and several cytochrome P450 enzymes (such as CYP7A1 and CYP8B1), phase II enzymes (SULT1E1, Gsta2, Ugt1a1), drug and endobiotic transporters (OCT1, Mrp2, Mrp3, Oatp1a, and Oatp4) as well as intermediate metabolism enzymes (PEPCK1 and G6Pase) have been shown as down-regulated genes after PXR activation. In this review, I summarize our current knowledge of PXR-mediated repression and coactivation interference in PXR-controlled gene expression regulation.

• Klíčová slova
• PXR, cross-talk, gene regulation, metabolism, nuclear receptor,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH