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

Pregnane X receptor (PXR) is a member of the nuclear receptor (NR) superfamily of ligand-activated transcription factors and is activated by a huge variety of endobiotics and xenobiotics, including many clinical drugs. PXR plays key roles not only as a xenosensor in the regulation of both major phase I and II drug metabolism and transporters but also as a physiological sensor in the modulation of bile acid and cholesterol metabolism, glucose and lipid metabolism, and bone and endocrine homeostasis. Post-translational modifications such as phosphorylation have been shown to modulate the activity of many NRs, including PXR, and constitute an important mechanism for crosstalk between signaling pathways and regulation of genes involved in both xenobiotic and endobiotic metabolism. In addition, microRNAs have recently been shown to constitute another level of PXR activity regulation. The objective of this review is to comprehensively summarize current understanding of post-transcriptional and post-translational modifications of PXR in regulation of xenobiotic-metabolizing cytochrome P450 (CYP) genes, mainly in hepatic tissue. We also discuss the importance of PXR in crosstalk with cell signaling pathways, which at the level of transcription modify expression of genes associated with some physiological and pathological stages in the organs. Finally, we indicate that these PXR modifications may have important impacts on CYP-mediated biotransformation of some clinically used drugs.

• MeSH
• biotransformace MeSH
• enzymová indukce účinky léků   MeSH
• interakční proteinové domény a motivy MeSH
• játra účinky léků   enzymologie   metabolismus   MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• posttranskripční úpravy RNA * účinky léků   MeSH
• posttranslační úpravy proteinů * účinky léků   MeSH
• pregnanový X receptor MeSH
• steroidní receptory chemie   genetika   metabolismus   MeSH
• systém (enzymů) cytochromů P-450 genetika   metabolismus   MeSH
• xenobiotika metabolismus   farmakokinetika   toxicita   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• messenger RNA MeSH
• pregnanový X receptor MeSH
• steroidní receptory MeSH
• systém (enzymů) cytochromů P-450 MeSH
• xenobiotika MeSH

Metformin is widely used in the treatment of type-2 diabetes. The pleotropic effects of metformin on glucose and lipid metabolism have been proposed to be mediated by the activation of AMP-activated protein kinase (AMPK) and the subsequent up-regulation of small heterodimer partner (SHP). SHP suppresses the functions of several nuclear receptors involved in the regulation of hepatic metabolism, including pregnane X receptor (PXR), which is referred to as a "master regulator" of drug/xenobiotic metabolism. In this study, we hypothesize that metformin suppresses the expression of CYP3A4, a main detoxification enzyme and a target gene of PXR, due to SHP up-regulation. We employed various gene reporter assays in cell lines and qRT-PCR in human hepatocytes and in Pxr(-/-) mice. We show that metformin dramatically suppresses PXR-mediated expression of CYP3A4 in hepatocytes. Consistently, metformin significantly suppressed the up-regulation of Cyp3a11 mRNA in the liver and intestine of wild-type mice, but not in Pxr(-/-) mice. A mechanistic investigation of the phenomenon showed that metformin does not significantly up-regulate SHP in human hepatocytes. We further demonstrate that AMPK activation is not involved in this process. We show that metformin disrupts PXR's interaction with steroid receptor coactivator-1 (SRC1) in a two-hybrid assay independently of the PXR ligand binding pocket. Metformin also inhibited vitamin D receptor-, glucocorticoid receptor- and constitutive androstane receptor (CAR)-mediated induction of CYP3A4 mRNA in human hepatocytes. We show, therefore, a suppressive effect of metformin on PXR and other ligand-activated nuclear receptors in transactivation of the main detoxification enzyme CYP3A4 in human hepatocytes.

• MeSH
• aktivace transkripce MeSH
• cytochrom P-450 CYP3A genetika   metabolismus   MeSH
• hepatocyty účinky léků   metabolismus   MeSH
• hypoglykemika farmakologie   MeSH
• koaktivátory jaderných receptorů metabolismus   MeSH
• konstitutivní androstanový receptor MeSH
• kultivované buňky MeSH
• lidé MeSH
• membránové proteiny genetika   metabolismus   MeSH
• messenger RNA metabolismus   MeSH
• metformin farmakologie   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• polohový reflex účinky léků   MeSH
• pregnanový X receptor MeSH
• proteinkinasy aktivované AMP fyziologie   MeSH
• receptory cytoplazmatické a nukleární metabolismus   fyziologie   MeSH
• receptory glukokortikoidů fyziologie   MeSH
• receptory kalcitriolu fyziologie   MeSH
• reportérové geny MeSH
• signální transdukce MeSH
• steroidní receptory genetika   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• Cyp3a11 protein, mouse MeSH Prohlížeč
• cytochrom P-450 CYP3A MeSH
• hypoglykemika MeSH
• koaktivátory jaderných receptorů MeSH
• konstitutivní androstanový receptor MeSH
• membránové proteiny MeSH
• messenger RNA MeSH
• metformin MeSH
• nuclear receptor subfamily 0, group B, member 2 MeSH Prohlížeč
• pregnanový X receptor MeSH
• proteinkinasy aktivované AMP MeSH
• receptory cytoplazmatické a nukleární MeSH
• receptory glukokortikoidů MeSH
• receptory kalcitriolu MeSH
• steroidní receptory MeSH