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.

• Keywords
• CYP450, PXR, cancer, gene regulation, inflammation, marine origin, natural compound,
• MeSH
• Biological Products chemistry   isolation & purification   pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Molecular Structure MeSH
• Porifera chemistry   MeSH
• Pregnane X Receptor metabolism   MeSH
• Gene Expression Regulation drug effects   MeSH
• Urochordata chemistry   MeSH
• Aquatic Organisms chemistry   MeSH
• Drug Development * MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Biological Products MeSH
• Ligands MeSH
• Pregnane X Receptor MeSH

The constitutive androstane receptor (CAR) is a nuclear receptor involved mainly in xenobiotic and endobiotic metabolism regulation. CAR is activated directly by its ligands via the ligand binding domain (LBD) or indirectly by inhibition of the epidermal growth factor (EGF) signaling. We found that leflunomide (LEF) and its main metabolite teriflunomide (TER), both used for autoimmune diseases treatment, induce the prototype CAR target gene CYP2B6 in primary human hepatocytes. As TER was discovered to be an EGF receptor antagonist, we sought to determine if TER is an indirect activator of CAR. In primary human hepatocytes and in differentiated HepaRG cells, we found that LEF and TER up-regulate CAR target genes CYP2B6 and CYP3A4 mRNAs and enzymatic activities. TER stimulated CAR+A mutant translocation into the nucleus but neither LEF nor TER activated the CAR LBD, CAR3 variant or pregnane X receptor (PXR) in gene reporter assays. Interestingly, TER significantly up-regulated CAR mRNA expression, a result which could be a consequence of both EGF receptor and ELK-1 transcription factor inhibition by TER or by TER-mediated activation of glucocorticoid receptor (GR), an upstream hormonal regulator of CAR. We can conclude that TER is a novel indirect CAR activator which through EGF inhibition and GR activation controls both detoxification and some intermediary metabolism genes.

• Keywords
• CAR, cytochrome P450, gene regulation, metabolism, nuclear receptor,
• Publication type
• Journal Article MeSH

The constitutive androstane receptor (CAR) is a critical nuclear receptor in the gene regulation of xenobiotic and endobiotic metabolism. The LanthaScreen(TM) TR-FRET CAR coactivator assay provides a simple and reliable method to analyze the affinity of a ligand to the human CAR ligand-binding domain (LBD) with no need to use cellular models. This in silico assay thus enables the study of direct CAR ligands and the ability to distinguish them from the indirect CAR activators that affect the receptor via the cell signaling-dependent phosphorylation of CAR in cells. For the current paper we characterized the pharmacodynamic interactions of three known CAR inverse agonists/antagonists-PK11195, clotrimazole and androstenol-with the prototype agonist CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3] thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) using the TR-FRET LanthaScreen(TM) assay. We have confirmed that all three compounds are inverse agonists of human CAR, with IC50 0.51, 0.005, and 0.35 μM, respectively. All the compounds also antagonize the CITCO-mediated activation of CAR, but only clotrimazole was capable to completely reverse the effect of CITCO in the tested concentrations. Thus this method allows identifying not only agonists, but also antagonists and inverse agonists for human CAR as well as to investigate the nature of the pharmacodynamic interactions of CAR ligands.

• MeSH
• Biological Assay methods   MeSH
• Isoquinolines pharmacology   MeSH
• Clotrimazole pharmacology   MeSH
• Constitutive Androstane Receptor MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Oximes pharmacology   MeSH
• Receptors, Cytoplasmic and Nuclear agonists   antagonists & inhibitors   metabolism   MeSH
• Thiazoles pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 6-(4-chlorophenyl)imidazo(2,1-b)(1,3)thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime MeSH Browser
• Isoquinolines MeSH
• Clotrimazole MeSH
• Constitutive Androstane Receptor MeSH
• Oximes MeSH
• PK 11195 MeSH Browser
• Receptors, Cytoplasmic and Nuclear MeSH
• Thiazoles MeSH