Warfarin, a potential pollutant in aquatic environment acting through Pxr signaling pathway and γ-glutamyl carboxylation of vitamin K-dependent proteins
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Pregnane X receptor
Accidental ingestion of anticoagulant rodenticide bait by poultry rarely leads to clinical signs of poisoning, but represents a risk for the consumer because of potential residues in the laid eggs. An assay was conducted for a better risk assessment. Three groups of laying hens were given a single oral dose of 10, 30 or 90 mg warfarin/kg BW. Eggs were collected for 14 d, and warfarin was analyzed by reversed-phase high-performance liquid chromatography. Warfarin was present in the white for 3 to 4 d following anticoagulant ingestion, while concentration increased in the yolk until the 5th or 6th d, and then gradually decreased. At the end of experimentation, warfarin was still detected at below 100 ng/g in the yolk of eggs in each group.
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It is becoming increasingly evident that constitutive, induced, and regulated expression of genes important to the drug disposition process such as drug transporters, phase I and II metabolic enzymes are largely under the transcriptional control of certain nuclear receptor (NR) family members. In the past decade, important new insights regarding the role and relevance of ligand-activated nuclear receptors such as such as the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in terms of their activation by endogenous biochemicals, natural products, as well as synthetic compounds have led to a much better understanding of the xenobiotic-mediated induction process and the clinical relevance of such NRs to drug therapy in general. However, in addition to CAR and PXR, many orphan and adopted orphan NRs have recently been identified as key regulators of drug disposition genes. Indeed, nuclear receptors including farnesoid X receptor, peroxisome proliferator-activated receptor, and hepatocyte nuclear factors (1α, 3 and 4α) exhibit overlapping ligand specificities and regulate multiple gene targets, resulting in tissue- and organ-specific expression of drug disposition genes. In this review, the biology, pathophysiology, and the potential clinical relevance of such NRs to drug disposition and response are discussed. Keywords: nuclear receptors, gene transcription, phase I metabolism, phase II metabolism, transporters
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Introduction: 'Orphan' nuclear receptors belong to the nuclear receptor (NR) superfamily of transcriptional factors. Binding of ligands to these receptors results in the recruitment of the co-activators, thereby regulating the expression of cognate target genes. Areas covered: This review discusses the transcriptional regulation of P450 genes by two major xenobiotic nuclear receptors, pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Additional PXR and CAR target genes include those encoded for UDP-glucuronosyltransferases, glutathione S-transferases, sulfotransferases and drug transporters. The authors discuss the involvement of PXR and CAR in endobiotic metabolism. They also review the polymorphisms of PXR and CAR. Expert opinion: PXR and CAR are both xenobiotic and endobiotic receptors. A remarkably diverse set of chemicals can activate PXR and CAR. There is significant cross-talk among xenobiotic receptors. Future studies are needed to focus on the polymorphisms of the nuclear receptors and the complex regulatory networks among nuclear receptors. Considerations should be given while designing PXR- or CAR-targeting pharmaceutics to avoid adverse drug effects. In the meantime, due to the diverse functions of PXR and CAR, agonists or antagonists for these receptors may have therapeutic potentials in managing certain diseases and enhancing therapeutic indexes.
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Induction of drug metabolism was described more than 40 years ago. Progress in understanding the molecular mechanism of induction of drug-metabolizing enzymes was made recently when the important roles of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), two members of the nuclear receptor superfamily of transcription factors, were discovered to act as sensors for lipophilic xenobiotics, including drugs. CAR and PXR bind as heterodimeric complexes with the retinoid X receptor to response elements in the regulatory regions of the induced genes. PXR is directly activated by xenobiotic ligands, whereas CAR is involved in a more complex and less well understood mechanism of signal transduction triggered by drugs. Most recently, analysis of these xenobiotic-sensing nuclear receptors and their nonmammalian precursors such as the chicken xenobiotic receptor suggests an important role of PXR and CAR also in endogenous pathways, such as cholesterol and bile acid biosynthesis and metabolism. In this review, recent findings regarding xenosensors and their target genes are summarized and are put into an evolutionary perspective in regard to how a living organism has derived a system that is able to deal with potentially toxic compounds it has not encountered before.
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Pregnane X receptor
Constitutive androstane receptor
Farnesoid X receptor
Liver X receptor
Liver receptor homolog-1
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1. Pival at 0·025% is somewhat less toxic than warfarin at 0·005% to R. norvegicus when ingested for periods up to 72 hr. It is also less acceptable in a dry cereal bait. 2. Pival and warfarin at 0·025 % are about equally toxic and equally acceptable to R. rattus . 3. Young R. rattus appear to be more resistant than heavier rats to both Pival and warfarin. 4. The fungicidal properties of Pival are discussed.
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Pregnane X receptor
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Warfarin is commonly used worldwide as a rodenticide. It inhibits coagulation of blood by inhibiting vitamin K 2,3-epoxide reductase (VKOR) activity. An inadequate supply of vitamin K blocks the production of prothrombin and causes hemorrhage. It has been reported that repeated or long-term treatments with this drug cause resistance in wild rodents. However, the mechanism of warfarin resistance in rodents is still not known precisely. Recent studies reported and identified the function of the molecule, vitamin K epoxide reductase complex subunit 1 (VKORC1), which is the main unit of VKOR. An amino acid substitution in VKORC1 is one of the supposed mechanisms of warfarin resistance. An accelerated detoxification system involving cytochrome P450 (CYP) could also cause the rodenticide resistance. Administration of SKF-525A, a potent inhibitor for P450, increased the mortality due to reduction of warfarin metabolism in warfarin-resistant rats. Meanwhile, the appearance of warfarin-resistant rodents has led to the development of the more effective and toxic rodenticide superwarfarin, which is widely used in Europe and the USA. However, animals resistant to this second-generation rodenticide have already been reported in Europe. In this review, we focus on the mechanism and the pleiotropic effects of pesticide resistance in wild rodents.
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The pregnane X receptor (PXR) is a member of the nuclear receptor family of ligand-regulated transcription factors. Like many former orphan nuclear receptors, it contains both DNA and ligand binding domains and binds to response elements in the regulatory regions of target genes as a heterodimer with RXRα. Unlike the vast majority of nuclear receptors, however, PXR responds to a wide variety of chemically distinct xenobiotics and endobiotics, regulating the expression of genes central to both drug and bile acid metabolism. We review the structural basis of PXRs promiscuity in ligand binding, its recruitment of transcriptional coregulators, its potential formation of higher-order nuclear receptor complexes, and its control of target gene expression. Structural flexibility appears to be central to the receptors ability to conform to ligands that differ both in size and shape. We also discuss the clinical implications of PXRs role in the drugdrug interactions, cancer, and cholestatic liver disease.
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Constitutive androstane receptor
Small heterodimer partner
Xenobiotic
Orphan receptor
Liver receptor homolog-1
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Pregnane X receptor
Constitutive androstane receptor
Small heterodimer partner
Farnesoid X receptor
Liver receptor homolog-1
Estrogen-related receptor gamma
Crosstalk
PELP-1
Liver X receptor
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