Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple drug resistance (mdr) genes encode P-glycoprotein, which is responsible for resistance to some cancer chemotherapeutic drugs and efflux of xenobiotics of cells. Thus, mdr can protect organs from xenobiotics. In rats, there are two mdr1 genes capable of xenobiotic transport, mdr1a and mdr1b. The purpose of this study was to determine the tissue distribution of rat mdr1a and mdr1b mRNA and whether microsomal enzyme inducers that increase phase I and II drug-metabolizing enzymes coordinately regulate mdr1a and/or mdr1b. The mRNA levels of mdr1a and mdr1b were determined using branched-DNA signal amplification technology. The highest level of expression of mdr1a mRNA was observed in the gastrointestinal tract, with levels increasing, respectively, from duodenum, jejunum, and ileum to large intestine. Expression levels of mdr1a mRNA in the cerebral cortex, cerebellum, kidney, lung, and liver were less than one-tenth of that in the ileum. The tissue distribution of mdr1b mRNA was similar to mdr1a with highest expression in the gastrointestinal tract but only about 3-fold higher than in most other tissues. The induction of mdr1a and mdr1b mRNA transcripts in liver, kidney, and ileum by treatment of rats with 18 chemicals representing aryl hydrocarbon receptor ligands, constitutive androstane receptor ligands, pregnane X receptor ligands, peroxisome proliferator-activated receptor ligands, electrophile-response-element activators, and CYP4502E1 inducers was assessed. Hepatic, renal, and intestinal expression of mdr1a and mdr1b mRNA were not significantly altered by treatment of rats with any of these classes of ligands. In conclusion, the primary expression of rat mdr1 genes is in the gastrointestinal tract where they are thought to function to decrease the absorption of some xenobiotics. Rat mdr1 gene expression is not readily increased by microsomal enzyme inducers in rats through coordinate mechanisms with phase I and II drug-metabolizing enzymes.
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PMID:Tissue distribution and chemical induction of multiple drug resistance genes in rats. 1206 43

During the past several years, important advances have been made in our understanding of the mechanisms that regulate the expression of genes that determine drug clearance, including phase I and phase II drug-metabolising enzymes and drug transporters. Orphan nuclear receptors have been recognised as key mediators of drug-induced changes in both metabolism and efflux mechanisms. In this review, we summarise recent findings regarding the function of nuclear receptors in regulating drug-metabolising and transport systems, and the relevance of these receptors to clinical drug-drug interactions and the development of new drugs. Emphasis is given to two newly recognised 'orphan' receptors (the pregnane X receptor [PXR] and the constitutive androstane receptor [CAR]) and their regulation of cytochrome P450 enzymes, such as CYP3A4, CYP2Cs and CYP2B6; and transporters, such as P-glycoprotein (MDR1), multidrug resistance-associated proteins (MRPs) and organic anion transporter peptide 2 (OATP2). Although 'cross-talk' occurs between these two receptors and their target sequences, significant species differences exist between ligand-binding and activation profiles for both receptors, and PXR appears to be the predominant or 'master' regulator of hepatic drug disposition in humans. Several important physiological processes, such as cholesterol synthesis and bile acid metabolism, are also tightly controlled by certain ligand-activated orphan nuclear receptors (farnesoid X receptor [FXR] and liver X receptor [LXR]). In general, their ability to bind a broad range of ligands and regulate an extensive array of genes that are involved in drug clearance and disposition makes these orphan receptors attractive targets for drug development. Drugs have the capacity to alter nuclear receptor expression (modulators) and/or serve as ligands for the receptors (agonists or antagonists), and thus can have synergistic or antagonistic effects on the expression of drug-metabolising enzymes and transporters. Coadministration of drugs that are nuclear receptor agonists or antagonists can lead to severe toxicity, a loss of therapeutic efficacy or an imbalance in physiological substrates, providing a novel molecular mechanism for drug-drug interactions.
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PMID:Role of orphan nuclear receptors in the regulation of drug-metabolising enzymes. 1467 87

Major determinants of the bioavailability of drugs are the degree of intestinal absorption and the hepatic first-pass effect. Drugs need to overcome several membrane barriers before reaching the systemic circulation, each of which expresses an array of specialized transport proteins for drug uptake or efflux. The P-glycoprotein MDR1 (multidrug resistance gene product, ABCB1) is expressed at the apical surface of enterocytes, where it mediates the efflux of xenobiotics into the intestinal lumen before these can access the portal circulation. Increased expression of MDR1 reduces the bioavailability of MDR1 substrates such as digoxin, cyclosporin, and taxol. Numerous xenobiotics can induce the MDR1 gene through activation of the nuclear pregnane X receptor (PXR). This explains the risk for drug interactions that is inherent to pharmacotherapy with PXR ligands such as rifampin, phenobarbital, statins, and St. John's wort. Other PXR-regulated genes include cytochrome P450 3A4, the digoxin and bile salt transporter Oatp2 (organic anion transporting polypeptide 2, Slc01a4) of the basolateral hepatocyte membrane, and the xenobiotic efflux pump Mrp2 (multidrug resistance associated protein 2, Abcc2) of the canalicular hepatocyte membrane. A second orphan nuclear receptor that is activated by xenobiotics is the constitutive androstane receptor (CAR), which induces Mrp2 and Mrp3 (Abcc3). The PXR and CAR are thus important "xenosensors" that mediate drug-induced activation of the detoxifying transport and enzyme systems in liver and intestine.
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PMID:Regulation of drug and bile salt transporters in liver and intestine. 1470 63

Drug metabolizing enzymes (DMEs) play central roles in the metabolism, elimination and detoxification of xenobiotics and drugs introduced into the human body. Most of the tissues and organs in our body are well equipped with diverse and various DMEs including phase I, phase II metabolizing enzymes and phase III transporters, which are present in abundance either at the basal unstimulated level, and/or are inducible at elevated level after exposure to xenobiotics. Recently, many important advances have been made in the mechanisms that regulate the expression of these drug metabolism genes. Various nuclear receptors including the aryl hydrocarbon receptor (AhR), orphan nuclear receptors, and nuclear factor-erythoroid 2 p45-related factor 2 (Nrf2) have been shown to be the key mediators of drug-induced changes in phase I, phase II metabolizing enzymes as well as phase III transporters involved in efflux mechanisms. For instance, the expression of CYP1 genes can be induced by AhR, which dimerizes with the AhR nuclear translocator (Arnt), in response to many polycyclic aromatic hydrocarbon (PAHs). Similarly, the steroid family of orphan nuclear receptors, the constitutive androstane receptor (CAR) and pregnane X receptor (PXR), both heterodimerize with the retinoid X receptor (RXR), are shown to transcriptionally activate the promoters of CYP2B and CYP3A gene expression by xenobiotics such as phenobarbital-like compounds (CAR) and dexamethasone and rifampin-type of agents (PXR). The peroxisome proliferator activated receptor (PPAR), which is one of the first characterized members of the nuclear hormone receptor, also dimerizes with RXR and has been shown to be activated by lipid lowering agent fibrate-type of compounds leading to transcriptional activation of the promoters on CYP4A gene. CYP7A was recognized as the first target gene of the liver X receptor (LXR), in which the elimination of cholesterol depends on CYP7A. Farnesoid X receptor (FXR) was identified as a bile acid receptor, and its activation results in the inhibition of hepatic acid biosynthesis and increased transport of bile acids from intestinal lumen to the liver, and CYP7A is one of its target genes. The transcriptional activation by these receptors upon binding to the promoters located at the 5-flanking region of these CYP genes generally leads to the induction of their mRNA gene expression. The physiological and the pharmacological implications of common partner of RXR for CAR, PXR, PPAR, LXR and FXR receptors largely remain unknown and are under intense investigations. For the phase II DMEs, phase II gene inducers such as the phenolic compounds butylated hydroxyanisol (BHA), tert-butylhydroquinone (tBHQ), green tea polyphenol (GTP), (-)-epigallocatechin-3-gallate (EGCG) and the isothiocyanates (PEITC, sulforaphane) generally appear to be electrophiles. They generally possess electrophilic-mediated stress response, resulting in the activation of bZIP transcription factors Nrf2 which dimerizes with Mafs and binds to the antioxidant/electrophile response element (ARE/EpRE) promoter, which is located in many phase II DMEs as well as many cellular defensive enzymes such as heme oxygenase-1 (HO-1), with the subsequent induction of the expression of these genes. Phase III transporters, for example, P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs), and organic anion transporting polypeptide 2 (OATP2) are expressed in many tissues such as the liver, intestine, kidney, and brain, and play crucial roles in drug absorption, distribution, and excretion. The orphan nuclear receptors PXR and CAR have been shown to be involved in the regulation of these transporters. Along with phase I and phase II enzyme induction, pretreatment with several kinds of inducers has been shown to alter the expression of phase III transporters, and alter the excretion of xenobiotics, which implies that phase III transporters may also be similarly regulated in a coordinated fashion, and provides an important mean to protect the body from xenobiotics insults. It appears that in general, exposure to phase I, phase II and phase III gene inducers may trigger cellular "stress" response leading to the increase in their gene expression, which ultimately enhance the elimination and clearance of these xenobiotics and/or other "cellular stresses" including harmful reactive intermediates such as reactive oxygen species (ROS), so that the body will remove the "stress" expeditiously. Consequently, this homeostatic response of the body plays a central role in the protection of the body against "environmental" insults such as those elicited by exposure to xenobiotics.
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PMID:Induction of phase I, II and III drug metabolism/transport by xenobiotics. 1583 10

MDR1/P-glycoprotein is an efflux transporter determining the absorption and presystemic elimination of many xenobiotics in the gut. Thus, interindividual differences in MDR1 expression may affect the efficacy of drug treatment. The expression of MDR1 is partially controlled by the pregnane X receptor (PXR), which mediates induction by many xenobiotics. Since it has been described that the nuclear receptors PXR and constitutive androstane receptor (CAR) can bind to the same binding sites, we investigated the role of CAR in the regulation of MDR1 gene expression. We demonstrate here by gel shift and transfection experiments that CAR binds to distinct nuclear receptor response elements in the -7.8 kbp enhancer of MDR1 and transactivates MDR1 expression through DR4 motifs to which the receptor binds as a heterodimer with RXR or as a monomer, respectively. Expression of the endogenous MDR1 gene is elevated in cells stably expressing CAR, thus arguing for the functional relevance of CAR-dependent activation of MDR1 . The physiological relevance of the regulation of MDR1 by CAR is further suggested by correlation of the expression of CAR and MDR1 in the human small intestine. In summary, our data suggest that CAR plays a role in the regulation of intestinal MDR1 expression.
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PMID:A role for constitutive androstane receptor in the regulation of human intestinal MDR1 expression. 1600 37

Caco-2 cell line is extensively used as an in vitro model in studying small intestinal absorption but it lacks proper expression of efflux pumps and cytochrome P450 enzymes that are involved in absorption and first pass metabolism of drugs. We created two novel Caco-2 cell lines expressing orphan nuclear receptors pregnane X receptor and constitutive androstane receptor that regulate many genes involved in xenobiotic metabolism. We conducted a systematic study on expression of some metabolic genes, P-glycoprotein activity and absorption properties of several drugs with these new cell lines and previously described modified Caco-2 cell lines (MDR1 transfection, vincristine treatment and 1alpha,25-dihydroxyvitamin D3 treatment). A short culture time medium was also included in the study. Most modified cell lines formed tight differentiated monolayers. MDR1, CYP2C9 and CYP3A4 genes were upregulated in some cell lines. Elevated P-glycoprotein activities were observed by calcein-AM uptake experiments but this did not affect significantly the permeability of selected P-glycoprotein substrates. Some cell lines had similar passive and active permeability properties to Caco/WT cells while in few cell lines these were altered. Passive transcellular permeability was modestly elevated in all modified cell lines. In addition, several compounds showed pH-dependent permeability properties.
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PMID:Absorption properties and P-glycoprotein activity of modified Caco-2 cell lines. 1611 71

Membrane transporters play a critical role in the absorption, distribution, and elimination of both endogenous substrates and xenobiotics. Defects in transporter function can lead to altered drug disposition including toxicity or loss of efficacy. Inflammation is one condition during which variable drug response has been demonstrated, and this can be attributed, at least in part, to changes in the expression of transporter genes. Thus, knowledge of the mechanisms behind transporter regulation can significantly contribute to our ability to predict variations in drug disposition among individuals and during inflammatory disease. The discovery of several xenobiotic-activated nuclear hormone receptors during the past decade including the pregnane X receptor, constitutive androstane receptor, and farnesoid X receptor has contributed greatly toward this endeavor. These receptors regulate the expression of transporters such as P-glycoprotein, MRP2, MRP3, BCRP, and OATP2 (Oatp1a1/OATP1B1), all of which undergo altered expression during an inflammatory response. Nuclear receptors may therefore play an important role in mediating this effect. This review presents what is currently known about the role of nuclear receptors in transporter regulation during inflammation. The use of this knowledge toward understanding interindividual variation in drug response and drug interactions during inflammation as well toward the development of therapeutics to treat transporter-related diseases will also be discussed.
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PMID:Regulation of transporters by nuclear hormone receptors: implications during inflammation. 1807 49

Induction of drug enzyme activity in the intestine can strongly determine plasma levels of drugs. It is therefore important to predict drug-drug interactions in human intestine in vitro. We evaluated the applicability of human intestinal precision-cut slices for induction studies in vitro. Morphological examination and intracellular ATP levels indicated tissue integrity up to 24 h of incubation, whereas in proximal jejunum slices, the metabolic rate toward most substrates remained at 40 to 50% of initial values. In colon slices, the cytochrome P450 conversions were below the detection limit, but conjugation rates remained relatively constant during incubation. The inducibility of drug-metabolizing enzymes and P-glycoprotein was evaluated using prototypical inducers for five induction pathways. beta-Naphthoflavone (aryl hydrocarbon receptor ligand) induced CYP1A1 (132-fold in colon and 362-fold in proximal jejunum) and UDP glucuronosyltransferase (UGT) 1A6 mRNA (9.8-fold in colon and 3.2-fold in proximal jejunum). In proximal jejunum, rifampicin (RIF) [pregnane X receptor (PXR) ligand] induced CYP3A4 (5.2-fold), CYP2B6 (2-fold), UGT1A6 (2.2-fold), and multidrug resistance-1 (MDR1)/ABCB1 mRNA (2.7-fold), whereas 6beta-hydroxytestosterone formation (CYP3A4) increased 2-fold. In colon, RIF induced UGT1A6 32-fold and MDR1 2.2-fold. Dexamethasone (glucocorticoid receptor and PXR ligand) induced CYP3A4 mRNA (3.5-fold) and activity (5-fold) in proximal jejunum. Phenobarbital (constitutive androstane receptor activator) induced CYP3A4 (4.1-fold, only in jejunum), CYP2B6 (4.9-fold in colon and 2.3-fold in proximal jejunum), and MDR1/ABCB1 mRNA and CYP3A4 activity (2-fold only proximal jejunum). Quercetin (nuclear factor-E2-related factor 2 activator) induced UGT1A6 mRNA (6.7-fold in colon and 2.2-fold in proximal jejunum). In conclusion, this study shows that human intestinal precision-cut slices are useful to study induction of drug-metabolizing enzymes and transporters in the human intestine.
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PMID:Induction of metabolism and transport in human intestine: validation of precision-cut slices as a tool to study induction of drug metabolism in human intestine in vitro. 1809 37

Our work contributes to the understanding of the mechanisms of drug resistance in epilepsis. This study aimed to investigate i) the levels of expression of P-glycoprotein (P-gp), and multidrug resistance-associated proteins (MRP)1 and 2, ii) the activation of the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), and iii) the relationship between increased P-gp and MRPs expression and PXR and CAR activation, in immortalized rat brain microvascular endothelial cell lines, GPNT and RBE4, following treatment with the antiepileptic drugs (AEDs), topiramate, phenobarbital, carbamazepine, tiagabine, levetiracetam, and phenytoin, using Western blotting and immunocytochemistry methods. Carbamazepine, phenobarbital and phenytoin induced the highest levels of P-gp and MPRs expression that was associated with increased activation of PXR and CAR receptors as compared to levetiracetam, tiagabine and topiramate. We conclude that P-gp and MRPs are differently overexpressed in GPNT and RBE4 by various AEDs and both PXR and CAR are involved in the drug-resistant epilepsy induced by carbamazepine, phenobarbital and phenytoin.
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PMID:Induction of nuclear receptors and drug resistance in the brain microvascular endothelial cells treated with antiepileptic drugs. 1847 23

Unlike classical enzymes, drug-metabolizing enzymes (DMEs), such as the liver microsomal cytochrome P450, UDP-glucuronyltransferase, epoxide hydrolase, and flavin-containing monooxygenase, all exhibit broad substrate specificities, low turnover rates, atypical kinetics, and other unusual properties. Receptors (the pregnane X receptor, NR1I2; the constitutive androstane receptor, NR1I3; and the aromatic hydrocarbon receptor) responsible for the induction of DMEs and transporters (P-glycoprotein) responsible for drug transport also have broad substrate specificities. These promiscuous proteins are all intimately involved in drug disposition. Promiscuous proteins, by definition, are known for diversity, but not specificity, in their interaction with drugs. In this review, we analyzed recent advances on the three dimensional structures and kinetic properties of DMD proteins from crystallography, mutational, and kinetic studies to gain insights into the structural and biochemical basis for the promiscuous ligand-protein interactions of the proteins. Large substrate-binding cavities (SBCs), binding of more than one substrate/effector and binding of substrates in alternative orientations and locations within the SBCs, rotation of a substrate at the active site, and substantial substrate-induced conformational changes of the SBCs are common features of the promiscuous DMEs, receptors, and transporters, and therefore, are important parameters to be considered in dealing with drug metabolism issues and safety evaluation of drugs and environmental chemicals.
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PMID:The challenges of dealing with promiscuous drug-metabolizing enzymes, receptors and transporters. 1853 74


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