Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vectorial transport of xenobiotics across the hepatocyte is mediated by various transport and transfer proteins that differ in ligand specificity and function. The influx of xenobiotics from the blood across the sinusoidal membrane of the hepatocyte can occur through passive or active transport processes. Once in the cell, xenobiotics can be sequestered by intracellular transfer proteins that prevent refluxing of the chemical back through the sinusoidal membrane. Transfer proteins may also facilitate the localization of the xenobiotics within the cell to sites of metabolism (i.e., the endoplasmic reticulum) or elimination (i.e., the canalicular membrane). Intracellular transfer proteins include glutathione S-transferases, fatty acid-binding proteins, and 3 alpha-hydroxysteroid dehydrogenase. Intracellular nuclear transfer proteins have also been identified that facilitate the transfer of chemical carcinogens from the cytoplasm into the cell nucleus. Several active transport proteins exist on the canalicular membrane of the hepatocyte that mediate the efflux of chemicals from the cell into the biliary canaliculus. Xenobiotic efflux proteins include the multispecific organic anion transporter, that eliminates xenobiotics that have undergone conjugation with glutathione, glucuronic acid, and possibly sulfate; and, P-glycoprotein, an active transporter that actively effluxes a variety of structurally diverse xenobiotics. Induction of P-glycoprotein by the amplification of its gene has been identified as a major cause of resistance of tumor cells to the toxicity of a variety of anti-cancer drugs. The hepatic induction of P-glycoprotein may also contribute to acquired resistance of organisms to environmental toxicants. Continued elucidation of xenobiotic transport and transfer processes at the cellular levels will significantly advance our understanding of processes involved in xenobiotic toxicity and acquired resistance to chemical toxicity.
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PMID:Hepatic vectorial transport of xenobiotics. 790 59

beta-Estradiol 17beta-D-glucuronide (E(2)17G), an endogenous cholestatic metabolite of estradiol, has been identified as a substrate for both hepatic P-glycoprotein (P-gp) and the multispecific organic anion transporter (MOAT), the liver-specific homologue of the multidrug resistance protein. The aim of the present studies was to determine the role of hepatic P-gp and MOAT in E(2)17G-mediated cholestasis and its biliary excretion using the isolated perfused rat liver. A bolus dose of E(2)17G (2 micromol) alone decreased the bile flow maximally from 1.5 to 0.3 microl/min/g liver. In the presence of an infusion of 1.5 microM daunorubicin or 1.0 microM Taxol, P-gp substrates, E(2)17G cholestasis was blocked such that 2 micromol E(2)17G decreased the bile flow from 1.48 to 1.31 or from 1.70 to 1.31 microl/min/g liver, respectively. In the presence of 1 and 3 microM Taxol, the log dose-response curves for E(2)17G cholestasis were shifted to the right 2-fold and 5-fold, respectively, in a parallel manner. Taxol (10 and 50 microM) inhibited the ATP-dependent transport of 10 microM E(2)17G in canalicular plasma membrane vesicles by 46 and 81%, respectively. Daunorubicin (1.5 microM) also shifted the log dose-response curve for E(2)17G cholestasis to the right about 4-fold. Neither Taxol nor daunorubicin decreased the biliary excretion of E(2)17G. Infusion of cyclosporine (6 microM), an inhibitor of both P-gp and MOAT, significantly blocked both E(2)17G cholestasis and biliary excretion, such that 16 micromol E(2)17G decreased the bile flow only 15-20%. In contrast, bromosulfophthalein, a MOAT substrate, had no effect on either E(2)17G-mediated cholestasis or its biliary excretion. These data indicate that P-gp plays an essential role in E(2)17G-mediated cholestasis and suggest that MOAT functions to deliver high concentrations of E(2)17G to P-gp.
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PMID:MDR1 substrates/modulators protect against beta-estradiol-17beta-D-glucuronide cholestasis in rat liver. 889 55

Rat liver cells express the multispecific organic anion transporter (cmoat, cmrp, mrp2) and P-glycoprotein (Pgp) in their canalicular membranes, proteins that are homologous to the multidrug-resistance related protein (MRP) and multidrug resistance (MDR) gene products in multidrug resistant tumor cells. We tested whether genistein, a modulator of drug resistance in tumor cells, affects biliary secretion of substrates of canalicular multispecific organic anion transporter (cmoat) (glucuronides of bilirubin and rhodamine, glutathione conjugate of bromsulphthalein) and of P-glycoprotein (Pgp) (rhodamine), respectively. Using the isolated perfused rat liver of control Wistar rats (TR+) and of a mutant strain (TR-) that expresses Pgp but not cmoat, we show that genistein effectively inhibits the secretion of anionic substrates of cmoat in Wistar rats but stimulates secretion of cationic rhodamine in TR- rats. Genistein is subject to glucuronidation and sulfatation and secretion of genistein and its metabolites stimulates bile flow in Wistar rats, but secretion is nearly absent in TR- rats. Because genistein and its metabolites are substrates for cmoat, inhibition of anion secretion by genistein is partially explained by competition for this transporter. Genistein is also a substrate of uridindiphosphate (UDP)-glucuronyltransferase isoenzyme(s). Inhibition of glucuronidation reduces the availability of bilirubin and rhodamine glucuronates for transport via cmoat, but unconjugated cationic rhodamine becomes available for transport via Pgp at an increased cellular concentration. Daidzein, a genistein analogue with no effect on protein tyrosine kinase (PTK) shows Similar effects on secretion of organic anions and cations supporting the conclusion that genistein affects transport in liver mainly through competition with other substrates at the sites of glucuronidation and transport via cmoat.
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PMID:Modulation of liver canalicular transport processes by the tyrosine-kinase inhibitor genistein: implications of genistein metabolism in the rat. 939 86

The multidrug resistance protein (MRP) has been shown to mediate ATP-dependent efflux of anticancer agents of diverse structure, such as daunorubicin (DNR), vincristine and etoposide. Thus, this protein does confer a multidrug resistant phenotype to cancer cells, similar to P-glycoprotein (Pgp). The substrate specificity of both transporter proteins is partly overlapping but is otherwise very distinct; because MRP is a multiple organic anion transporter, it transports certain glutathione conjugates and may be partly dependent on intracellular glutathione levels for the transport of anthracyclines. We have studied the transport kinetics of a series of anthracyclines in MRP and Pgp that overexpress tumor cell lines to obtain information on the substrate specificity of these proteins. The anthracyclines have modifications in the sugar moiety. The mean active efflux coefficient Ka, used to characterize the efficiency of the active efflux, was very similar for DNR and one of its 4'-deoxy-derivatives (eso-DNR) for MRP and Pgp [10-20 x 10(-10)/sec/(cells/ml)]. The permanently neutral derivatives 3'-deamino-3'-hydroxy-doxorubicin (OH-DOX) and 3'-deamino-3'-hydroxy-daunorubicin (OH-DNR) were effluxed by both proteins but had a lower Ka [2 x 10(-10) and 6 x 10(-10)/sec/(cells/ml) (OH-DOX)] and 2 x 10(-10) and 5 x 10(-10)/sec/(cells/ml) (OH-DNR)] for MRP and Pgp. Two anthracyclines, the doxorubicin derivative pirarubicin and 2'-bromo-4'-epi-DNR seemed to have a slightly higher Ka value for Pgp than for MRP. The apparent Michaelis-Menten constants (K(m)) and maximal efflux rates (VM) for the active transport were within a narrow range for both transporters, except for OH-DOX and OH-DNR, which had a lower VM in the case of MRP-mediated transport, suggesting a role of the amino group in the interaction with glutathione. Determination of the Hill coefficient (nH) of the MRP-mediated efflux gave most values close to 2, which suggests cooperativity of the transport of anthracyclines as reported before for Pgp. In conclusion, the transport kinetics of anthracyclines by MRP and Pgp are very similar.
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PMID:Kinetics of anthracycline efflux from multidrug resistance protein-expressing cancer cells compared with P-glycoprotein-expressing cancer cells. 944 42

Multidrug resistance protein (MRP) and P-glycoprotein (Pgp) are both members of the superfamily of ATP binding cassette plasma membrane drug transport proteins, which may be partly responsible for multidrug resistance of tumor cells. Although MRP has been identified as an organic anion transporter and Pgp as a transporter of certain positively charged compounds, there is considerable overlap in resistance spectrum, suggesting that both proteins transport important anticancer agents such as doxorubicin, etoposide, and vincristine. To obtain more insight in the handling of drugs by both proteins, we performed a detailed kinetic analysis of the efflux of calcein-acetoxymethyl ester (CAL-AM), a common neutral substrate for both proteins and compared it with the kinetics of efflux of calcein (CAL) which is only effluxed by MRP. CAL, the hydrolysis product of the nonfluorescent CAL-AM, is negatively charged and highly fluorescent. For this purpose Pgp+ K562/ADR and MRP+ GLC4/ADR tumor cells were incubated with CAL-AM in ATP-rich or ATP-depleted buffer, and the calcein formation was followed in time by fluorescence development. The intracellular CAL could be distinguished from effluxed (extracellular) CAL by addition to the medium of Co2+, which completely quenched the extracellular CAL fluorescence. The results showed that the Vmax for efflux of CAL-AM and CAL by MRP were very similar (1.0-1.2 x 10(5) molecules/cell/s) but that the Km for CAL-AM was much lower (0.05 microM) than for CAL (268 microM). The latter therefore is much less efficiently transported by MRP than CAL-AM. The Km for CAL-AM transport by Pgp (0.12 microM) was similar to that for MRP. Compared to previously published data for anthracyclines, the kinetic data for MRP-mediated CAL-AM pumping are most similar to those for the neutral hydroxydaunorubicin. These data give a quantitative account of transport properties of MRP for two related but differently charged compounds.
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PMID:Kinetic analysis of calcein and calcein-acetoxymethylester efflux mediated by the multidrug resistance protein and P-glycoprotein. 948 70

Polarized liver cells, hepatocytes, are involved in carbohydrate, protein and fat metabolism, breakdown of hemoglobin and production of bile. They are also involved in overall detoxification processes in an organism associated with the transport of bile salts, cholesterol, phospholipids, endo- and xenobiotics, end-products of cellular metabolism and ions through the canalicular region of the hepatocyte plasma membrane. Uptake of the above-mentioned compounds into hepatocytes through the basolateral region of plasma membrane is followed by their chemical modification by enzymes of detoxification phase I (e.g. cytochromes P-450) and phase II (e.g. glutathione S-transferases). Canalicular transport participates in phase III of detoxification, and the molecular machinery involved in this process is localized in the canalicular region of the plasma membrane. Canalicular transport includes the following transport systems: a specific canalicular transporter for bile salts, a multidrug resistance 2 P-glycoprotein (MDR2) participating in the transport of lipids, a multidrug resistance 3 P-glycoprotein (MDR3) responsible for the transport of organic cations and the multispecific organic anion transporter (cMOAT) involved in the transport of non-bile acid organic anions. The cMOAT transport system is discussed in this detailed review.
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PMID:Participation of the multispecific organic anion transporter in hepatobiliary excretion of glutathione S-conjugates, drugs and other xenobiotics. 956 41

One of the most challenging research areas in pharmacology in the new millennium is to understand why individuals respond differently to drug therapy and to what extent that individual variability in disposition is responsible for the observed differences in therapeutic efficacy and adverse reactions. To answer these complex questions, drug-metabolism research will rely on multidisciplinary approaches more than ever to investigate the many components involved in drug metabolism and disposition. Major research challenges include the following: (1) the genetic variation of drug targets (receptors, enzymes, etc.), drug transporters (multispecific organic anion transporter, P-glycoprotein, alpha-1-acid glycoprotein, etc.), and drug-metabolizing enzymes (cytochrome P450s and other enzymes); (2) the structure and function of all genetic variants of drug receptors, transporters, and metabolizing enzymes; (3) the induction, repression, and inhibition of all components involved in drug disposition; (4) the development of noninvasive in vivo methods to determine the physiological significance of various components in the handling of specific therapeutic agents in humans; (5) the mechanism of idiosyncratic adverse drug reactions; and (6) the pharmacokinetic and pharmacodynamic relationships to explain the individual differences in therapeutic efficacy and drug safety. Thus successful drug-metabolism research in the new millennium must integrate receptor biology, enzymology, recombinant DNA technology, biochemical toxicology, and drug disposition into study design and conduct balanced in vitro and in vivo experiments to allow a full understanding of the mechanisms of individual variability in drug therapy and drug safety.
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PMID:Drug-metabolism research challenges in the new millennium: individual variability in drug therapy and drug safety. 986 Sep 31

This paper describes some successful examples of a tissue selective drug delivery by utilizing specialized transporter(s) expressed in the targeted tissue cells. These are as follows: (1) oral delivery via H(+)/oligopeptide transporter, rat or human Pept1, in the intestine for beta-lactam antibiotics and a newly synthesized dipeptide, L-dopa-L-phenylalanine; (2) tumor cell specific delivery via the newly discovered H(+)/oligopeptide transporter(s) expressed in human fibrosarcoma cell line HT-1080 for model oligopeptides, glycylsarcosine and carnosine; (3) oral and hepatic delivery via an H(+)/monocarboxylate transporter in the intestine and an organic anion transporter in the liver for HMG-CoA reductase inhibitor, pravastatin; and (4) lung selective delivery via some type of transporter and avoidance of transfer into the brain via P-glycoprotein at the blood-brain barrier for a new quinolone antibacterial, HSR-903.
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PMID:Tissue selective drug delivery utilizing carrier-mediated transport systems. 1051 56

Incubation of PC 12 cells with the sulfonylurea drug, glipizide (1-100 microM), increased intracellular levels of the acidic metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The levels of these acids in the medium were decreased, indicating the presence of a sulfonylurea-sensitive organic anion transporter. In the present study, we demonstrate that the sulfonylurea-sensitive transport of acidic dopamine metabolites is unidirectional, ATP dependent, unaffected by ouabain or by tetrodotoxin and blocked by drugs that interact with the multidrug-resistance protein-1 (MRP1). However, over-expression of MRP1 did not affect transport of the acid metabolites. The pharmacological profile and ion dependence of the transporter also differs from that of known ATP-binding cassette (ABC) family members. Using microdialysis, we also demonstrated a sulfonylurea-sensitive transport process in the striatum of freely moving rats. These results show that acidic dopamine metabolites are actively secreted from dopaminergic cells into surrounding extracellular fluid by a previously undescribed transporter.
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PMID:Acidic dopamine metabolites are actively extruded from PC12 cells by a novel sulfonylurea-sensitive transporter. 1088 41

The kidney plays an important role in the elimination of numerous hydrophilic xenobiotics, including drugs, toxins, and endogenous compounds. It has developed high-capacity transport systems to prevent urinary loss of filtered nutrients, as well as electrolytes, and simultaneously to facilitate tubular secretion of a wide range of organic ions. Transport systems for organic anions and cations are primarily involved in the secretion of drugs in renal tubules. The identification and characterization of organic anion and cation transporters have been progressing at the molecular level. To date, many members of the organic anion transporter (OAT), organic cation transporter (OCT), and organic anion-transporting polypeptide (oatp) gene families have been found to mediate the transport of diverse organic anions and cations. It has also been suggested that ATP-dependent primary active transporters such as MDR1/P-glycoprotein and the multidrug resistance-associated protein (MRP) gene family function as efflux pumps of renal tubular cells for more hydrophobic molecules and anionic conjugates. Tubular reabsorption of peptide-like drugs such as beta-lactam antibiotics across the brush-border membranes appears to be mediated by two distinct H+/peptide cotransporters: PEPT1 and PEPT2. Renal disposition of drugs is the consequence of interaction and/or transport via these diverse secretory and absorptive transporters in renal tubules. Studies of the functional characteristics, such as substrate specificity and transport mechanisms, and of the localization of cloned drug transporters could provide information regarding the cellular network involved in renal handling of drugs. Detailed information concerning molecular and cellular aspects of drug transporters expressed in the kidney has facilitated studies of the mechanisms underlying renal disposition as well as transporter-mediated drug interactions.
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PMID:Cellular and molecular aspects of drug transport in the kidney. 1097 58


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