Enniatin B1 is a substrate of intestinal P-glycoprotein, multidrug resistance-associated protein 2 and breast cancer resistance protein
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Enniatins are cyclic hexadepsipeptides produced by various fungi, known to have ionophoric, antibiotic and insecticidal activity. The aim of the present study was to evaluate the intestinal absorption characteristics of enniatin B 1 (ENN-B 1 ). Using the human intestinal Caco-2 cell line, we found that the permeability of ENN-B 1 in the basolateral to apical direction was 6.7× higher as compared to the permeability in the opposite direction, indicating involvement of apically located transporters. Transport of ENN-B 1 in the apical to basolateral direction was increased significantly upon treatment of Caco-2 cells with the P-glycoprotein (Pgp) inhibitor verapamil and the multidrug resistance-associated protein 2 (MRP2) inhibitor MK571, but only weakly and not significantly after treatment with the breast cancer resistance protein (BCRP) inhibitor fumitremorgin C. Additionally, MDCK II cells over-expressing Pgp, MRP2 or BCRP, showed reduced sensitivity towards ENN-B 1 . These data demonstrate for the first time that ENN-B 1 is a substrate of MRP2 and suggests that Pgp, MRP2 and possibly BCRP are involved in transport of ENN-B 1 across the intestine.Keywords:
Abcg2
P-glycoprotein
Caco-2
Efflux
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P-glycoprotein
ABCC1
Multidrug Resistance-Associated Proteins
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The goal of the present study was to determine the effects of glyceollins on intestinal ABCC2 (ATP Binding Cassette C2, multidrug resistance protein 2, MRP2) and ABCG2 (ATP Binding Cassette G2, breast cancer resistance protein, BCRP) function using the Caco-2 cell intestinal epithelial cell model. Glyceollins are soy-derived phytoestrogens that demonstrate anti-proliferative activity in several sources of cancer cells. 5 (and 6)-carboxy-2′,7′-dichloroflourescein (CDF) was used as a prototypical MRP2 substrate; whereas BODIPY-prazosin provided an indication of BCRP function. Comparison studies were conducted with genistein. Glyceollins were shown to inhibit MRP2-mediated CDF transport, with activity similar to the MRP2 inhibitor, MK-571. They also demonstrated concentration-dependent inhibition BCRP-mediated efflux of BODIPY-prazosin, with a potency similar to that of the recognized BCRP inhibitor, Ko143. In contrast, genistein did not appear to alter MRP2 activity and even provided a modest increase in BCRP efflux of BODIPY-prazosin. In particular, glyceollin inhibition of these two important intestinal efflux transporters suggests the potential for glyceollin to alter the absorption of other phytochemicals with which it might be co-administered as a dietary supplement, as well as alteration of the absorption of pharmaceuticals that may be administered concomitantly.
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Isoflavonoid
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ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.
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Mitoxantrone
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We compared the inhibitory effect of various cyclodextrins (CyDs) on P‐glycoprotein (P‐gp) and multidrug resistance‐associated protein 2 (MRP2) function and examined the contribution of cholesterol to the inhibitory effect of 2,6‐di‐ O ‐methyl‐β‐cyclodextrin (DM‐β‐CyD) on the efflux activity of the function in Caco‐2 cell monolayers. Of various CyDs, DM‐β‐CyD significantly impaired the efflux activity of P‐gp and MRP2. DM‐β‐CyD released P‐gp and MRP2 from the monolayers in the apical side's transport buffer and decreased the extent of cholesterol as well as P‐gp and MRP2 in caveolae of Caco‐2 cell monolayers, but not caveolin and flotillin‐1. On the other hand, DM‐β‐CyD did not change MDR1 and MRP2 mRNA levels. Therefore, these results suggest that the inhibitory effect of DM‐β‐CyD on P‐gp and MRP2 function, at least in part, could be attributed to the release of these transporters from the apical membranes into the medium as secondary effects through cholesterol‐depletion in caveolae after treatment of Caco‐2 cell monolayers with DM‐β‐CyD.
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Enniatins are cyclic hexadepsipeptides produced by various fungi, known to have ionophoric, antibiotic and insecticidal activity. The aim of the present study was to evaluate the intestinal absorption characteristics of enniatin B 1 (ENN-B 1 ). Using the human intestinal Caco-2 cell line, we found that the permeability of ENN-B 1 in the basolateral to apical direction was 6.7× higher as compared to the permeability in the opposite direction, indicating involvement of apically located transporters. Transport of ENN-B 1 in the apical to basolateral direction was increased significantly upon treatment of Caco-2 cells with the P-glycoprotein (Pgp) inhibitor verapamil and the multidrug resistance-associated protein 2 (MRP2) inhibitor MK571, but only weakly and not significantly after treatment with the breast cancer resistance protein (BCRP) inhibitor fumitremorgin C. Additionally, MDCK II cells over-expressing Pgp, MRP2 or BCRP, showed reduced sensitivity towards ENN-B 1 . These data demonstrate for the first time that ENN-B 1 is a substrate of MRP2 and suggests that Pgp, MRP2 and possibly BCRP are involved in transport of ENN-B 1 across the intestine.
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Caco-2
Efflux
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ATP-binding cassette (ABC) multidrug transporters are drug efflux pumps located in the plasma membrane that utilize the energy of ATP hydrolysis to extrude a wide spectrum of endogenous and exogenous compounds from cells, including numerous (anticancer) drugs and/or their metabolites. The studies described in this thesis focus on the pharmacological functions of the ABC transporters: P-glycoprotein (P-gp/ABCB1), the Multidrug Resistance Proteins 2 and 3 (MRP2/ABCC2 and MRP3/ABCC3) and the Breast Cancer Resistance Protein (BCRP/ABCG2). Most results presented in this thesis were obtained by studying single and combination ABC multidrug transporter knockout mice. As ABC multidrug transporters do not only have very broad, but also substantially overlapping substrate specificities, they can often partially, or sometimes even fully, compensate for the loss of each other. Combination ABC drug transporter knockout mice are therefore invaluable tools to study the separate roles and functional overlap of ABC multidrug transporters. We generated and characterized combination P-gp/Mrp2 knockout mice and used these to assess the distinct roles of P-gp and Mrp2 in the pharmacokinetics of the anticancer drug paclitaxel. Although paclitaxel is an excellent P-gp substrate, Mrp2 was found to almost exclusively mediate the excretion of paclitaxel from the liver into the bile, whereas P-gp had little effect. This finding is especially interesting because Mrp2 was thus far thought to mainly affect organic anionic drugs in vivo. However, we show that Mrp2 can also be a major determinant of the pharmacokinetic behavior of highly lipophilic anti-cancer drugs, even in the presence of other efficient transporters. P-gp and BCRP combination knockout mice enabled us to demonstrate that both multidrug transporters act in concert at the blood-brain barrier in restricting the brain penetration of the novel tyrosine kinase inhibitor anticancer drugs dasatinib and sorafenib. Brain penetration of dasatinib was primarily restricted by P-gp, whereas loss of BCRP had no effect. However, when both transporters were absent a disproportionate increase in brain penetration of dasatinib was observed. In contrast, for sorafenib it was the other way around, i.e. absence of P-gp had no effect while BCRP deficiency resulted in markedly elevated brain levels. Again, simultaneous loss of both transporters resulted in a highly increased brain penetration. When we combined dasatinib with the dual P-gp and BCRP inhibitor elacridar we found that the brain penetration in wild-type mice could be increased to P-gp/BCRP knockout levels. These findings might be clinically relevant for patients with intracranial tumors, as concomitant administration of an inhibitor of P-gp and ABCG2 with dasatinib, sorafenib and possibly other tyrosine kinase inhibitors might result in better therapeutic responses in these patients. In conclusion, the studies described in this thesis demonstrate the power of combination ABC multidrug transporter knockout mouse models to study the pharmacological functions of ABC multidrug transporters. We expect that combination ABC transporter knockout mice will be extensively used as preclinical research tools.
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Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17β-d-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.
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Efflux
Organic anion-transporting polypeptide
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Estrone sulfate
Multidrug Resistance-Associated Proteins
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Probenecid
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Paracellular transport
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SY31-1 Our research focuses on genes and proteins that cause drug resistance in tumors, and/or influence the pharmacological and toxicological behavior of anticancer and many other drugs and toxins, including carcinogens. Insight into these systems may improve chemotherapy approaches for cancer as well as pharmacotherapy in a broader sense, and increase insights in factors determining susceptibility to carcinogens. To study the physiological, pharmacological and toxicological roles of the proteins involved, and their interactions, we generate and analyze knockout or transgenic mice lacking or overexpressing the relevant genes. Cell lines obtained from these mice are further used as tools to identify and characterize drug resistance genes. To date, we have primarily focused on plasma membrane proteins of the ATP binding cassette (ABC) transporter family, encompassing amongst others P-glycoprotein (P-gp or ABCB1), MRP2 (ABCC2) and BCRP (ABCG2). These proteins actively export a wide range of anticancer, anti-HIV/AIDS, and many other drugs from cells. This ATP-dependent drug extrusion can cause multidrug resistance (MDR) in tumor cells (1). P-gp, MRP2 and BCRP all localize to the apical membrane of polarized epithelial cells, resulting in vectorial transport of drug substrates, and there is considerable (albeit not complete) overlap in substrate specificity between these transporters. Expression of these transporters by cDNA transfection into polarized epithelial cell lines offers excellent tools to study their transport characteristics in vitro. In the past, we and others have generated knockout mice deficient for P-gp and Bcrp1, the murine homologue of BCRP. Experiments in P-gp and Bcrp1 knockout mice indicated that these transporters can variously protect an organism against exogenous toxins and drugs by limiting penetration of substrates into brain, testis, and fetus, by restricting uptake of orally administered substrates, and by mediating excretion of substrates via liver and intestine. Mice lacking Bcrp1 look overall normal, but they are extremely sensitive to the dietary chlorophyll breakdown product pheophorbide a, resulting in severe, sometimes lethal phototoxic lesions on light-exposed skin (2). Pheophorbide a is a porphyrin that occurs in various plant-derived foods and food supplements. Bcrp1 transports pheophorbide a and is highly efficient in limiting its uptake from ingested food. Furthermore, as predicted from previous in vivo inhibition experiments, Bcrp1 knockout mice demonstrated a 6-fold increased oral uptake, and 2-fold increased fetal penetration of topotecan. Bcrp1 knockout mice also displayed a novel type of protoporphyria: Erythrocyte levels of the heme precursor and phototoxin protoporphyrin IX were 10-fold increased. These results indicate that humans or animals with low or absent BCRP activity may be at increased risk for developing protoporphyria and diet-dependent phototoxicity, and provide a striking illustration of the importance of drug transporters in protection from toxicity of normal food constituents. The data imply that prolonged inhibition of BCRP by administration of BCRP inhibitors to patients should be monitored carefully for unexpected side effects. We have also identified a pronounced role for Bcrp1 in the pharmacokinetics of, and hence possibly protection from, dietary carcinogens (3). The food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is the most abundant heterocyclic amine found in various protein-containing foods. PhIP is mutagenic and carcinogenic in rodents, and it has been implicated in human breast carcinogenesis. Humans on a normal western diet are exposed to PhIP on a daily basis. We investigated whether Bcrp1 could affect PhIP exposure of the body, as this could implicate BCRP activity in the cancer risk due to PhIP. Using polarized cell lines we found that PhIP is efficiently transported by murine Bcrp1. In vivo pharmacokinetic studies in Bcrp1 knockout mice showed that Bcrp1 effectively restricts the exposure of mice to ingested PhIP, by decreasing its uptake from the gut lumen and by mediating hepatobiliary and intestinal elimination of PhIP. Intra- or interindividual differences in BCRP activity in humans may thus also affect the exposure to PhIP and related food carcinogens, with possible implications for cancer susceptibility. We are currently extending the functional analysis of BCRP and Bcrp1 in the pharmacokinetics of several anticancer drugs and dietary carcinogens. Moreover, by more detailed analysis of expression of Bcrp1 in mice and other species we have identified several additional organs where BCRP/Bcrp1 may have physiological and pharmacologically relevant functions. Some of these newly identified functions and their implications will be discussed.
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ABCC1
Multidrug Resistance-Associated Proteins
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Knockout mouse
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Intestinal ATP binding cassette (ABC) transporters may affect the bioavailability and effectiveness of orally administered drugs. Available studies on regional expression of intestinal efflux transporters were done with selected intestinal segments only and inconsistent with regard to the variability of transporter expression and the course of expression along the intestine. For an evaluation of the consistency between mRNA and protein expression, relative expression levels of P-glycoprotein (Pgp; ABCB1), breast cancer resistance protein (Bcrp; ABCG2), and multidrug resistance-associated protein (Mrp) 2 (ABCC2) were determined using quantitative real-time-polymerase chain reaction and Western blot in rat intestinal segments from duodenum, jejunum, ileum, and colon. In addition, the protein expression of Pgp, Bcrp, and Mrp2 from the entire rat intestine was studied by a complete 3-cm segmentation to evaluate the predictive power of expression analyses from selected intestinal segments. Pgp showed an increase from proximal to distal regions, Bcrp showed an arcuate pattern with highest expression toward the end of small intestine, and Mrp2 decreased along the intestinal axis from proximal to distal parts. No gender specific differences could be observed. Regarding the concordance of mRNA and protein expression, Pgp and Bcrp mRNA samples allow good estimations about the corresponding protein expression (for Pgp limited to the mdr1a isoform), but for Mrp2, pronounced deviation could be observed. All transporters showed considerable intra- and interindividual variability, especially at the protein level, making it problematic to take transporter expressions of small sections exemplary for general assumptions on intestinal abundances.
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P-glycoprotein
Efflux
Multidrug Resistance-Associated Proteins
Jejunum
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The intestinal epithelial membrane expresses ATP-binding cassette (ABC) transporters such as P-glycoprotein (P-gp), multi-drug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), in addition to various solute carrier (SLC) transporters. These ABC transporters affect the oral bioavailability of their substrate drugs.To review the contribution of ABC efflux transporters such as P-gp, MRP2, MRP3, and BCRP in the intestinal absorption of substrate drugs.Discussion was made by focusing on the site-specific expression and function of these ABC transporters, and the solubility and permeability of their substrate compounds.The increase in the solubility and permeability of orally administered drugs could be the key to escape barrier function of ABC transporters, especially P-gp.
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