PMC:6194691 / 57380-62016 JSONTXT

{"project":"MyTest","denotations":[{"id":"30340614-7392035-30706116","span":{"begin":353,"end":356},"obj":"7392035"},{"id":"30340614-7910522-30706117","span":{"begin":598,"end":601},"obj":"7910522"},{"id":"30340614-2563168-30706118","span":{"begin":678,"end":681},"obj":"2563168"},{"id":"30340614-2463300-30706118","span":{"begin":678,"end":681},"obj":"2463300"},{"id":"30340614-1975805-30706118","span":{"begin":678,"end":681},"obj":"1975805"},{"id":"30340614-1356979-30706118","span":{"begin":678,"end":681},"obj":"1356979"},{"id":"30340614-12486090-30706118","span":{"begin":678,"end":681},"obj":"12486090"},{"id":"30340614-16361063-30706118","span":{"begin":678,"end":681},"obj":"16361063"},{"id":"30340614-1968065-30706119","span":{"begin":1063,"end":1066},"obj":"1968065"},{"id":"30340614-7910961-30706119","span":{"begin":1063,"end":1066},"obj":"7910961"},{"id":"30340614-24624364-30706119","span":{"begin":1063,"end":1066},"obj":"24624364"},{"id":"30340614-19325113-30706119","span":{"begin":1063,"end":1066},"obj":"19325113"},{"id":"30340614-19325113-30706120","span":{"begin":1167,"end":1170},"obj":"19325113"},{"id":"30340614-18619525-30706121","span":{"begin":1989,"end":1992},"obj":"18619525"},{"id":"30340614-23789951-30706122","span":{"begin":1994,"end":1997},"obj":"23789951"},{"id":"30340614-12438926-30706123","span":{"begin":1999,"end":2002},"obj":"12438926"},{"id":"30340614-12706238-30706123","span":{"begin":1999,"end":2002},"obj":"12706238"},{"id":"30340614-12958161-30706123","span":{"begin":1999,"end":2002},"obj":"12958161"},{"id":"30340614-15126373-30706123","span":{"begin":1999,"end":2002},"obj":"15126373"},{"id":"30340614-17196184-30706123","span":{"begin":1999,"end":2002},"obj":"17196184"},{"id":"30340614-18619525-30706124","span":{"begin":2071,"end":2074},"obj":"18619525"},{"id":"30340614-23789951-30706125","span":{"begin":2076,"end":2079},"obj":"23789951"},{"id":"30340614-16361063-30706126","span":{"begin":2081,"end":2084},"obj":"16361063"},{"id":"30340614-17196184-30706127","span":{"begin":2086,"end":2089},"obj":"17196184"},{"id":"30340614-15314169-30706127","span":{"begin":2086,"end":2089},"obj":"15314169"},{"id":"30340614-15501592-30706127","span":{"begin":2086,"end":2089},"obj":"15501592"},{"id":"30340614-18619525-30706128","span":{"begin":2331,"end":2334},"obj":"18619525"},{"id":"30340614-21291474-30706129","span":{"begin":2336,"end":2339},"obj":"21291474"},{"id":"30340614-17196184-30706130","span":{"begin":2341,"end":2344},"obj":"17196184"},{"id":"30340614-9489736-30706131","span":{"begin":2346,"end":2349},"obj":"9489736"},{"id":"30340614-9681461-30706131","span":{"begin":2346,"end":2349},"obj":"9681461"},{"id":"30340614-10421622-30706131","span":{"begin":2346,"end":2349},"obj":"10421622"},{"id":"30340614-12817896-30706131","span":{"begin":2346,"end":2349},"obj":"12817896"},{"id":"30340614-18680196-30706131","span":{"begin":2346,"end":2349},"obj":"18680196"},{"id":"30340614-11879359-30706132","span":{"begin":2432,"end":2435},"obj":"11879359"},{"id":"30340614-15101825-30706132","span":{"begin":2432,"end":2435},"obj":"15101825"},{"id":"30340614-16190927-30706132","span":{"begin":2432,"end":2435},"obj":"16190927"},{"id":"30340614-25481827-30706133","span":{"begin":2619,"end":2621},"obj":"25481827"},{"id":"30340614-21118088-30706134","span":{"begin":2623,"end":2626},"obj":"21118088"},{"id":"30340614-23789951-30706135","span":{"begin":2628,"end":2631},"obj":"23789951"},{"id":"30340614-26187753-30706136","span":{"begin":2633,"end":2636},"obj":"26187753"},{"id":"30340614-12535575-30706137","span":{"begin":2643,"end":2646},"obj":"12535575"},{"id":"30340614-15134482-30706137","span":{"begin":2643,"end":2646},"obj":"15134482"},{"id":"30340614-16025095-30706137","span":{"begin":2643,"end":2646},"obj":"16025095"},{"id":"30340614-16337012-30706137","span":{"begin":2643,"end":2646},"obj":"16337012"},{"id":"30340614-16714484-30706137","span":{"begin":2643,"end":2646},"obj":"16714484"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"ABC efflux transporters\nIt has long been appreciated that the brain represents a pharmacological sanctuary and is selectively “protected” from the toxic effects of many chemotherapeutic agents. These include vincristine and doxorubicin (aka adriamycin), which fail to penetrate the blood–brain barrier as well as their lipid solubilities would suggest [162]. A major part of this failure to penetrate has since been attributed to the presence of the multidrug transporter, P-glycoprotein. Absence of this transporter in knock-out mice was shown to allow entry of toxic agents including ivermectin [203]. P-glycoprotein was found to be located in the luminal membrane (see e.g. [204–209]) of the endothelial cells and is believed to act there to transport substrates out of the cells so rapidly that little remains to penetrate the abluminal membrane and enter the brain.\nIt is believed by many that P-glycoprotein, a transmembrane protein, acts by removing its lipophilic substrates from the lipid layer of the cell membrane, depositing them back into the blood [210–213]. Its structure has been investigated in both substrate-free and inhibitor bound conformations [213] and binding sites for various of its many substrates identified within the large cavity seen in the substrate-free conformation. It is the binding and hydrolysis of ATP that provides the motive force leading to a large conformational change in the P-glycoprotein and the transfer and expulsion of its substrates. There are two ATP binding sites located on the cytoplasmic side of the protein.\nP-glycoprotein, otherwise called ABCB1, is a member of the ABC (ATP-Binding Cassette) family of proteins many of which are primary active transporters that utilize the hydrolysis of ATP to fuel substrate transport. Since its discovery, other ABC active transporters with broad substrate profiles have been found in the luminal membrane of the endothelial cells. These include Breast Cancer Resistance Protein, BCRP (ABCG2) [180, 197, 214–218] and Multidrug Resistance Proteins, MRPs 4 and 5 (ABCC4 and 5) [180, 197, 209, 218–221]. MRP1 (ABCC1) has also been implicated but levels of this transporter are thought to be low in brain endothelial cells in situ and only increase in cultured brain endothelial cells once they are removed from the brain microenvironment [180, 184, 218, 222–226]. MRP1 and MRP2 are apparently upregulated and clearly expressed in epilepsy [227–229].\nThe role of efflux from endothelial cell to blood by ABC transporters in preventing influx of many substances from blood into the brain has been extensively reviewed (see e.g. [57, 196, 197, 199, 221, 230–234]. The regulation of P-glycoprotein, BCRP and MRP2 at the blood–brain barrier has been reviewed by Miller [221].\nThe role of ABC transporters in efflux from the brain parenchyma differs depending on the nature of the substrate. As described in Fig. 9, for substances that are sufficiently lipid soluble to cross the endothelial cell membranes rapidly by passive transport, the presence of ABC efflux transporters can greatly reduce blood-to-brain influx, as observed experimentally. However, as also explained in Fig. 9 the ABC transporters in the luminal membrane will have only a modest effect, e.g. a doubling, on the rate of brain-to-blood efflux. This may be of little consequence as the rate of efflux for lipid soluble substances is already high.\nFig. 9 The influence of ABC transporters on the movements of lipophilic substances. The substance is presumed to be able to enter and leave the endothelial cells by diffusion with rate constant kdiff., which for simplicity in this example is assumed to be same on both sides. The substance is expelled from the cell by ABC transporters on the luminal side at a rate, kactiveccell. With these assumptions the effect of the ABC transporters on influx can be calculated by setting cisf = 0 and the effect on efflux by setting cplasma = 0. In both sets of equations, the first line states that at steady-state the net flux into the cell on one side must equal the net flux out of the cell on the other. From the next to the last lines of both sets of equations, if the rate of ABC mediated expulsion from the cell is small or zero, the rate constants for both influx and efflux are (kdiff./2). By contrast from the last lines if the rate of ABC mediated expulsion is large, influx to the brain, J→, becomes very small, while efflux from the brain, J←, is doubled compared to the efflux with no ABC transporter\nThe role of ABC transporters for solutes with low passive permeability across the membranes is considered in the next section."}

{"project":"2_test","denotations":[{"id":"30340614-7392035-30706116","span":{"begin":353,"end":356},"obj":"7392035"},{"id":"30340614-7910522-30706117","span":{"begin":598,"end":601},"obj":"7910522"},{"id":"30340614-2563168-30706118","span":{"begin":678,"end":681},"obj":"2563168"},{"id":"30340614-2463300-30706118","span":{"begin":678,"end":681},"obj":"2463300"},{"id":"30340614-1975805-30706118","span":{"begin":678,"end":681},"obj":"1975805"},{"id":"30340614-1356979-30706118","span":{"begin":678,"end":681},"obj":"1356979"},{"id":"30340614-12486090-30706118","span":{"begin":678,"end":681},"obj":"12486090"},{"id":"30340614-16361063-30706118","span":{"begin":678,"end":681},"obj":"16361063"},{"id":"30340614-1968065-30706119","span":{"begin":1063,"end":1066},"obj":"1968065"},{"id":"30340614-7910961-30706119","span":{"begin":1063,"end":1066},"obj":"7910961"},{"id":"30340614-24624364-30706119","span":{"begin":1063,"end":1066},"obj":"24624364"},{"id":"30340614-19325113-30706119","span":{"begin":1063,"end":1066},"obj":"19325113"},{"id":"30340614-19325113-30706120","span":{"begin":1167,"end":1170},"obj":"19325113"},{"id":"30340614-18619525-30706121","span":{"begin":1989,"end":1992},"obj":"18619525"},{"id":"30340614-23789951-30706122","span":{"begin":1994,"end":1997},"obj":"23789951"},{"id":"30340614-12438926-30706123","span":{"begin":1999,"end":2002},"obj":"12438926"},{"id":"30340614-12706238-30706123","span":{"begin":1999,"end":2002},"obj":"12706238"},{"id":"30340614-12958161-30706123","span":{"begin":1999,"end":2002},"obj":"12958161"},{"id":"30340614-15126373-30706123","span":{"begin":1999,"end":2002},"obj":"15126373"},{"id":"30340614-17196184-30706123","span":{"begin":1999,"end":2002},"obj":"17196184"},{"id":"30340614-18619525-30706124","span":{"begin":2071,"end":2074},"obj":"18619525"},{"id":"30340614-23789951-30706125","span":{"begin":2076,"end":2079},"obj":"23789951"},{"id":"30340614-16361063-30706126","span":{"begin":2081,"end":2084},"obj":"16361063"},{"id":"30340614-17196184-30706127","span":{"begin":2086,"end":2089},"obj":"17196184"},{"id":"30340614-15314169-30706127","span":{"begin":2086,"end":2089},"obj":"15314169"},{"id":"30340614-15501592-30706127","span":{"begin":2086,"end":2089},"obj":"15501592"},{"id":"30340614-18619525-30706128","span":{"begin":2331,"end":2334},"obj":"18619525"},{"id":"30340614-21291474-30706129","span":{"begin":2336,"end":2339},"obj":"21291474"},{"id":"30340614-17196184-30706130","span":{"begin":2341,"end":2344},"obj":"17196184"},{"id":"30340614-9489736-30706131","span":{"begin":2346,"end":2349},"obj":"9489736"},{"id":"30340614-9681461-30706131","span":{"begin":2346,"end":2349},"obj":"9681461"},{"id":"30340614-10421622-30706131","span":{"begin":2346,"end":2349},"obj":"10421622"},{"id":"30340614-12817896-30706131","span":{"begin":2346,"end":2349},"obj":"12817896"},{"id":"30340614-18680196-30706131","span":{"begin":2346,"end":2349},"obj":"18680196"},{"id":"30340614-11879359-30706132","span":{"begin":2432,"end":2435},"obj":"11879359"},{"id":"30340614-15101825-30706132","span":{"begin":2432,"end":2435},"obj":"15101825"},{"id":"30340614-16190927-30706132","span":{"begin":2432,"end":2435},"obj":"16190927"},{"id":"30340614-25481827-30706133","span":{"begin":2619,"end":2621},"obj":"25481827"},{"id":"30340614-21118088-30706134","span":{"begin":2623,"end":2626},"obj":"21118088"},{"id":"30340614-23789951-30706135","span":{"begin":2628,"end":2631},"obj":"23789951"},{"id":"30340614-26187753-30706136","span":{"begin":2633,"end":2636},"obj":"26187753"},{"id":"30340614-12535575-30706137","span":{"begin":2643,"end":2646},"obj":"12535575"},{"id":"30340614-15134482-30706137","span":{"begin":2643,"end":2646},"obj":"15134482"},{"id":"30340614-16025095-30706137","span":{"begin":2643,"end":2646},"obj":"16025095"},{"id":"30340614-16337012-30706137","span":{"begin":2643,"end":2646},"obj":"16337012"},{"id":"30340614-16714484-30706137","span":{"begin":2643,"end":2646},"obj":"16714484"}],"text":"ABC efflux transporters\nIt has long been appreciated that the brain represents a pharmacological sanctuary and is selectively “protected” from the toxic effects of many chemotherapeutic agents. These include vincristine and doxorubicin (aka adriamycin), which fail to penetrate the blood–brain barrier as well as their lipid solubilities would suggest [162]. A major part of this failure to penetrate has since been attributed to the presence of the multidrug transporter, P-glycoprotein. Absence of this transporter in knock-out mice was shown to allow entry of toxic agents including ivermectin [203]. P-glycoprotein was found to be located in the luminal membrane (see e.g. [204–209]) of the endothelial cells and is believed to act there to transport substrates out of the cells so rapidly that little remains to penetrate the abluminal membrane and enter the brain.\nIt is believed by many that P-glycoprotein, a transmembrane protein, acts by removing its lipophilic substrates from the lipid layer of the cell membrane, depositing them back into the blood [210–213]. Its structure has been investigated in both substrate-free and inhibitor bound conformations [213] and binding sites for various of its many substrates identified within the large cavity seen in the substrate-free conformation. It is the binding and hydrolysis of ATP that provides the motive force leading to a large conformational change in the P-glycoprotein and the transfer and expulsion of its substrates. There are two ATP binding sites located on the cytoplasmic side of the protein.\nP-glycoprotein, otherwise called ABCB1, is a member of the ABC (ATP-Binding Cassette) family of proteins many of which are primary active transporters that utilize the hydrolysis of ATP to fuel substrate transport. Since its discovery, other ABC active transporters with broad substrate profiles have been found in the luminal membrane of the endothelial cells. These include Breast Cancer Resistance Protein, BCRP (ABCG2) [180, 197, 214–218] and Multidrug Resistance Proteins, MRPs 4 and 5 (ABCC4 and 5) [180, 197, 209, 218–221]. MRP1 (ABCC1) has also been implicated but levels of this transporter are thought to be low in brain endothelial cells in situ and only increase in cultured brain endothelial cells once they are removed from the brain microenvironment [180, 184, 218, 222–226]. MRP1 and MRP2 are apparently upregulated and clearly expressed in epilepsy [227–229].\nThe role of efflux from endothelial cell to blood by ABC transporters in preventing influx of many substances from blood into the brain has been extensively reviewed (see e.g. [57, 196, 197, 199, 221, 230–234]. The regulation of P-glycoprotein, BCRP and MRP2 at the blood–brain barrier has been reviewed by Miller [221].\nThe role of ABC transporters in efflux from the brain parenchyma differs depending on the nature of the substrate. As described in Fig. 9, for substances that are sufficiently lipid soluble to cross the endothelial cell membranes rapidly by passive transport, the presence of ABC efflux transporters can greatly reduce blood-to-brain influx, as observed experimentally. However, as also explained in Fig. 9 the ABC transporters in the luminal membrane will have only a modest effect, e.g. a doubling, on the rate of brain-to-blood efflux. This may be of little consequence as the rate of efflux for lipid soluble substances is already high.\nFig. 9 The influence of ABC transporters on the movements of lipophilic substances. The substance is presumed to be able to enter and leave the endothelial cells by diffusion with rate constant kdiff., which for simplicity in this example is assumed to be same on both sides. The substance is expelled from the cell by ABC transporters on the luminal side at a rate, kactiveccell. With these assumptions the effect of the ABC transporters on influx can be calculated by setting cisf = 0 and the effect on efflux by setting cplasma = 0. In both sets of equations, the first line states that at steady-state the net flux into the cell on one side must equal the net flux out of the cell on the other. From the next to the last lines of both sets of equations, if the rate of ABC mediated expulsion from the cell is small or zero, the rate constants for both influx and efflux are (kdiff./2). By contrast from the last lines if the rate of ABC mediated expulsion is large, influx to the brain, J→, becomes very small, while efflux from the brain, J←, is doubled compared to the efflux with no ABC transporter\nThe role of ABC transporters for solutes with low passive permeability across the membranes is considered in the next section."}