Abstract
1. P-Glycoprotein is a 170-kDa transmembrane glycoprotein active efflux system that confers multidrug resistance in tumors, as well as normal tissues including brain.
2. The classical model of multidrug resistance in brain places the expression of P-glycoprotein at the luminal membrane of the brain microvascular endothelial cell. However, recent studies have been performed with human brain microvessels and double-labeling confocal microscopy using (a) the MRK16 antibody to human P-glycoprotein, (b) an antiserum to glial fibrillary acidic protein (GFAP), an astrocyte foot process marker, or (c) an antiserum to the GLUT1 glucose transporter, a brain endothelial plasma membrane marker. These results provide evidence for a revised model of P-glycoprotein function at the brain microvasculature. In human brain capillaries, there is colocalization of immunoreactive P-glycoprotein with astrocytic GFAP but not with endothelial GLUT1 glucose transporter.
3. In the revised model of multidrug resistance in brain, P-glycoprotein is hypothesized to function at the plasma membrane of astrocyte foot processes. These astrocyte foot processes invest the brain microvascular endothelium but are located behind the blood–brain barrier in vivo, which is formed by the brain capillary endothelial plasma membrane.
4. In the classical model, an inhibition of endothelial P-glycoprotein would result in both an increase in the blood–brain barrier permeability to a given drug substrate of P-glycoprotein and an increase in the brain volume of distribution (V D) of the drug. However, in the revised model of P-glycoprotein function in brain, which positions this protein transporter at the astrocyte foot process, an inhibition of P-glycoprotein would result in no increase in blood–brain barrier permeability, per se, but only an increase in the V D in brain of P-glycoprotein substrates.
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REFERENCES
Barrand, M. A., Robertson, K. J., and von Weikersthal, S. F. (1995). Comparisons of P-glycoprotein expression in isolated rat brain microvessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epididymal fat pad and from aorta. FEBS 374:179-183.
Beaulieu, E., Demeule, M., Pouliot, J.-F., Averill-Bates, D. A., Murphy, G. F., and Béliveau, R. (1995). P-Glycoprotein of blood-brain barrier: Cross-reactivity of MAb C219 with a 190 kDa protein in bovine and rat isolated brain capillaries. Biochim. Biophys. Acta 1233:27-32.
Becker, I., Becker, K.-F., Meyermann, R., and Hollt, V. (1991). The multidrug-resistance gene MDR-1 is expressed in human glial tumors. Acta Neuropathol. 82:516-519.
Cefalu, W. T., and Pardridge, W. M. (1985). Restrictive transport of a lipid-soluble peptide (cyclosporin) through the blood-brain barrier. J. Neurochem. 45:1954-1956.
Chen, A.-Y., Yu, C., Bodley, A., Peng, F., and Liu, L. F. (1993). A new mammalian DNA topoisomerase I poison Hoechst 33342: Cytotoxicity and drug resistance in human cell cultures. Cancer Res. 53:1332-1337.
Colombo, T., Zucchetti, M., and D'Incalci, M. (1994). Cyclosporin A markedly changes the distribution of doxorubicin in mice and rats. J. Pharmacol. Exp. Ther. 269:22-27.
Cordon-Cardo, C., O'Brien, J. P., Casals, D., Rittman-Grauer, L., Biedler, J. L., Melamed, M. R., and Bertino, J. R. (1989). Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA 86:695-698.
Cordon-Cardo, C., O'Brien, J. P., Boccia, J., Casals, D., Bertino, J. R., and Melamed, M. R. (1990). Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor stissues. J. Histochem. Cytochem. 38:1277-1287.
DeLange, E. C. M., DeBoer, A. G., and Breimer, D. D. (1995). Pharmacokinetics of the P-glycoprotein substrate rhodamine-123 in brain, determined by microdialysis and homogenates in mdr1a (−/−) and (+/+) mice. In Abstracts of the 1995 Cerebral Vascular Biology Conference, Paris, France, p. 60.
Fojo, A. T., Ueda, K., Slamon, D. J., Poplack, D. G., Gottesman, M. M., and Pastan, I. (1987). Expression of a multidrug-resistance gene in human tumors and tissues. Proc. Natl. Acad. Sci. USA 84:265-269.
Fontaine, M., Elmquist, W. F., and Miller, D. W. (1996). Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers. Life Sci. 59:1521-1531.
Georges, E., Tsuruo, T., and Ling, V. (1993). Topology of P-glycoprotein as determined by epitope mapping of MRK-16 monoclonal antibody. J. Biol. Chem. 268:1792-1798.
Gottesman, M. M., and Pastan, I. (1993). Biochemistry of multidrug resistance mediated by the multidrug transporter. Annu. Rev. Biochem. 62:385-427.
Hegmann, E. J., Bauer, H. C., and Kerbel, R. S. (1992). Expression and functional activity of P-glycoprotein in cultured cerebral capillary endothelial cells. Cancer Res. 52:6969-6975.
Huwyler, J., Drewe, J., Klusemann, C., and Fricker, G. (1996). Evidence for P-glycoprotein-modulated penetration of morphine-6-glucuronide into brain capillary endothelium. Br. J.Pharmacol. 118:1879-1885.
Jetté, L., and Béliveau, R. (1993). P-Glycoprotein is strongly expressed in brain capillaries. In Drewes, L. R., and Betz, A. L. (eds.), Frontiers in Cerebral Vascular Biology, Plenum Press, New York, pp. 121-125.
Jetté, L., Têtu, B., and Béliveau, R. (1993). High levels of P-glycoprotein detected in isolated brain capillaries. Biochim. Biophys. Acta 1150:147-154.
Jetté, L., Murphy, G. F., Leclerc, J.-M., and Béliveau, R. (1995a). Interaction of drugs with P-glycoprotein in brain capillaries. Biochem. Pharmacol. 50:1701-1709.
Jetté, L., Pouliot, J.-F., Murphy, G. F., and Béliveau, R. (1995b). Isoform I (mdr3) is the major form of P-glycoprotein expressed in mouse brain capillaries. Biochem. J. 305:761-766.
Juliano, R. L., and Ling, V. (1979). A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455:152-162.
Kartner, N., Evernden-Porelle, D., Bradley, G., and Ling, V. (1985). Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Nature 316:820-823.
Kessel, D., Bollerill, V., and Wodinsky, I. (1968). Uptake and retention of daunomycin by mouse leukemic cells as factors in drug response. Cancer Res. 28:938-941.
Lum, B. L., Fisher, G. A., Brophy, N. A., Yahanda, A. M., Adler, K. M., Kaubisch, S., Halsey, J., and Sikic, B. I. (1993). Clinical trials of modulation of multidrug resistance. Cancer 72:3502-3514.
Mayer, U., Wagenaar, E., Beijnen, J. H., Smit, J. W., Meijer, D. K. F., van Asperen, J., Borst, P., and Schinkel, A. H. (1996). Substantial excretion of digoxin via the intestinal mucosa and the prevention of long-term digoxin accumulation in the brain by the mdr1a P-glycoprotein. Br. J. Pharmacol. 19:1038-1044.
Morgan, M. E., Singhal, D., and Anderson, B. D. (1996). Quantitative assessment of blood-brain barrier damage during microdialysis. J. Pharmacol. Exp. Ther. 277:1167-1176.
Moro, V., Kacem, K., Springhetti, V., Seylaz, and Lasbennes, F. (1995). Microvessels isolated from brain: Localization of muscarinic sites by radioligand binding and immunofluorescent techniques. J. Cereb. Blood Flow Metab. 15:1082-1092.
Pardridge, W. M. (1991). Peptide Drug Delivery to the Brain, Raven Press, New York.
Pardridge, W. M., Boado, R. J., and Farrell, C. R. (1990). Brain-type glucose transporter (GLUT1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. J. Biol. Chem. 265:18035-18040.
Pardridge, W. M., Buciak, J. L., and Friden, P. M. (1991). Selective transport of anti-transferrin receptor antibody through the blood-brain barrier in vivo. J. Pharmacol. Exp. Ther. 259:66-70.
Pardridge, W. M., Kang, Y.-S., Buciak, J. L., and Yang, J. (1995). Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm. Res. 12:807-816.
Pardridge, W. M., Golden, P. L., Bickel, U., and Kang, Y.-S. (1997). Brain microvascular and astrocyte localization of P-glycoprotein. J. Neurochem. 68:1278-1285.
Qin, Y., and Sato, T. N. (1995). Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood-brain barrier development. Dev. Dynam. 202:172-180.
Riordan, J. R., and Ling, V. (1979). Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability. J. Biol. Chem. 254:12701-12705.
Sakata, A., Tamai, I., Kawazu, K., Deguchi, Y., Ohnishi, T., Saheki A., and Tsuji, A. (1994). In vivo evidence for ATP-dependent and P-glycoprotein-mediated transport of cyclosporin A at the blood-brain barrier. Biochem. Pharmacol. 48:1989-1992.
Samoto, K., Ikezaki, K., Yokoyama, N., and Fukui, M. (1994). P-glycoprotein expression in brain capillary endothelial cells after focal ischaemia in the rat. Neurol. Res. 16:217-223.
Schinkel, A. H., Smit, J. J. M., Van Tellingen, O., Beijnen, J. H., Wagenaar, E., Van Deemter, L., Mol, C. A. A. M., Van der Valk, M. A., Robanus-Maandag, E. C., Te Riele, H. P. J., Berns, A. J. M., and Borst, P. (1994). Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77:491-502.
Schinkel, A. H., Wagenaar, E., Mol, C. A. A. M., and van Deemter, L. (1996). P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:2517-2524.
Shalinsky, D. R., Andreeff, M., and Howell, S. B. (1990). Modulation of drug sensitivity by dipyridamole in multidrug resistant tumor cells in vitro. Cancer Res. 50:7537-7543.
Stewart, P. A. (1994). Glial-vascular relations. In Welch, K. M. A., Caplan, L. R., and Reis, D. J. (eds.), Primer on Cerebrovascular Diseases, Academic Press, New York, pp. 17-20.
Stewart, P. A., Béliveau, R., and Rogers, K. A. (1996). Cellular localization of P-glycoprotein in brain versus gonadal capillaries. J. Histochem. Cytochem. 44:679-685.
Sugawara, I., Hamada, H., Tsuruo, T., and Mori, S. (1990). Specialized localization of P-glycoprotein recognized by MRK 16 monoclonal antibody in endothelial cells of the brain and spinal cord. Jpn. J. Cancer Res. 81:727-730.
Tatsuta, T., Naito, M., Oh-hara, T., Sugawara, I., and Tsuruo, T. (1992). Functional involvement of Pglycoprotein in blood-brain barrier. J. Biol. Chem. 267:20383-20391.
Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I., and Willingham, M. C. (1989). Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: Evidence for localization on brain capillaries and crossreactivity of one antibody with a muscle protein. J. Histochem. Cytochem. 37:159-164.
Tishler, D. M., Weinberg, K. I., Hinton, D. R., Barbaro, N., Annett, G. M., and Raffel, C. (1995). MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia 36:1-6.
Tsuji, A., Terasaki, T., Takabatake, Y., Tenda, Y., Tamai, I., Yamashima, T., Moritani, S., Tsuruo, T., and Yamashita, J. (1992). P-Glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sci. 51:1427-1437.
Tsuji, A., Tamai, I., Sakata, A., Tenda, Y., and Terasaki, T. (1993). Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter, P-glycoprotein. Biochem. Pharmacol. 46:1096-1099.
Wang, Q., Yang, H., Miller, D. W., and Elmquist, W. F. (1995). Effect of the P-glycoprotein inhibitor, cyclosporin A, on the distribution of rhodamine-123 to the brain: An in vivo microdialysis study in freely-moving rats. Biochem. Biophys. Res. Commun. 211:719-726.
Weiler-Guettler, H., Zinke, H., Schepelmann, S., Seehaus, B., and Gassen, H. G. (1993). In Pardridge, W. M. (ed.), The Blood-Brain Barrier: Cellular and Molecular Biology, Raven Press, New York, pp. 323-338.
White, F. P., Dutton, G. R., and Norenberg, M. D. (1981). Microvessels isolated from rat brain: Localization of astrocyte processes by immunohistochemical techniques. J. Neurochem. 36:328-332.
Zaman, G. J. R., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., Pinedo, H. M., Scheper, R. J., Baas, F., Broxterman, H. J., and Borst, P. (1994). The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc. Natl. Acad. Sci. USA 91:8822-8826.
Zamora, J. M., Pearce, H. L., and Beck, W. T. (1988). Physical-chemical properties shared by compounds that modulate multidrug resistance in human leukemic cells. Mol. Pharmacol. 33:454-462.
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Golden, P.L., Pardridge, W.M. Brain Microvascular P-Glycoprotein and a Revised Model of Multidrug Resistance in Brain. Cell Mol Neurobiol 20, 165–181 (2000). https://doi.org/10.1023/A:1007093521681
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DOI: https://doi.org/10.1023/A:1007093521681