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Expression and Functional Activity of P-Glycoprotein in Cultured Cerebral Capillary Endothelial Cells¹

Cancer Research Division, Reichmann Research Building, Sunnybrook Health Science Centre, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada [E. J. H., R. S. K.], and Institute für Molekularbiologie der Österreichischen Akademie der Wissenschaften, Salzburg, Austria[H. C. B.]

² To whom requests for reprints should be addressed, at Cancer Research Division, Sunnybrook Health Science Centre, 2075 Bayview Ave., Toronto, Ontario, Canada M4N 3M5.

Analysis of a panel of endothelial cells passaged between 5 and 25 times and derived from various organs and species demonstrated that murine and porcine cerebral capillary endothelial cells actively excluded the fluorescent dye rhodamine 123, a substrate of P-glycoprotein. In addition, rhodamine 123 accumulation could be enhanced by the multidrug resistance chemosensitizer verapamil, known to reduce P-glycoprotein-mediated drug efflux. Cloned murine and porcine cerebral capillary endothelial cells were immunoreactive with the C219 monoclonal antibody to P-glycoprotein, and a C219 epitope-specific blocking peptide could abolish staining. The antiproliferative and cytotoxic effects of vincristine, but not cis-platinum(II) diamminedichloride, were increased by the addition of either verapamil or cyclosporin A to brain endothelial cell cultures in a 72-h assay, as determined by [³H]thymidine incorporation and total protein measurement. Cyclosporin A was a more effective reversal agent than verapamil. Thus, a P-glycoprotein isoform may be constitutively expressed in brain endothelial cells in vitro and supports the available data on in situ immunohistochemical staining of P-glycoprotein at the blood-brain barrier. In addition, these findings may indicate that one function of P-glycoprotein in vivo at the blood-brain barrier is the exclusion of xenobiotics from central nervous system tissues.

¹ This work was supported by a grant from the Medical Research Council of Canada to R. S. K. R. S. K. is a Terry Fox Career Scientist of the National Cancer Institute of Canada. E. J. H. was supported by a studentship award from the Medical Research Council of Canada.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/28/92. Accepted 10/23/92.

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