Altered expression of unidirectional extrusion routes for methotrexate and cholate in an efflux variant of L1210 cells.
The specificity and function of two unidirectional anion-efflux pumps in mouse L1210 cells were evaluated using a variant cell line selected for growth in the presence of cholate and bromosulfophthalein. Transport analysis revealed that cholate efflux in the variant L1210/C7 cell line had declined 8-fold, due to the loss of a bromosulfophthalein-sensitive efflux system, the major extrusion route for cholate in parental cells. Efflux measurements showed further that a bromosulfophthalein-sensitive efflux system for methotrexate was also absent in L1210/C7 cells. Total unidirectional efflux of methotrexate, however, was similar in the variant and parental cells, since the loss in the bromosulfophthalein-sensitive system was compensated by a rise in a second probenecid-sensitive route. The latter was identified from inhibitor studies to be the same system which acts as a minor efflux route for methotrexate in parental cells. These results support the hypothesis that L1210 cells contain a bromosulfophthalein-sensitive efflux system which mediates the unidirectional extrusion of either methotrexate or cholate, and a second probenecid-sensitive route which differs from the bromosulfophthalein-sensitive system in inhibitor specificity and also in its ability to transport methotrexate but not cholate.
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037.
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Henderson
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Hughes
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002793:Cholic Acids / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions; D004361:Drug Tolerance; D005089:Exocytosis / Q000187:drug effects; D007939:Leukemia L1210 / Q000235:genetics* / Q000378:metabolism; D008727:Methotrexate / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D011339:Probenecid / Q000494:pharmacology; D013448:Sulfobromophthalein / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D002793:Cholic Acids; D013448:Sulfobromophthalein; D011339:Probenecid; D008727:Methotrexate