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. Transp ort analysis revealed that cholate efflux in the variant L1210/C7 cell line had declined 8-fold, due to the loss of a bromosulfophthalein-se nsitive efflux system, the major extrusion route for cholate in parent al cells. Efflux measurements showed further that a bromosulfophthalei n-sensitive efflux system for methotrexate was also absent in L1210/C7 cells. Total unidirectional efflux of methotrexate, however, was simi lar in the variant and parental cells, since the loss in the bromosulf ophthalein-sensitive system was compensated by a rise in a second prob enecid-sensitive route. The latter was identified from inhibitor studi es to be the same system which acts as a minor efflux route for methot rexate in parental cells. These results support the hypothesis that L1 210 cells contain a bromosulfophthalein-sensitive efflux system which mediates the unidirectional extrusion of either methotrexate or cholat e, and a second probenecid-sensitive route which differs from the brom osulfophthalein-sensitive system in inhibitor specificity and also in its ability to transport methotrexate but not cholate.