DISTINCT SYSTEMS MEDIATE THE UNIDIRECTIONAL EFFLUX OF METHOTREXATE AND CHOLATE IN HUMAN CCRF-CEM CELLS

Human CCRF-CEM cells were shown to contain energy-dependent and unidir ectional efflux systems for the extrusion of methotrexate and cholate. Efflux activity was sensitive to temperature and to energy deprivatio n by treatment with antimycin A and to various other compounds which d o not affect energy metabolism. A comparison of inhibitor sensitivitie s revealed that methotrexate and cholate efflux exhibit substantial di fferences in half-maximal inhibition (IC50) by indomethacin, reserpine , ethacrynic acid, ketoprofen, probenecid, and bromosulfophthalein, al though these systems could not be distinguished by their responses to prostaglandin A(1), meclofenamic acid, indoprofen, and biphenylacetic acid. Comparisons between cell lines showed that methotrexate efflux i n CCRF-CEM cells exhibits an inhibitor response comparable to a second ary efflux system for methotrexate in L1210 cells (system II), whereas the inhibitor response of cholate efflux in CCRF-CEM cells resembles efflux system I in L1210 cells, the primary efflux route for both meth otrexate and cholate. These results indicate that CCRF-CEM cells conta in similar but separate systems for the efflux of methotrexate and cho late. CCRF-CEM cells thus differ from L1210 cells in that the latter m ediate the efflux of methotrexate and cholate primarily via a single s ystem. (C) 1995 Academic Press, Inc.