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 unidirectional efflux systems for the extrusion of methotrexate and cholate. Efflux activity was sensitive to temperature and to energy deprivation by treatment with antimycin A and to various other compounds which do not affect energy metabolism. A comparison of inhibitor sensitivities revealed that methotrexate and cholate efflux exhibit substantial differences in half-maximal inhibition (IC50) by indomethacin, reserpine, ethacrynic acid, ketoprofen, probenecid, and bromosulfophthalein, although these systems could not be distinguished by their responses to prostaglandin A1, meclofenamic acid, indoprofen, and biphenylacetic acid. Comparisons between cell lines showed that methotrexate efflux in CCRF-CEM cells exhibits an inhibitor response comparable to a secondary 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 methotrexate and cholate. These results indicate that CCRF-CEM cells contain similar but separate systems for the efflux of methotrexate and cholate. CCRF-CEM cells thus differ from L1210 cells in that the latter mediate the efflux of methotrexate and cholate primarily via a single system.
Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, California 92037.
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Henderson
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Hughes
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Saxena
D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D019826:Cholic Acid; D002793:Cholic Acids / Q000378:metabolism*; D004137:Dinitrochlorobenzene / Q000494:pharmacology; D004976:Ethacrynic Acid / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008727:Methotrexate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D011454:Prostaglandins A / Q000494:pharmacology
D002793:Cholic Acids; D004137:Dinitrochlorobenzene; D011454:Prostaglandins A; C039702:methotrexate N-hydroxysuccinimide ester; D019826:Cholic Acid; D004976:Ethacrynic Acid; C100573:prostaglandin A1; D007213:Indomethacin; D008727:Methotrexate