Transport of phosphatidylcholine in MDR3-negative epithelial cell lines via drug-induced MDR1 P-glycoprotein

Human MDR1 P-glycoprotein (P-gp) is a membrane efflux pump for cytotoxics, whereas MDR3 P-gp is a phosphatidylcholine transporter. We have examined a role for MDR1 P-gp in phosphatidylcholine transport in MDR3-negative epithe lial cells that have been induced to express the MDR1 P-gp by exposure to c ytotoxics. The accumulation and retention of the fluorescently labelled pho sphatidylcholine analogue, C12-NBD-PC, was studied in resistant, KBV1 and M CFadr, and sensitive, KB3-1 and MCF7, cells. Lower accumulation and decreas ed retention of C12-NBD-PC was evident in resistant cells, e.g., KBV1 accum ulated 56%, and MCFadr accumulated 60%, of C12-NBD-PC levels in KB3-1 and M CF7, respectively. Treatment with the MDR1 P-gp inhibitor, verapamil, alter ed the kinetics of C12-NBD-PC in the resistant cells to more closely follow the pattern of C12-NBD-PC handling by sensitive cells. Comparison of C12-N BD-PC to that of the model MDR1 P-gp substrate, rhodamine-123, indicated ph osphatidylcholine turnover kinetics by MDR1 P-gp to be relatively low. The transport by MDR1 P-gp of phosphatidylcholine from inner to outer membrane leaflet may regulate P-gp function and fulfill a role in the MDR1 multidrug -resistant phenotype. (C) 1999 Academic Press.