Modulation of human P-glycoprotein epitope expression by temperature and/or resistance modulating agents

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Abstract
Three monoclonal antibodies (mAb), MRK16, MM4.17 and MCS7, directed against distinct epltopes on the external domain of human P-glycoproteln (Pgp), were used to follow Its expression on multldrug resistant (MDR)- cells. The linear MM4.17 epitope and conformatlonal MRK16 epitope showed a 4-fold higher expression at 37°C than at 4°C, while the detection of the conformatlonal MCS7 epitope did not change. Inhibition of Pgp function, by a short pretreatment of the MDR-cells with resistance-modulating agents (RMA), such as SDZ PSC 833 and SDZ 280-446, could not be related to depletion of Pgp from the cell surface, since their expression of the MM4.17 and MRK16 epltopes was found unchanged. However, a substantially higher expression of MC57 epitopes was found on RMA-treated cells than on untreated ones. Since this effect correlated to the strength of different RMA In reversing the MDR phenotype, MC57 epltopes might be more efficiently expressed on Inactivated) forms of the Pgp molecules, suggesting that RMA might Inhibit Pgp function by disturbing the conformation of individual Pgp molecules, their topographical distribution or polymerization status In the membrane.

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