MODULATION OF HUMAN P-GLYCOPROTEIN EPITOPE EXPRESSION BY TEMPERATURE AND OR RESISTANCE-MODULATING AGENTS/

Three monoclonal antibodies (mAb), MRK16, MM4.17 and MC57, directed ag ainst distinct epitopes on the external domain of human P-glycoprotein (Pgp), were used to follow its expression on multidrug resistant (MDR )-cells. The linear MM4.17 epitope and conformational MRK16 epitope sh owed a 4-fold higher expression at 37 degrees C than at 4 degrees C, w hile the detection of the conformational MC57 epitope did not change. Inhibition of Pgp function, by a short pretreatment of the MDR-cells w ith resistance-modulating agents (RMA), such as SDZ PSC 833 and SDZ 28 0-446, could not be related to depletion of Pgp from the cell surface, since their expression of the MM4.17 and MRK16 epitopes was found unc hanged. However, a substantially higher expression of MC57 epitopes wa s found on RMA-treated cells than on untreated ones, Since this effect correlated to the strength of different RMA in reversing the Mon phen otype, MC57 epitopes might be more efficiently expressed on inactivate (d) forms of the Pgp molecules, suggesting that RMA might inhibit Pgp function by disturbing the conformation of individual Pgp molecules, t heir topographical distribution or polymerization status in the membra ne.