COOPERATIVE, COMPETITIVE AND NONCOMPETITIVE INTERACTIONS BETWEEN MODULATORS OF P-GLYCOPROTEIN

We measured the effects of individual modulators and of pairs of modul ators of the multidrug resistance pump, P-glycoprotein, on the accumul ation of labelled daunomycin into multidrug-resistant P388 leukemia ce lls at 37 degrees C and developed a kinetic analysis which enables suc h data to be modelled in terms of co-operative, competitive or non-com petitive interaction between pairs of modulators. The modulators verap amil, cyclosporin and trifluoperazine interacted with P-glycoprotein a s single molecules, while vinblastine, mefloquine, dipyridamole, tamox ifen and quinidine displayed Hill numbers close to 2, suggesting that pairs of modulator molecules need to act together in order to bring ab out effective reversal of P-glycoprotein. When the modulators were pre sented to P-glycoprotein in pairs, we found examples of both competiti ve and non-competitive behaviour. We interpret these results on a mode l in which two modulatory sites exit on the MDR pump. To one of these, mefloquine, vinblastine and tamoxifen bind preferentially; to the oth er, verapamil, dipyridamole, trifluoperazine and quinidine bind (but m efloquine and tamoxifen only weakly if at all). Cyclosporin A can inte ract with both sites.