FIG. 4.

Hypothetical mechanisms of the efflux pumps. (A) The mouse MDR2 protein flips over the phosphatidylcholine from the inner leaflet to the outer leaflet, as shown by Ruetz and Gros (32). (B) The AcrB pump captures the substrates from both the inner and outer leaflets of the membrane bilayer. In this manner, any lipophilic or amphiphilic nonphospholipid molecule that becomes inserted spontaneously into the bilayer can be captured and pumped out. In this mechanism, the AcrB protein is assumed to have a flippase-like activity so that it can excrete drugs from the cytosol (below the bilayer in the figure) as well as from the periplasm (above the bilayer). (C) The AcrB protein is seen to be capable of capturing substrates only from the outer leaflet. In this case, the substrate in the inner leaflet, originally coming from the cytosol, must be flipped over (possibly spontaneously) to the outer leaflet before being captured by the pump protein.