Flippase model

Although the mechanism of transport by MDRl and similar ABC proteins has not been definitively demonstrated, a likely candidate is the flippase model depicted in Figure... 

According to the flippase model of MDR activity, a substrate molecule diffuses into the cytosolic leaflet of the plasma membrane, then is flipped to the exoplasmic leaflet in an ATP-powered process, and finally diffuses from the membrane into the extracellular space (see Figure 7-12). 

Figure 9.35 Three proposed models of P-gp drug efflux, (a) The pore model, in which cytosolic drug is transported through a protein channel, (b) the flippase model, where drug associated with the inner leaflet of the membrane bilayer is flipped into the onter leaflet where it might passively diffuse out of the cell, and, (c) the hydrophobic vacuum cleaner model, where drug associated with the inner leaflet of the bilayer is exported out through the protein. (Reprinted with permission from Varma, M.V.S., et al. P-glycoprotein inhibitors and their screening A perspective from bioavailability enhancement. Pharmacol. Res. 2003, 48, 347-359, copyright 2003, Elsevier).

A FIGURE 7-11 Structural model of E coli lipid flippase, an ABC protein homologous to mammalian MDRl. The... 

Fig. 9.15. Proposed mechanism by which P-glycoprotein (P-gp) secretes substrates. (1) Passive drug uptake across cell membrane. (2a) Formation of hydrophobic channel (pore) between the intracellular and extracellular space. (2b) Flippase activity, whereby the drug is flipped from the inner leaflet to the outer leaflet of the cell membrane. (2c) Vacuum cleaner model, in which drug interacts with P-gp in the lipid bilayer and is subsequently secreted back into the extracellular space. (From Matheney C, Lamb M, Brouwer K, et al. Pharmacokinetics and pharmacodynamic implications of P-glycoprotein modulation. Reviews of Therapeutics 2001 21 778-796 with permission.)...

Early examples of synthetic flippases were lipidated polymers, which used bilayer distortion to bring about lipid flip-flop. In contrast to these mechanical flippases, synthetic species that apply the principles of molecular recognition to create phospholipid complexes capable of transverse diffusion have been shown to enhance lipid flip-flop in model membrane systems. Boon and Smith generated asymmetric bilayers by adding synthetic NBD phospholipids to the outer leaflet of POPC vesicles and then determined the rate of flip-flop to the inner leaflet... 

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