Transporters, mediating multidrug efflux

Dhar S, Nygren P, Liminga G, et al. Relationship between cytotoxic drug response patterns and activity of drug efflux transporters mediating multidrug resistance. Eur J Pharmacol 1998 346(2-3) 315-322. 

An alternative to most of these mechanisms is the existence of efficient efflux systems, so that toxic concentrations of the drug are not achieved. There are three major families of proton-dependent multidrug efflux systems (1) the major facilitator superfamily, (2) the small multidrug resistance family, and (3) the resistance/nodulation/cell division family (Paulsen et al. 1996). It should be emphasized that several of these systems are involved not with antibiotic efflux but with, for example, acriflavine, chlorhexidine, and crystal violet. An attempt is made only to outline a few salient features of the resistance/nodulation/cell division family that mediates antibiotic efflux, and these are given in Table 3.3 (Nikaido 1996). They consist of a transporter, a linker, and an outer membrane channel. 

Although the competition of two substrates for the same P-gp normally results in an inhibitory effect on the P-gp-mediated transport of the substrates, stimulation of P-gp-mediated efflux transport has been reported in some cases. The P-gp-mediated doxombicin efflux out of multidrug-resistant HCT-15 colon cells was significantly increased by some flavonoids (13). Similarly, rhodamine 123 and Hoechst 33342 stimulated the rate of P-gp-mediated transport of each other in P-gp-enriched plasma membrane vesicles isolated from Chinese hamster ovary CHRB30 cells (14). Interestingly, Hoechst 33342 transport was increased by daunorubicin and doxombicin, while rhodamine 123 transport was inhibited by daunombicin and doxombicin (14). These results strongly suggest that molecular mechanisms of P-gp interaction are quite complex and cannot be predicted readily. 

Transporters, which mediate multidrug efflux, have usually been divided into four classes depending on (1) whether they are conducted by proton motive force (PMF) or by ATP, and (2) whether they consist of a single protein that has any one of the 4-, 12-, or 14-transmembrane-spanning domains [194,195] or whether they are a more complex multicomponent transporter [183]. The more complex transporters, in addition to a multidrug efflux protein (MexB, for example), contain a membrane fusion protein sueh as MexA and an outer membrane protein such as OprM [194]. 

Reyes CL, Ward A, Yu J, Chang G (2006) The stmctures of MsbA insight into ABC transporter-mediated multidrug efflux. FEBS Lett 580(4) 1042-1048... 

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