Figure 8.

Models for the preferential inhibition of Hxts caused by nonspecific interaction between cationic amphiphiles and membranes. (A) Hexoses are selectively transported across the plasma membrane via oscillated changes in the Hxts between outward- and inward-facing conformations (no drug). Active Hxts transporting hexoses are indicated as white shapes, and inactive Hxts without transporting hexoses are indicated as black shapes. The dotted boxes indicate the oscillation area for the conformational change of Hxts. At low concentrations, cationic amphiphilic drugs (e.g., local anesthetics, phenothiazines, and cationic surfactants) nonspecifically intercalate into the inner leaflet of membranes (drugs, low). When the drugs penetrate into the oscillation area of Hxts, their structural changes are prevented as the outward-facing configuration (black shapes), resulting in glucose starvation. Additional hexoses stimulate the oscillation of Hxts by efficient interaction with hexoses (drugs, low + excess hexoses) and thus prevent drug penetration into the oscillating area, thereby conferring resistance to drugs (white shapes). Once the drugs penetrate into the oscillating area, the stuck Hxts no longer oscillate efficiently, even in the presence of additional hexose (black shapes). Increasing the drug concentrations destroys membranes by excessively penetrating into the lipid layer, and thus Hxts do not exist in the plasma membrane and lose their function (drugs, high). (B) A certain concentration of cationic amphiphiles preferentially inhibits the function of abundant Hxts in plasma membrane (left). In the case of scarce Hxts, the drugs inhibit various targets, thereby diminishing the preference of Hxts as a drug target (right).