ALTERED DRUG TRANSLOCATION MEDIATED BY THE MDR PROTEIN - DIRECT, INDIRECT, OR BOTH

Overexpression of the MDR protein, or p-glycoprotein (p-GP), in cells leads to decreased initial rates of accumulation and altered intracell ular retention of chemotherapeutic drugs and a variety of other compou nds. Thus, increased expression of the protein is related to increased drug resistance. Since several homologues of the MDR protein (CRP, It pGPA, PDR5, sapABCDF) are also involved in conferring drug resistance phenomena in microorganisms, elucidating the function of the MDR prote in at a molecular level will have important general applications. Alth ough MDR protein function has been studied for nearly 20 years, interp retation of most data is complicated by the drug-selection conditions used to create model MDR cell lines. Precisely what level of resistanc e to particular drugs is conferred by a given amount of MDR protein, a s well as a variety of other critical issues, are not yet resolved. Da ta from a number of laboratories has been gathered in support of at le ast four different models for the MDR protein. One model is that the p rotein uses the energy released from ATP hydrolysis to directly transl ocate drugs out of cells in some fashion. Another is that MDR protein overexpression perturbs electrical membrane potential (Delta Psi) and/ or intracellular pH (pH(i)) and thereby indirectly alters translocatio n and intracellular retention of hydrophobic drugs that are cationic, weakly basic, and/or that react with intracellular targets in a pH(i) or Delta Psi-dependent manner. A third model proposes that the protein alternates between drug pump and Cl- channel (or channel regulator) c onformations, implying that both direct and indirect mechanisms of alt ered drug translocation may be catalyzed by MDR protein. A fourth is t hat the protein acts as an ATP channel. Our recent work has tested pre dictions of these models via kinetic analysis of drug transport and si ngle-cell photometry analysis of pH(i), Delta Psi, and volume regulati on in novel MDR and CFTR transfectants that have not been exposed to c hemotherapeutic drugs prior to analysis. This paper reviews these data and previous work from other laboratories, as well as relevant transp ort physiology concepts, and summarizes how they either support or con tradict the different models for MDR protein function.