Journal of Bioenergetics and Biomembranes

, Volume 28, Issue 6, pp 541–555

Altered drug translocation mediated by the MDR protein: Direct, indirect, or both?

  • Paul D. Roepe
  • LiYong Wei
  • Mary M. Hoffman
  • Friederike Fritz
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Abstract

Overexpression of the MDR protein, or p-glycoprotein (p-GP), in cells leads to decreased initial rates of accumulation and altered intracellular retention of chemotherapeutic drugs and a variety of other compounds. Thus, increased expression of the protein is related to increased drug resistance. Since several homologues of the MDR protein (CRP, ltpGPA, PDR5, sapABCDF) are also involved in conferring drug resistance phenomena in microorganisms, elucidating the function of the MDR protein at a molecular level will have important general applications. Although MDR protein function has been studied for nearly 20 years, interpretation of most data is complicated by the drug-selection conditions used to create model MDR cell lines. Precisely what level of resistance to particular drugs is conferred by a given amount of MDR protein, as well as a variety of other critical issues, are not yet resolved. Data from a number of laboratories has been gathered in support of at least four different models for the MDR protein. One model is that the protein uses the energy released from ATP hydrolysis to directly translocate drugs out of cells in some fashion. Another is that MDR protein overexpression perturbs electrical membrane potential (δψ) and/or intracellular pH (pHi) and therebyindirectly alters translocation and intracellular retention of hydrophobic drugs that are cationic, weakly basic, and/or that react with intracellular targets in a pHi, or δψ-dependent manner. A third model proposes that the protein alternates between drug pump and Cl channel (or channel regulator) conformations, implying that both direct and indirect mechanisms of altered drug translocation may be catalyzed by MDR protein. A fourth is that the protein acts as an ATP channel. Our recent work has tested predictions of these models via kinetic analysis of drug transport and single-cell photometry analysis of pHi, δψ, and volume regulation in novel MDR and CFTR transfectants that have not been exposed to chemotherapeutic drugs prior to analysis. This paper reviews these data and previous work from other laboratories, as well as relevant transport physiology concepts, and summarizes how they either support or contradict the different models for MDR protein function.

Key words

Multidrug resistance intracellular pH membrane potential 

Abbreviations

MDR

multidrug resistance

p-GP

p-glycoprotein

CRP

chloroquine resistance protein

ItpGPA

Leshmenia tarantolae p Glycoprotein

PDR5

pleiotropic drug resistance protein 5

sapABCDF

Salmonella typhimurium ABC transporter complex

bR

bacteriorhodopsin

ΔμH*

proton electrochemical potential

ATP

adenosine triphosphate

ADP

adenosine diphosphate

Pi

free inorganic phosphate

δψ

electrical membrane potential

pHi

intracellular (cytoplasmic) pH

TPP+

tetraphenylphosphonium

BCECF-AM

2′,7′-bis(carboxyethyl)-5,6-carboxyfluorescein acetoxy methyl ester

LUV

large unilamellar vesicle

CFTR

cystic fibrosis transmembrane conductance regulator

δpH

pH gradient across the plasma membrane

ABC

ATP-binding cassette

PKC

protein kinase C

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Copyright information

© Plenum Publishing Corporation 1996

Authors and Affiliations

  • Paul D. Roepe
    • 1
    • 2
  • LiYong Wei
    • 1
    • 2
  • Mary M. Hoffman
    • 1
    • 2
  • Friederike Fritz
    • 1
    • 2
  1. 1.Molecular Pharmacology and Therapeutics Program at the Raymond & Beverly Sackler Foundation LaboratoryMemorial Sloan Kettering Cancer CenterNew York
  2. 2.Department of PharmacologyCornell University Medical CollegeNew York

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