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

Authors: Roepe, P. D.; Wei, L.; Hoffman, M. M.; Fritz, F.
Article Title: Altered drug translocation mediated by the MDR protein: Direct, indirect, or both?
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, ItpGPA, PDR5, sapABCDF) are also involved in conferring drag 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 (pH(i)) and thereby indirectly 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 pH(i), 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.
Keywords: review; nonhuman; animals; mice; models, biological; drug resistance; transmembrane conductance regulator; adenosine triphosphate; drug transport; hydrolysis; multidrug resistance; p-glycoprotein; drug resistance, multiple; photometry; cricetinae; glycoprotein p; chloride channel; cell ph; cell membrane potential; membrane potential; humans; intracellular ph
Journal Title: Journal of Bioenergetics and Biomembranes
Volume: 28
Issue: 6
ISSN: 0145-479X
Publisher: Springer  
Date Published: 1996-12-01
Start Page: 541
End Page: 555
Language: English
PUBMED: 8953386
PROVIDER: scopus
DOI: 10.1007/BF02110444
Notes: Review -- Export Date: 22 November 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Friederike   Fritz
    4 Fritz
  2. Paul D. Roepe
    26 Roepe