Role of the plasma membrane leaflets in drug uptake and multidrug resistance

The FEBS Journal
Hagar KatzirGera D Eytan

Abstract

The present study aimed to investigate the role played by the leaflets of the plasma membrane in the uptake of drugs into cells and in their extrusion by P-glycoprotein and multidrug resistance-associated protein 1. Drug accumulation was monitored by fluorescence resonance energy transfer from trimethylammonium-diphenyl-hexatriene (TMA-DPH) located at the outer leaflet to a rhodamine analog. Uptake of dye into cells whose mitochondria had been inactivated was displayed as two phases of TMA-DPH fluorescence quenching. The initial phase comprised a rapid drop in fluorescence that was neither affected by cooling the cells on ice, nor by activity of mitochondria or ABC transporters. This phase reflects the association of dye with the outer leaflet of the plasma membrane. The subsequent phase of TMA-DPH fluorescence quenching occurred in drug-sensitive cell lines with a half-life in the range 20-40 s. The second phase of fluorescence quenching was abolished by incubation of the cells on ice and was transiently inhibited in cells with active mitochondria. Thus, the second phase of fluorescence quenching reflects the accumulation of dye in the cytoplasmic leaflet of the plasma membrane, presumably as a result of flip-flop of dye acros...Continue Reading

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Citations

Jan 18, 2011·American Journal of Physiology. Lung Cellular and Molecular Physiology·Zhuohui GanMarilyn P Merker
Jan 4, 2013·PloS One·Mariame A HassanTakashi Kondo
Jan 15, 2014·Journal of the American Chemical Society·Grace Y Stokes, John C Conboy
Sep 17, 2010·Trends in Cell Biology·Theodore L Steck, Yvonne Lange
Mar 29, 2011·Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation·Yong-Xian HuHe Huang
May 24, 2011·Biochemical Society Transactions·Rupak DoshiHendrik W van Veen
Dec 18, 2019·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Joanna KopeckaChiara Riganti

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