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alpha-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein

Research output: Contribution to Journal/MagazineJournal articlepeer-review

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  • Sterenn Davis
  • Benjamin M. Davis
  • Joanna L. Richens
  • Kelly-Ann Vere
  • Peter G. Petrov
  • C. Peter Winlove
  • Paul O'Shea
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<mark>Journal publication date</mark>08/2015
<mark>Journal</mark>JOURNAL OF LIPID RESEARCH
Issue number8
Volume56
Number of pages8
Pages (from-to)1543-1550
Publication StatusPublished
Early online date29/05/15
<mark>Original language</mark>English

Abstract

α-Tocopherol (vitamin E) has attracted considerable attention as a potential protective or palliative agent. In vitro, its free radical-scavenging antioxidant action has been widely demonstrated. In vivo, however, vitamin E treatment exhibits negligible benefits against oxidative stress. α-Tocopherol influences lipid ordering within biological membranes and its derivatives have been suggested to inhibit the multi-drug efflux pump, P-glycoprotein (P-gp). This study employs the fluorescent membrane probe, 1-(3-sulfonatopropyl)-4-[β[2-(di-n-octylamino)-6-naphthyl]vinyl] pyridinium betaine, to investigate whether these effects are connected via influences on the membrane dipole potential (MDP), an intrinsic property of biological membranes previously demonstrated to modulate P-gp activity. α-Tocopherol and its non-free radical-scavenging succinate analog induced similar decreases in the MDP of phosphatidylcholine vesicles. α-Tocopherol succinate also reduced the MDP of T-lymphocytes, subsequently decreasing the binding affinity of saquinavir for P-gp. Additionally, α-tocopherol succinate demonstrated a preference for cholesterol-treated (membrane microdomain enriched) cells over membrane cholesterol-depleted cells. Microdomain disruption via cholesterol depletion decreased saquinavir’s affinity for P-gp, potentially implicating these structures in the influence of α-tocopherol succinate on P-gp. This study provides evidence of a microdomain dipole potential-dependent mechanism by which α-tocopherol analogs influence P-gp activity. These findings have implications for the use of α-tocopherol derivatives for drug delivery across biological barriers.