title: α-Tocopherols modify the membrane dipole potential leading to modulation of ligand binding by P-glycoprotein.
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.
authors.affiliation: Biomedical Physics Group, School of Physics, University of Exeter, Exeter, United Kingdom.
authors.forename: Sterenn
authors.initials: S
authors.lastname: Davis
authors.affiliation: Cell Biophysics Group, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Davis
authors.affiliation: Cell Biophysics Group, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Richens
authors.affiliation: Cell Biophysics Group, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Kelly-Ann
authors.initials: KA
authors.lastname: Vere
authors.affiliation: Biomedical Physics Group, School of Physics, University of Exeter, Exeter, United Kingdom.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Petrov
authors.affiliation: Biomedical Physics Group, School of Physics, University of Exeter, Exeter, United Kingdom.
authors.forename: C Peter
authors.initials: CP
authors.lastname: Winlove
authors.affiliation: Cell Biophysics Group, School of Life Sciences, University of Nottingham, Nottingham, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Shea
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D019169:Jurkat Cells; D007653:Ketocholesterols / Q000494:pharmacology; D008024:Ligands; D008564:Membrane Potentials / Q000187:drug effects*; D008958:Models, Molecular; D008968:Molecular Conformation; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011485:Protein Binding / Q000187:drug effects; D011726:Pyridinium Compounds / Q000737:chemistry; D019258:Saquinavir / Q000378:metabolism*; D053835:Unilamellar Liposomes / Q000737:chemistry / Q000378:metabolism; D024502:alpha-Tocopherol / Q000494:pharmacology*
chemical_list: C089669:1-(3-sulfonatopropyl)-4-(beta-(2-(di-n-octylamino)-6-naphthyl)vinyl)pyridinium betaine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D005456:Fluorescent Dyes; D007653:Ketocholesterols; D008024:Ligands; C059737:N-fluoresceinylphosphatidylethanolamine; D010714:Phosphatidylethanolamines; D011726:Pyridinium Compounds; D053835:Unilamellar Liposomes; D024502:alpha-Tocopherol; D019258:Saquinavir; C003001:7-ketocholesterol
keywords: antioxidants; cholesterol; lipid rafts; saquinavir; vitamin E