Molecular mechanism of alpha-tocopheryl-phosphate transport across the cell membrane.
alpha-Tocopheryl-phosphate (alpha-TP) is synthesized and hydrolyzed in animal cells and tissues where it modulates several functions. alpha-TP is more potent than alpha-T in inhibiting cell proliferation, down-regulating CD36 transcription, inhibiting atherosclerotic plaque formation. Administration of alpha-TP to cells or animals requires its transfer through membranes, via a transporter. We show here that alpha-TP is passing the plasma membrane via a system that is inhibited by glibenclamide and probenecid, inhibitors of a number of transporters. Glibenclamide and probenecid prevent dose-dependently alpha-TP inhibition of cell proliferation. The two inhibitors act on ATP binding cassette (ABC) and organic anion transporters (OAT). Since ABC transporters function to export solutes and alpha-TP is transported into cells, it may be concluded that alpha-TP transport may occur via an OAT family member. Due to the protection by glibenclamide and probenecid on the alpha-TP induced cell growth inhibition it appears that alpha-TP acts after its uptake inside cells.
Negis
Yesim
Y
Vascular Biology Laboratory, The Jean Mayer USDA Human Nutrition Center at Tufts University, Boston, MA 02111, USA.
Meydani
Mohsen
M
Zingg
Jean-Marc
JM
Azzi
Angelo
A
D000277:Adjuvants, Pharmaceutic / Q000494:pharmacology; D001692:Biological Transport; D018955:CD36 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008954:Models, Biological; D010710:Phosphates / Q000378:metabolism*; D011339:Probenecid / Q000494:pharmacology; D014158:Transcription, Genetic; D024502:alpha-Tocopherol / Q000378:metabolism*
D000277:Adjuvants, Pharmaceutic; D018955:CD36 Antigens; D007004:Hypoglycemic Agents; D010710:Phosphates; D024502:alpha-Tocopherol; D011339:Probenecid; D005905:Glyburide