title: Effect of tacrolimus on activity and expression of P-glycoprotein and ATP-binding cassette transporter A5 (ABCA5) proteins in hematoencephalic barrier cells.
abstract: Tacrolimus is an agent used in clinical immunosuppressive drug therapies. A wide spectrum of adverse effects has been reported in association with this immunosuppressor, including neurotoxic effect. The upper limit of therapeutic blood concentrations of tacrolimus has been described as 30 ng/ml in immunosuppressed patients. We investigated the effect of this therapeutic dose of tacrolimus on the expression and activity of the multidrug resistance protein 1 (MDR1 or Pgp, P-glycoprotein) and ATP-binding cassette transporters A5 (ABCA5) in human brain microvascular endothelial cells (HBMEC), derived from Blood-Brain Barrier (BBB) endothelium, these being the most predominantly expressed transcripts in these cells. The expression and activity of MDR1 transporter decreased with 30 ng/ml tacrolimus. The cell viability was not changed with the therapeutic dose used. By contrast, ABCA5 transcripts, of unknown role as yet, increased their expression at this concentration. We propose that the secondary cytotoxic effects of this immunosuppressor on CSN, besides the functional blockade related to multidrug resistance proteins, such as MDR1, and probably ABCA5, could be linked to variations in the expression levels of these proteins at the BBB.
authors.affiliation: Laboratorio de Bioquímica y Farmacología Tumoral, Instituto de Bioquímica, Facultad de Ciencias, Universidad Austral de Chile, P.O. Box 567, Campus Isla Teja, Valdivia, Chile.
authors.forename: Claudia Andrea
authors.initials: CA
authors.lastname: Quezada
authors.forename: Wallys Ximena
authors.initials: WX
authors.lastname: Garrido
authors.forename: Mauricio Alejandro
authors.initials: MA
authors.lastname: González-Oyarzún
authors.forename: María Cecilia
authors.initials: MC
authors.lastname: Rauch
authors.forename: Mónica Roxana
authors.initials: MR
authors.lastname: Salas
authors.forename: Rody Enrique
authors.initials: RE
authors.lastname: San Martín
authors.forename: Alejandro Andrés
authors.initials: AA
authors.lastname: Claude
authors.forename: Alejandro Javier
authors.initials: AJ
authors.lastname: Yañez
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Slebe
authors.forename: Juan Guillermo
authors.initials: JG
authors.lastname: Cárcamo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology*; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: C471294:ABCA5 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D005452:Fluoresceins; D007166:Immunosuppressive Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D053148:Caspase 3; C022616:thiazolyl blue; C007740:fluorexon; D016559:Tacrolimus