Ionophore and Biometal Modulation of P-glycoprotein Expression and Function in Human Brain Microvascular Endothelial Cells.
Pharm Res
; 35(4): 83, 2018 Mar 05.
Article
en En
| MEDLINE
| ID: mdl-29508078
ABSTRACT
PURPOSE:
Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown.METHODS:
Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in-cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper. The fluorescent P-gp substrate rhodamine-123 was employed to observe functional modulation, and inductively coupled plasma mass spectrometry (ICP-MS) provided information on biometal trafficking.RESULTS:
A 24-h treatment with clioquinol, zinc and copper (0.5, 0.5 and 0.1 µM) induced a significant upregulation of P-gp (1.7-fold) assessed by in-cell western and this was confirmed with western blotting (1.8-fold increase). This same treatment resulted in a 23% decrease in rhodamine-123 accumulation over a 1 h incubation. ICP-MS demonstrated that while t8his combination treatment had no effect on intracellular zinc concentrations, the treatment significantly enhanced bioavailable copper (4.6-fold).CONCLUSIONS:
Enhanced delivery of copper to human brain microvascular endothelial cells is associated with enhanced expression and function of the important efflux pump P-gp, which may provide therapeutic opportunities for P-gp modulation.Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Oligoelementos
/
Barrera Hematoencefálica
/
Microvasos
/
Ionóforos
Límite:
Humans
Idioma:
En
Revista:
Pharm Res
Año:
2018
Tipo del documento:
Article
País de afiliación:
Australia