Cyclosporin A and vehicle toxicity in primary cultures of rabbit renal proximal tubule cells.
The capability of cyclosporin to produce direct injury to primary proximal tubular renal cells was studied. These cells, when grown on Millicell inserts, retain the functional polarity of the proximal tubule, i.e., generate a transepithelial pH gradient (apical compartment acidic) that is reversibly blocked by amiloride addition only if it is added to the apical compartment. Administration of ouabain to the basal compartment also blocks the generation of the transepithelial pH gradient. Additionally, the cells were more responsive to parathyroid hormone (PTH), a proximal tubule characteristic, than to arginine vasopressin (AVP), a distal tubule characteristic. The following substances were tested for their effect on the capacity of these cells to generate a pH gradient: Sandimmune, the commercial form of cyclosporin A; the free form of the drug; Cremophor EL, the vehicle used in the commercial preparation; and ethanol, the vehicle used to dissolve the free form. Sandimmune, at 25-50 microM, inhibited the generation of the pH gradient within 24 h. Surprisingly, Cremophor also blocked the development of a pH gradient, although somewhat less effectively. In contrast, 10 microM cyclosporin, regardless of the form tested, had no effect for up to 96 h. These findings show that cyclosporin, in the form of Sandimmune, has a direct toxic effect on these cells; they also suggest that the vehicle, Cremophor, may contribute to the well-established nephrotoxicity of cyclosporin A.
Sokol
P P
PP
Department of Pharmacology, State University of New York, Syracuse 13210.
Capodagli
L C
LC
Dixon
M
M
Holohan
P D
PD
Ross
C R
CR
Coulson
R
R
Jones
D B
DB
D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D002462:Cell Membrane / Q000502:physiology / Q000648:ultrastructure; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology* / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D007700:Kinetics; D008854:Microscopy, Electron; D008855:Microscopy, Electron, Scanning; D010042:Ouabain / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D011817:Rabbits
D003524:Cyclosporins; D010281:Parathyroid Hormone; D014677:Pharmaceutical Vehicles; D001127:Arginine Vasopressin; D005576:Colforsin; D010042:Ouabain; C000515:cremophor EL; D000584:Amiloride; D005990:Glycerol