In vitro FK506 kidney tubular cell toxicity.
Nephrotoxicity is the most prominent side effect of the new immunosuppressive drug FK506. Some of the histopathological changes associated with cyclosporine (CyA) nephrotoxicity such as tubular vacuolization and glomerular thrombosis have also been reported with FK506 therapy. In this study we used kidney tubular cells in culture to address the issue of FK506- and CyA-induced tubular damage. Exposure of tubular cells to high concentrations of FK506 or CyA (10, 50 and 100 microM) induced a time- and dose-dependent cell injury in vitro characterized by a direct cytotoxic effect on tubular cells as expressed by release of 3H-thymidine from prelabelled cells, N-acetyl-beta-D-glucosaminidase (NAG) release and cell detachment. Ultrastructural changes (vacuolization, swelling and mitochondrial enlargement) and inhibition of the growth (DNA and RNA synthesis) of cultured tubular cells were also observed at high concentrations of FK506 and CyA. These concentrations are higher than those reached in clinical situations, but close to the concentrations that may be reached by FK506 or CyA in tissues. Low concentrations of FK506 and CyA (1, 0.1 and 0.01 microM) were not cytotoxic and induced only a minimal inhibitory effect on the growth of tubular cells in vitro. At the same concentration CyA induced more cell detachment, more NAG release and a stronger inhibitory effect on cell growth than FK506 (P < 0.01). Since an evident cytotoxic effect was observed only at high concentrations, we can speculate that tubular toxicity is due to the accumulation of drug in the cells inducing cell disruption and death.
Moutabarrik
A
A
Department of Urology, Osaka University, Osaka, Japan.
Ishibashi
M
M
Kameoka
H
H
Kawaguchi
N
N
Takano
Y
Y
Kokado
Y
Y
Onishi
S
S
Sonoda
T
T
Takahara
S
S
Okuyama
A
A
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000633:toxicity; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000633:toxicity; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects; D016559:Tacrolimus / Q000633:toxicity*; D014617:Vacuoles / Q000187:drug effects
D007166:Immunosuppressive Agents; D012313:RNA; D016572:Cyclosporine; D004247:DNA; D016559:Tacrolimus