Recently, it has been reported that continuous treatment with cyclosporin A
or tacrolimus induces encephalopathy in transplant patients. The mechanism
of immunosuppressant-induced encephalopathy is unclear. We investigated th
e cytotoxicity to brain capillary endothelial cells and the effect of these
two drugs on P-glycoprotein function using mouse brain capillary endotheli
al (MBEC4) cells. The transcellular transport of [H-3]sucrose was significa
ntly increased and the cellular viability, based on 3-(4, 5-dimethylthiazol
-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and trypan blue exclus
ion test, was decreased by cyclosporin A (approximately 50% at 5 mu M; P <
0.005), while tacrolimus showed a much smaller effect. These findings indic
ate that the toxicity of cyclosporin A was greater than that of tacrolimus.
The uptake of [H-3]vincristine, a substrate of P-glycoprotein, was increas
ed by these two drugs. The expression of P-glycoprotein in MBEC4 cells was
reduced, but there was no effect on mdr1b mRNA levels. The decrease in the
expression of P-glycoprotein may be due to the inhibition of the turnover o
f P-glycoprotein, which involves translation. In conclusion, the direct cyt
otoxic effect on the brain capillary endothelial cells and the inhibition o
f P-glycoprotein may be partly involved in the occurrence of immunosuppress
ant-induced encephalopathy. (C) 1999 Elsevier Science B.V. All rights reser
ved.