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Free Content Tissue Distribution of Calcineurin and its Sensitivity to Inhibition by Cyclosporine

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The immunosuppressive activity of cyclosporine is mediated by inhibiting calcineurin phosphatase. However, calcineurin is widely distributed in other tissues. We examined the degree of calcineurin inhibition by cyclosporine in various tissues. In vitro, the cyclosporine concentration inhibiting 50% (IC50) of calcineurin was ∼ 10 ng/mL in human and mouse leukocytes suspensions. In vitro and in vivo IC50s of cyclosporine in homogenates of mouse kidney, heart, liver, testis, and spleen were also comparable (9–48 ng/mL). The maximum calcineurin inhibition by cyclosporine varied, from 83 to 95% of calcineurin activity in spleen, kidney, liver, and testis to 60% in heart and only 10% in brain. Maximum calcineurin inhibition was increased by the addition of cyclophilin A, indicating that cyclophilin concentrations were limiting in some tissues, at least in this assay. Western analysis of mouse tissues showed significantly less cyclophilin in heart than other tissues. cyclosporine concentrations per weight of tissue protein were highest in kidney and liver and lowest in brain and testis after oral dosing, with intermediate levels in spleen, heart, and whole blood. Thus each cyclosporine dose produces rapid and widespread inhibition of calcineurin in tissues, with differences in total susceptibility of each tissue.

Keywords: Calcineurin; cyclosporine; distribution

Document Type: Research Article


Affiliations: 1: Medical Microbiology & Immunology, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada 2: Indiana University School of Medicine, Indianapolis, IN, USA 3: Nephrology Department, Hospital Medical Center Siglo XXI, IMMS, Mexico City, Mexico 4: Medicine and

Publication date: November 1, 2001


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