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Effect of tacrolimus on energy metabolism in human umbilical endothelial cells

Sabine Illsinger, Catrin Göken, Matthias Brockmann, Inga Thiemann, Jolanthe Bednarczyk, Karl-Heinz Schmidt, Thomas Lücke, Ludwig Hoy, Nils Janzen, Anibh M. Das

Ann Transplant 2011; 16(2): 68-75

ID: 881868


Background:    Tacrolimus has a wide spectrum of adverse effects, including neurotoxic and vascular events. Vascular dysfunction due to interference of tacrolimus with mitochondrial function in endothelial cells may contribute to these adverse reactions.
    Material/Methods:    We evaluated the impact of clinically relevant tacrolimus concentrations after 48 hours on energy metabolism in cultured human umbilical vein endothelial cells (HUVEC): Global fatty acid oxidation (FAO), activities of respiratory chain complexes I-V (RC), citratesynthase (CS), glycolytic enzymes and energy rich phosphates were measured.
    Results:    RC-complexes II+III were significantly compromised at 100 nmol/L and CS at 10, 25 and 50 nmol/L, while global FAO was not significantly impaired. Cellular lactate-dehydrogenase (LDH)-, hexokinase- and phosphofructokinase-activities were not altered; AMP levels increased after 48 hours at 200 nmol/L while energy charges remained stable. No cellular toxicity, assessed by light microscopy and LDH leakage was observed even at highest tacrolimus concentrations.
    Conclusions:    Tacrolimus partially impaired mitochondrial function in HUVEC at the level of RC-complexes II+III and CS. Part of tacrolimus toxicity and vascular dysfunction may arise from these metabolic alterations. To some extent, energy balance could be maintained by FAO and cytosolic energy production; energy consumption might be economized. Although only demonstrated for endothelial cells, it is conceivable that such effects will alter energy metabolism in different tissues with high oxidative demands.

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