title: Effect of tacrolimus on energy metabolism in human umbilical endothelial cells.
abstract: 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.
  
  
  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.
authors.affiliation: Clinic for Pediatric Kidney-, Liver- and Metabolic Diseases, Hannover Medical School, Germany. illsinger.sabine@mh-hannover.de
authors.forename: Sabine
authors.initials: S
authors.lastname: Illsinger
authors.forename: Catrin
authors.initials: C
authors.lastname: Göken
authors.forename: Matthias
authors.initials: M
authors.lastname: Brockmann
authors.forename: Inga
authors.initials: I
authors.lastname: Thiemann
authors.forename: Jolanthe
authors.initials: J
authors.lastname: Bednarczyk
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Schmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Lücke
authors.forename: Ludwig
authors.initials: L
authors.lastname: Hoy
authors.forename: Nils
authors.initials: N
authors.lastname: Janzen
authors.forename: Anibh
authors.initials: A
authors.lastname: Das
mesh_terms: D002478:Cells, Cultured; D004579:Electron Transport / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D016559:Tacrolimus / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D016559:Tacrolimus