title: Tacrolimus preconditioning of rat liver allografts impacts glutathione homeostasis and early reperfusion injury.
abstract: OBJECTIVE
  To characterize the immunosuppressant tacrolimus as a protective antioxidant in rat liver transplantation.
  
  
  METHODS
  Livers of male Lewis rats underwent 24 h of hypothermic preservation in UW solution and were rinsed with tacrolimus or placebo directly before transplantation. Markers of liver injury, such as enzymes and bile flow, were determined during a 2 h reperfusion period. Concentrations of reduced (GSH) and oxidized (GSSG) glutathione were analyzed in plasma, bile, and liver tissue for estimation of oxidant stress caused by reactive oxygen species (ROS).
  
  
  RESULTS
  Administration of tacrolimus (10 ng/mL) resulted in decreased ALT plasma levels (1740 ± 1169 U/l versus 3691 ± 1144 U/l; P < 0.05) at 2 h of reperfusion. While endogenous intracellular GSH concentrations remained unchanged, GSSG, the oxidation product of GSH, was markedly decreased at 2 h of reperfusion in preconditioned livers (47.0 ± 10.4 nm/g versus 71.8 ± 30.6 nm/g; P < 0.05). Correspondingly, GSSG bile concentrations (0.19 ± 0.04 mM versus 0.13 ± 0.04 mM; P < 0.05) as well as plasma GSSG levels (2.4 ± 0.3 mM versus 1.4 ± 0.2 mM; P < 0.05) were significantly increased upon reperfusion. These findings suggest that tacrolimus impacts post-ischemic GSH metabolism when administered as a rinse solution for liver allografts through an unknown pathway.
  
  
  CONCLUSIONS
  Hepatocellular injury following transplantation was significantly decreased by preconditioning with tacrolimus. One possible mechanism of action is the detoxification of ROS through the preservation of cytosolic and extracellular GSH/GSSG ratios.
authors.affiliation: Department of Surgery, Klinikum of Ludwig-Maximilians-University-Grosshadern, University of Munich, Munich, Germany. sebastian.pratschke@med.uni-muenchen.de
authors.forename: Sebastian
authors.initials: S
authors.lastname: Pratschke
authors.forename: Manfred
authors.initials: M
authors.lastname: Bilzer
authors.forename: Uwe
authors.initials: U
authors.lastname: Grützner
authors.forename: Martin
authors.initials: M
authors.lastname: Angele
authors.forename: Amanda
authors.initials: A
authors.lastname: Tufman
authors.forename: Karl-Walter
authors.initials: KW
authors.lastname: Jauch
authors.forename: Rolf J
authors.initials: RJ
authors.lastname: Schauer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects* / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019194:Ischemic Preconditioning; D008099:Liver / Q000098:blood supply* / Q000378:metabolism; D016031:Liver Transplantation / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control*; D016559:Tacrolimus / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D000975:Antioxidants; D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D005978:Glutathione; D019803:Glutathione Disulfide; D016559:Tacrolimus