Combined administration of membrane-permeable and impermeable iron-chelating drugs attenuates ischemia/reperfusion-induced hepatic injury

• Published in: Free radical biology & medicine Vol. 193; no. Pt 1; pp. 227 - 237
• Main Authors: Mantelou, Athina G., Barbouti, Alexandra, Goussia, Anna, Zacharioudaki, Argyro, Papoudou-Bai, Alexandra, Vlachou, Chara, Kokkoris, Stelios, Papalois, Apostolos, Galaris, Dimitrios, Glantzounis, Georgios K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-11-2022
• Subjects: Animals; Deferiprone; Desferrioxamine; Hepatic ischemia-reperfusion; Hydrogen Peroxide; Iron - metabolism; Iron Chelating Agents - pharmacology; Iron Chelating Agents - therapeutic use; Iron chelating drugs; Ischemia - drug therapy; Male; Oxidative stress; Pharmaceutical Preparations; Rabbits; Reactive Oxygen Species; Reperfusion; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Desferrioxamine; Oxidative stress; Iron chelating drugs; Reactive oxygen species; Deferiprone; Hepatic ischemia-reperfusion
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2022.10.266

The underlying pathophysiological mechanisms of hepatic ischemia-reperfusion (I/R) injury have not been completely elucidated. However, it is well known that oxidative stress, caused by a burst of reactive oxygen species (ROS) production during the reperfusion phase, plays a crucial role. A growing body of evidence indicates that the intracellular availability of free iron represents a requirement for ROS-induced adverse effects, as iron catalyzes the generation of highly reactive free radicals. The aim of this study was to examine whether a combination of iron chelators with varying lipophilicity could offer enhanced protection against I/R by diminishing the conversion of weak oxidants, like H2O2, to extremely reactive ones such as hydroxyl radicals (HO.).
HepG2 cells (hepatocellular carcinoma cell line) were exposed to oxidative stress conditions after pre-treatment with the iron chelators desferrioxamine (DFO) and deferiprone (DFP) alone or in combination. Labile iron pool was estimated using the calcein-acetoxymethyl ester (calcein-AM) method and DNA damage with the comet assay.
We subsequently used a rabbit model (male New Zealand white rabbits) of hepatic I/R-induced injury to investigate, by measuring biochemical (ALT, ALT, ALP, γGT) and histological parameters, whether this may be true for in vivo conditions.
The combination of a membrane-permeable iron chelator (DFP) with a strong membrane-impermeable one (DFO) raises the level of protection in both hepatic cell lines exposed to oxidative stress conditions and hepatic I/R rabbit model.
Our results show that combinations of iron chelators with selected lipophilicity and iron-binding properties may represent a valuable strategy to protect against tissue damage during reperfusion after a period of ischemia.
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•Excess production of reactive oxygen species triggers reperfusion injury.•Intracellular free iron catalyzes the generation of highly reactive free radicals.•Chelation of intracellular iron protects hepatic cell lines against oxidative stress.•Iron chelating drugs attenuates liver ischemia/reperfusion injury in rabbits.•Optimum protection is offered by combining membrane-permeable and impermeable drugs.