title: Deferoxamine but not dexrazoxane alleviates liver injury induced by endotoxemia in rats.
abstract: The purpose of the present study was to compare the activity of two different clinically available iron chelators on the development of acute liver injury after administration of the bacterial endotoxin (lipopolysaccharide [LPS]) in rats. Lipopolysaccharide was administered either alone or after pretreatment with dexrazoxane (DEX) or deferoxamine (DFO). Control groups received only saline or its combination with either chelator. After 8 h, untreated LPS rats developed liver injury, with signs of inflammation and oxidative stress. Lipopolysaccharide reduced plasma iron concentrations in association with increased production of hepcidin and the reduced liver expression of ferroportin. Administration of chelating agents to LPS animals showed distinct effects. Although both drugs were able to reduce liver iron content, together with corresponding changes in hepcidin and ferroportin expressions, only DFO showed a protective effect against liver injury despite relatively small liver concentrations. In sharp contrast, DEX failed to improve any hallmark of liver injury and even worsened the GSH/GSSG ratio, the indicator of oxidative stress in the tissue. High-performance liquid chromatography-mass spectrometry analysis showed marked liver accumulation of iron-chelating metabolite of DEX (ADR-925), whereas the parent compound was undetectable. Further downregulation of transporters involved in bile formation was observed after DFO in the LPS group as well as in healthy animals. Neither chelator imposed significant liver injury in healthy animals. In conclusion, we demonstrated marked differences in the modulation of endotoxemic liver impairment between two iron chelators, implicating that particular qualities of chelating agents may be of crucial importance.
authors.affiliation: *Department of Pharmacology, Charles University in Prague, Faculty of Medicine, †Department of Biological and Medical Sciences, Charles University Prague, Faculty of Pharmacy, ‡Departments of Physiology and §Medical Biochemistry, ∥Institute of Clinical Biochemistry and Diagnostics, and ¶Department of Histology and Embryology, Charles University in Prague, Faculty of Medicine, and **Department of Pharmaceutical Chemistry and Drug Analysis, Charles University Prague, Faculty of Pharmacy, Hradec Kralove, Czech Republic.
authors.forename: Jolana
authors.initials: J
authors.lastname: Cermanova
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Kadova
authors.forename: Eva
authors.initials: E
authors.lastname: Dolezelova
authors.forename: Marie
authors.initials: M
authors.lastname: Zagorova
authors.forename: Vaclav
authors.initials: V
authors.lastname: Safka
authors.forename: Milos
authors.initials: M
authors.lastname: Hroch
authors.forename: Tomas
authors.initials: T
authors.lastname: Laho
authors.forename: Magdalena
authors.initials: M
authors.lastname: Holeckova
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Mokry
authors.forename: Petra
authors.initials: P
authors.lastname: Kovarikova
authors.forename: Jan
authors.initials: J
authors.lastname: Bures
authors.forename: Martin
authors.initials: M
authors.lastname: Sterba
authors.forename: Stanislav
authors.initials: S
authors.lastname: Micuda
mesh_terms: D000818:Animals; D003676:Deferoxamine / Q000627:therapeutic use*; D064730:Dexrazoxane / Q000627:therapeutic use*; D019446:Endotoxemia / Q000150:complications*; D007502:Iron Chelating Agents / Q000627:therapeutic use*; D008107:Liver Diseases / Q000188:drug therapy* / Q000209:etiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D007502:Iron Chelating Agents; D064730:Dexrazoxane; D003676:Deferoxamine