title: The long-acting parenteral iron chelator, hydroxyethyl starch-deferoxamine, fails to protect against alcohol-induced liver injury in rats.
abstract: We studied the effect of the long-acting parenteral iron chelator, hydroxyethyl starch deferoxamine (HES-DFO) on liver nonheme iron, lipid peroxidation and pathologic changes in the liver in the intragastric feeding rat model for alcoholic liver disease. Male Wistar rats (225-250 g) were fed liquid diet and ethanol for 2 months. In control pair-fed animals, ethanol was isocalorically replaced by dextrose. Two additional groups of animals (dextrose and ethanol fed) received HES-DFO (25 mg deferoxamine equivalents/kg, three times a week). The blood ethanol level in the ethanol-fed animals was maintained between 150 and 350 mg/dl. For each animal, the levels of hepatic nonheme iron, lipid peroxidation and pathologic changes were evaluated. Ethanol administration caused fatty liver, necrosis and inflammation. Addition of HES-DFO to the ethanol diet increased the severity of pathologic changes, particularly necrosis and inflammation. The nonheme iron in alcohol-fed animals was significantly higher (18.3 +/- 4.3 microg liver) than in pair-fed dextrose controls (12.5 +/- 1.5 microg, P < .05). Addition of HES-DFO significantly increased nonheme iron levels in the dextrose-fed rats (17.1 +/- 2.0 microg/g, P < .02) but not in ethanol-fed rats (20.0 +/- 2.0). Ethanol increased levels of conjugated dienes; these levels were not altered by HES-DFO. The most significant observations in this study were: 1) the higher hepatic nonheme iron content in ethanol-fed rats compared with pair-fed dextrose controls; 2) the absence of changes in hepatic nonheme iron levels or lipid peroxidation in ethanol-fed groups treated with HES-DFO; and 3) the worsening of liver injury in ethanol-fed rats by HES-DFO.
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical, Boston, Massachusetts 02215, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Sadrzadeh
authors.forename: P E
authors.initials: PE
authors.lastname: Hallaway
authors.forename: A A
authors.initials: AA
authors.lastname: Nanji
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003676:Deferoxamine / Q000493:pharmacokinetics / Q000494:pharmacology*; D000431:Ethanol / Q000097:blood; D006895:Hydroxyethyl Starch Derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D006895:Hydroxyethyl Starch Derivatives; D007502:Iron Chelating Agents; C068460:hydroxyethyl starch-deferoxamine conjugate; D000431:Ethanol; D007501:Iron; D000410:Alanine Transaminase; D003676:Deferoxamine