title: Deferasirox protects against iron-induced hepatic injury in Mongolian gerbil.
abstract: Iron overload is associated with an increased risk of liver complications including fibrosis, cirrhosis, and hepatocellular carcinoma. Deferasirox is a new oral chelator with high iron-binding potency and selectivity. Here we investigate the ability of deferasirox to remove excessive hepatic iron and prevent iron-induced hepatic injury. Adult male Mongolian gerbils were divided into 3 groups (n=5/group)-control, iron overload (100 mg iron-dextran/kg body weight/5 days; intraperitoneal for 10 weeks), and iron overload followed by deferasirox treatment (100 mg deferasirox/kg body weight/d; pulse oral for 1 or 3 months). Compared with the nontreated iron overload group, deferasirox reduced hepatic iron concentration by 44% after 3 months of treatment (P<0.05). Histological analysis of hepatic tissue from the iron overloaded group detected frequent iron deposition, evidence of hepatic damage, and an accumulation of lipid vacuoles. Iron deposition was significantly diminished with deferasirox treatment, and no evidence of lipid accumulation was observed. Immunoblotting demonstrated that iron overload caused approximately 2-fold increase in hepatic ferritin expression (P<0.05), which was 48% lower after 3 months of deferasirox treatment (P<0.05). Deferasirox treatment also was associated with reduced hepatic protein oxidation, superoxide abundance, and cell death. The percentage of terminal deoxynucleotidyl transferase dUTP nick end labeling positive cells in the deferasirox-treated livers was 41% lower than that of iron overloaded group (P<0.05). Similarly, an iron-related increase in the expression of Bax/Bcl2, Bad, and caspase-3 were significantly lower after deferasirox treatment. These findings suggest that deferasirox may confer protection against iron-induced hepatic toxicity.
authors.affiliation: Department of Pharmaceutical and Administrative Sciences, School of Pharmacy, University of Charleston, Charleston, WV, USA.
authors.forename: Rabaa M
authors.initials: RM
authors.lastname: Al-Rousan
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Rice
authors.forename: Anjaiah
authors.initials: A
authors.lastname: Katta
authors.forename: Joseph
authors.initials: J
authors.lastname: Laurino
authors.forename: Ernest M
authors.initials: EM
authors.lastname: Walker
authors.forename: Miaozong
authors.initials: M
authors.lastname: Wu
authors.forename: William E
authors.initials: WE
authors.lastname: Triest
authors.forename: Eric R
authors.initials: ER
authors.lastname: Blough
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D053938:DNA Fragmentation / Q000187:drug effects; D000077588:Deferasirox; D004195:Disease Models, Animal; D005293:Ferritins / Q000378:metabolism; D005849:Gerbillinae; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019190:Iron Overload / Q000150:complications / Q000188:drug therapy; D007505:Iron-Dextran Complex / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D057170:Translational Research, Biomedical; D014230:Triazoles / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001565:Benzoates; D007502:Iron Chelating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D014230:Triazoles; D051028:bcl-2-Associated X Protein; D007505:Iron-Dextran Complex; D005293:Ferritins; D053148:Caspase 3; D000077588:Deferasirox