title: Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin.
abstract: The clinical use of doxorubicin (DOX), an anthracycline chemotherapeutic agent, is limited by cardiotoxicity. The possible involvement of iron in DOX-induced cardiotoxicity became evident from studies in which iron chelators were shown to be cardioprotective. Iron overload is found in hereditary hemochromatosis, a genetic disorder prevalent in individuals of European descent. We hypothesized that Hfe deficiency may increase susceptibility to DOX-induced toxicity. Acute cardiotoxicity and iron changes were studied after treatment with DOX in Hfe knock-out (Hfe-/-) mice and wild-type mice. DOX-induced iron metabolism changes were intensified in Hfe-/- mice, which accumulated significantly more iron in the heart, liver, and pancreas, but less in the spleen compared with wild-type mice. In addition, Hfe-deficient mice exhibited significantly greater sensitivity to DOX-induced elevations in serum creatine kinase and aspartate aminotransferase. Increased mortality after chronic DOX treatment was observed in Hfe-/- mice and Hfe+/-mice compared with wild-type mice. DOX-treated Hfe-/- mice had a higher degree of mitochondrial damage and iron deposits in the heart than did wild-type mice. These data demonstrate that Hfe deficiency in mice increases susceptibility to DOX-induced cardiotoxicity and suggest that genetic mutations related to defects in iron metabolism may contribute to its cardiotoxicity in humans.
authors.affiliation: Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, QC, Canada.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Miranda
authors.forename: Hortence
authors.initials: H
authors.lastname: Makui
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Soares
authors.forename: Marc
authors.initials: M
authors.lastname: Bilodeau
authors.forename: Jeannie
authors.initials: J
authors.lastname: Mui
authors.forename: Hajatollah
authors.initials: H
authors.lastname: Vali
authors.forename: Richard
authors.initials: R
authors.lastname: Bertrand
authors.forename: Nancy C
authors.initials: NC
authors.lastname: Andrews
authors.forename: Manuela M
authors.initials: MM
authors.lastname: Santos
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000633:toxicity*; D005260:Female; D020022:Genetic Predisposition to Disease; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D007501:Iron / Q000378:metabolism*; D019189:Iron Metabolism Disorders / Q000139:chemically induced* / Q000235:genetics / Q000401:mortality; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D015996:Survival Rate; D014168:Transferrin / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D014168:Transferrin; D004317:Doxorubicin; D007501:Iron; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003402:Creatine Kinase