Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin.
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.
Miranda
Carlos J
CJ
Hôpital Notre-Dame, Centre Hospitalier de l'Université de Montréal, QC, Canada.
Makui
Hortence
H
Soares
Ricardo J
RJ
Bilodeau
Marc
M
Mui
Jeannie
J
Vali
Hajatollah
H
Bertrand
Richard
R
Andrews
Nancy C
NC
Santos
Manuela M
MM
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
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