Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Miranda, CJ; Makui, H; Soares, RJ; Bilodeau, M; Mui, J; Vali, H; Bertrand, R; Andrews, NC; Santos, MM

Published Date

  • October 1, 2003

Published In

Volume / Issue

  • 102 / 7

Start / End Page

  • 2574 - 2580

PubMed ID

  • 12805055

Pubmed Central ID

  • 12805055

International Standard Serial Number (ISSN)

  • 0006-4971

Digital Object Identifier (DOI)

  • 10.1182/blood-2003-03-0869

Language

  • eng

Conference Location

  • United States