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PMID: 8787689 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

The protective role of manganese superoxide dismutase against adriamycin-induced acute cardiac toxicity in transgenic mice.

The Journal of clinical investigation ·Vol. 98 ·No. 5 ·1996-09-01 ·Pages 1253-60

Yen HC, Oberley TD, Vichitbandha S, Ho YS, St Clair DK

Abstract

Adriamycin (ADR) is a potent anticancer drug known to cause severe cardiac toxicity. Although ADR generates free radicals, the role of free radicals in the development of cardiac toxicity and the intracellular target for ADR-induced cardiac toxicity are still not well understood. We produced three transgenic mice lines expressing increased levels of human manganese superoxide dismutase (MnSOD), a mitochondrial enzyme, as an animal model to investigate the role of ADR-mediated free radical generation in mitochondria. The human MnSOD was expressed, functionally active, and properly transported into mitochondria in the heart of transgenic mice. The levels of copper-zinc SOD, catalase, and glutathione peroxidase did not change in the transgenic mice. Electron microscopy revealed dose-dependent ultrastructural alterations with marked mitochondrial damage in nontransgenic mice treated with ADR, but not in the transgenic littermates. Biochemical analysis indicated that the levels of serum creatine kinase and lactate dehydrogenase in ADR-treated mice were significantly greater in nontransgenic than their transgenic littermates expressing a high level of human MnSOD after ADR treatment. These results support a major role for free radical generation in ADR toxicity as well as suggesting mitochondria as the critical site of cardiac injury.

MeSH Terms
Animals Doxorubicin/toxicity Free Radicals/metabolism Heart/drug effects Humans Mice Mice, Inbred C3H Mice, Inbred C57BL Mice, Transgenic Mitochondria, Heart/drug effects,enzymology Myocardium/enzymology,pathology Recombinant Proteins/metabolism Superoxide Dismutase/genetics,metabolism
Chemicals
Free Radicals Recombinant Proteins Doxorubicin Superoxide Dismutase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Yen H C
University of Kentucky, Graduate Center for Toxicology, Lexington 40536, USA.
Oberley T D
Vichitbandha S
Ho Y S
St Clair D K
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI118909
Published
1996-09-01
Pages
1253-60
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC507548
Subset
IM
Grants
NCI NIH HHS · CA49797 · United States
NCI NIH HHS · CA59835 · United States
NHLBI NIH HHS · HL44571 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1172/JCI118909 PMC Full Text View journal details
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