Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity

Yujian Kang, Van Chen, Anding Yu, Mildred Voss-McCowan, Paul N. Epstein

Research output: Contribution to journalArticle

209 Citations (Scopus)

Abstract

Metallothionein (MT) may provide protection against doxorubicin-induced heart damage. To test this hypothesis, a heart-specific promoter was used to drive the expression of human MT-IIa gene in transgenic mice. Four healthy transgenic mouse lines were produced. Cardiac MT was constitutively overexpressed from 10- to 130-fold higher than normal. The MT concentration was not altered in liver, kidneys, lungs, or skeletal muscles. Other antioxidant components including glutathione, glutathione peroxidase, glutathione reductase, catalase, and superoxide dismutase were not altered in the MT-overexpressing heart. Mice (7-wk-old) from transgenic lines expressing MT activity 10- or 130-fold higher than normal and from nontransgenic controls were treated intraperitoneally with doxorubicin at a single dose of 20 mg/kg, and were killed on the 4th day after treatment. As compared to normal controls, transgenic mice exhibited a significant resistance to in vivo doxorubicin-induced cardiac morphological changes, and the increase in serum creatine phosphokinase activity. Atria isolated from transgenic mice and treated with doxorubicin in tissue bath was also more resistant to functional damage induced by this drug. The results provide direct evidence for the role of MT in cardioprotection against doxorubicin toxicity.

Original languageEnglish (US)
Pages (from-to)1501-1506
Number of pages6
JournalJournal of Clinical Investigation
Volume100
Issue number6
DOIs
StatePublished - Sep 15 1997

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Metallothionein
Doxorubicin
Transgenic Mice
Glutathione Reductase
Creatine Kinase
Glutathione Peroxidase
Cardiotoxicity
Baths
Catalase
Superoxide Dismutase
Glutathione
Skeletal Muscle
Antioxidants
Kidney
Lung
Liver
Serum
Pharmaceutical Preparations
Genes

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity. / Kang, Yujian; Chen, Van; Yu, Anding; Voss-McCowan, Mildred; Epstein, Paul N.

In: Journal of Clinical Investigation, Vol. 100, No. 6, 15.09.1997, p. 1501-1506.

Research output: Contribution to journalArticle

Kang, Yujian ; Chen, Van ; Yu, Anding ; Voss-McCowan, Mildred ; Epstein, Paul N. / Overexpression of metallothionein in the heart of transgenic mice suppresses doxorubicin cardiotoxicity. In: Journal of Clinical Investigation. 1997 ; Vol. 100, No. 6. pp. 1501-1506.
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