Inhibition of doxorubicin toxicity in cultured neonatal mouse cardiomyocytes with elevated metallothionein levels

Guang Wu Wang, Yujian Kang

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54 Citations (Scopus)

Abstract

Controversial results have been reported regarding whether metallothionein (MT) functions in doxorubicin (DOX) detoxification in the heart. To determine unequivocally the role of MT in cardiac protection against the toxicity of DOX, ventricular cardiomyocytes isolated from 1- to 3-day neonatal transgenic mice with high levels of cardiac MT and from nontransgenic control animals were applied. On the 6th day of culturing, MT concentrations in the transgenic cardiomyocytes were about 2-fold higher than those in the nontransgenic cells. DOX was added directly into the cultures. Compared with nontransgenic controls, transgenic cardiomyocytes displayed a significant (p < .05) resistance to DOX cytotoxicity, as measured by morphological alterations, cell viability, and lactate dehydrogenase leakage from the cells. This cytoprotective effect of MT correlated with its inhibition of DOX-induced lipid peroxidation. These observations demonstrate unequivocally that elevation of MT concentrations in the cardiomyocytes of 2- fold higher than normal provides efficient protection against DOX toxicity.

Original languageEnglish (US)
Pages (from-to)938-944
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume288
Issue number3
StatePublished - Mar 1 1999
Externally publishedYes

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Metallothionein
Cardiac Myocytes
Doxorubicin
L-Lactate Dehydrogenase
Transgenic Mice
Lipid Peroxidation
Cell Survival

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Inhibition of doxorubicin toxicity in cultured neonatal mouse cardiomyocytes with elevated metallothionein levels",
abstract = "Controversial results have been reported regarding whether metallothionein (MT) functions in doxorubicin (DOX) detoxification in the heart. To determine unequivocally the role of MT in cardiac protection against the toxicity of DOX, ventricular cardiomyocytes isolated from 1- to 3-day neonatal transgenic mice with high levels of cardiac MT and from nontransgenic control animals were applied. On the 6th day of culturing, MT concentrations in the transgenic cardiomyocytes were about 2-fold higher than those in the nontransgenic cells. DOX was added directly into the cultures. Compared with nontransgenic controls, transgenic cardiomyocytes displayed a significant (p < .05) resistance to DOX cytotoxicity, as measured by morphological alterations, cell viability, and lactate dehydrogenase leakage from the cells. This cytoprotective effect of MT correlated with its inhibition of DOX-induced lipid peroxidation. These observations demonstrate unequivocally that elevation of MT concentrations in the cardiomyocytes of 2- fold higher than normal provides efficient protection against DOX toxicity.",
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