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.
Footnotes
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Send reprint requests to: Dr. Y. James Kang, Department of Medicine, University of Louisville School of Medicine, 530 S. Jackson St., Louisville, KY 40202. E-mail:yjkang01{at}homer.louisville.edu
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↵1 This work was supported in part by National Institutes of Health Grant CA68125 and EI Award 9640091N from the American Heart Association (to Y.J.K.). Y.J.K. is a University Scholar of the University of Louisville. This work was presented in part at the Fourth International Metallothionein Meeting held in Kansas City, MO, September 17–20, 1997.
- Abbreviations:
- DOX
- doxorubicin
- MT
- metallothionein
- LDH
- lactate dehydrogenase
- MEM
- minimum essential medium
- FBS
- fetal bovine serum
- MTT
- 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide
- HBSS
- Hanks’ balanced salt solution
- DMEM
- Dulbecco’s modified Eagle’s medium
- Received May 28, 1998.
- Accepted September 29, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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Inhibition of Doxorubicin Toxicity in Cultured Neonatal Mouse Cardiomyocytes with Elevated Metallothionein Levels
