This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhou, Z. Articles by Kang, Y. J. Search for Related Content PubMed PubMed Citation Articles by Zhou, Z. Articles by Kang, Y. J.

(American Journal of Pathology. 2000;156:1653-1662.)
© 2000 American Society for Investigative Pathology

Regular Articles

Immunocytochemical Localization of Metallothionein and its Relation to Doxorubicin Toxicity in Transgenic Mouse Heart

From the Departments of Medicine and Pharmacology and Toxicology, University of Louisville School of Medicine, and Jewish Hospital Heart and Lung Institute, Louisville, Kentucky

Previous studies using a cardiac-specific metallothionein-overexpressing transgenic mouse model have demonstrated that metallothionein protects the heart from doxorubicin toxicity. The present study was undertaken to determine cellular and subcellular distribution of metallothionein and located the antioxidant action of this protein in the transgenic heart. Using light microscopic immunoperoxidase method, it was identified that the overexpressed metallothionein is localized exclusively in cardiomyocytes. The electron microscopic immunogold method revealed that elevated metallothionein is in nucleus, myofibers, and sarcoplasm. In contrast with these distributions, metallothionein in nontransgenic myocardium was undetectable by immunoperoxidase light microscopy and was seldom found in nucleus and myofibers by immunogold electron microscopy. Treatment with doxorubicin induced cytoplasmic vacuolization and severe damages in myofilaments and nucleus in nontransgenic myocardium. The most prominent injury, however, occurred in mitochondria, including striking size and shape changes, focal swelling and loss of cristae. These damages were rarely found in the doxorubicin-treated transgenic myocardium. In particular, the internal morphology of mitochondria was maintained essentially normal, although metallothionein was not localized in this compartment in transgenic hearts. This study thus demonstrates that although the subcellularly localized action of metallothionein is important, it also plays a significant role in protection against oxidative injury by doxorubicin in remote organelles.

This article has been cited by other articles:

				X. Li, H. Chen, and P. N. Epstein Metallothionein and Catalase Sensitize to Diabetes in Nonobese Diabetic Mice: Reactive Oxygen Species May Have a Protective Role in Pancreatic {beta}-Cells Diabetes, June 1, 2006; 55(6): 1592 - 1604. [Abstract] [Full Text] [PDF]

				X. Shen, S. Zheng, N. S. Metreveli, and P. N. Epstein Protection of Cardiac Mitochondria by Overexpression of MnSOD Reduces Diabetic Cardiomyopathy Diabetes, March 1, 2006; 55(3): 798 - 805. [Abstract] [Full Text] [PDF]

				K. E. Merten, W. Feng, L. Zhang, W. Pierce, J. Cai, J. B. Klein, and Y. J. Kang Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity J. Pharmacol. Exp. Ther., December 1, 2005; 315(3): 1314 - 1319. [Abstract] [Full Text] [PDF]

				L. Cai, J. Wang, Y. Li, X. Sun, L. Wang, Z. Zhou, and Y. J. Kang Inhibition of Superoxide Generation and Associated Nitrosative Damage Is Involved in Metallothionein Prevention of Diabetic Cardiomyopathy Diabetes, June 1, 2005; 54(6): 1829 - 1837. [Abstract] [Full Text] [PDF]

				X. Sun and Y. J. Kang Prior Increase in Metallothionein Levels Is Required to Prevent Doxorubicin Cardiotoxicity Experimental Biology and Medicine, September 1, 2002; 227(8): 652 - 657. [Abstract] [Full Text] [PDF]

				Z. Zhou, X. Sun, J. C. Lambert, J. T. Saari, and Y. J. Kang Metallothionein-Independent Zinc Protection from Alcoholic Liver Injury Am. J. Pathol., June 1, 2002; 160(6): 2267 - 2274. [Abstract] [Full Text] [PDF]

				Q. Liang, E. C. Carlson, R. V. Donthi, P. M. Kralik, X. Shen, and P. N. Epstein Overexpression of Metallothionein Reduces Diabetic Cardiomyopathy Diabetes, January 1, 2002; 51(1): 174 - 181. [Abstract] [Full Text] [PDF]

				H. Chen, E. C. Carlson, L. Pellet, J. T. Moritz, and P. N. Epstein Overexpression of Metallothionein in Pancreatic {beta}-Cells Reduces Streptozotocin-Induced DNA Damage and Diabetes Diabetes, September 1, 2001; 50(9): 2040 - 2046. [Abstract] [Full Text] [PDF]

				G.-W. Wang, J. B. Klein, and Y. J. Kang Metallothionein Inhibits Doxorubicin-Induced Mitochondrial Cytochrome c Release and Caspase-3 Activation in Cardiomyocytes J. Pharmacol. Exp. Ther., August 1, 2001; 298(2): 461 - 468. [Abstract] [Full Text] [PDF]

				G.-W. Wang, Z. Zhou, J. B. Klein, and Y. J. Kang Inhibition of hypoxia/reoxygenation-induced apoptosis in metallothionein-overexpressing cardiomyocytes Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2292 - H2299. [Abstract] [Full Text] [PDF]

				B. Ye, W. Maret, and B. L. Vallee Zinc metallothionein imported into liver mitochondria modulates respiration PNAS, February 8, 2001; (2001) 41619198. [Abstract] [Full Text]

				B. Ye, W. Maret, and B. L. Vallee Zinc metallothionein imported into liver mitochondria modulates respiration PNAS, February 27, 2001; 98(5): 2317 - 2322. [Abstract] [Full Text] [PDF]