Overexpression of Metallothionein in the Heart of Transgenic Mice Suppresses

Metallothionein (MT) may provide protection against doxo-rubicin-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 trans-genic mouse lines were produced. Cardiac MT was constitu-tively overexpressed from 10- to 130-fold higher than nor-mal. 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 al-tered 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 car-diac morphological changes, and the increase in serum cre-atine 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.