OVEREXPRESSION OF METALLOTHIONEIN IN THE HEART OF TRANSGENIC MICE SUPPRESSES DOXORUBICIN CARDIOTOXICITY

Metallothionein (MT) may provide protection against doxorubicin-induce d 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 con stitutively overexpressed from 10- to 130-fold higher than normal. The MT concentration was not altered in liver, kidneys, lungs, or skeleta l muscles. Other antioxidant components including glutathione, glutath ione peroxidase, glutathione reductase, catalase, and superoxide dismu tase were not altered in the MT-overexpressing heart. Mice (7-wk-old) from transgenic lines expressing MT activity 10- or 130-fold higher th an normal and from nontransgenic controls were treated intraperitoneal ly with doxorubicin at a single dose of 20 mg/kg, and were killed on t he 4th day after treatment. As compared to normal controls, transgenic mice exhibited a significant resistance to in vivo doxorubicin-induce d cardiac morphological changes, and the increase in serum creatine ph osphokinase 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 t he role of MT in cardioprotection against doxorubicin toxicity.