Metallothionein acts as a cytoprotectant against doxorubicin toxicity

The protective role of metallothionein (MT) against the myocardiotoxicity a nd hepatotoxicity of doxorubicin (Dox) was investigated in mice. Dox-induce d elevations of plasma creatine kinase activity, a measure of myocardiac da mage, and plasma glutamate pyruvate transaminase activity, reflecting hepat ic damage, were prevented by pretreatment with an MT inducer. Pretreatment with zinc induced MT in the liver and heart, thereby reducing Dox toxicity in these two organs. Pretratment with n-hexane also induced MT and reduced Dox toxicity, but only in the liver. In primary hepatocyte cultures, the le akage of lactate dehydrogenase induced by Dox was prevented by zinc pretrea tment. These results suggest that MT induction prevents Dox toxicity in viv o and in vitro. Furthermore, we determined that MT-null mice were more sens itive to the myocardiotoxic and hepatotoxic effects of Dox. These findings indicate that both basal and induced MT protect against Dox toxicity.