Induction of metallothionein by zinc protects from daunorubicin toxicity in rats

Abstract

Daunorubicin (DNR) is an anthracyline antibiotic used in the treatment of a variety of human cancers. Reactive oxygen species (ROS) produced in the metabolism of DNR have severe cardiotoxicity which consequently compromises its clinical use as anticancer drug. This study aimed to investigate the effect of DNR administration on both cardiac and hepatic tissues, and the possible protective role of zinc on the cardiotoxicity and hepatotoxicity produced by DNR. Administration of 10 or 20 mg/kg DNR to Sprague–Dawley rats, increases serum creatine kinase activity, and blood troponin T levels (as cardiotoxicity indices), alanine aminotransferase activity (as hepatotoxicity index), as well as cardiac and hepatic 2-thiobarbituric acid reactive substances (as an index of lipid peroxidation). Treatment with 20 mg/kg Zn prior to DNR, dramatically induced metallothionein-1 (MT-1) mRNA and MT protein in both heart and liver while DNR alone induced MT, but to a much lower degree than Zn. The analysis of MT protein isoforms revealed that MT-1 was the form induced, while metallothionein-2 (MT-2) levels remained practically unchanged. The increases in both MT protein and MT-1 mRNA ran parallel with the reduction of cardiac and hepatic toxicities. Our results indicate that MT induction by Zn is a highly effective approach in preventing cardiotoxicity and hepatotoxicity caused by DNR. These animal data suggest the use of Zn to reduce DNR-induced cardiotoxicity and hepatotoxicity in the chemotherapy of cancer patients.