Peroxiredoxins are involved in metallothionein protection from doxorubicin cardiotoxicity

Previous studies have shown that metallothionein (MT) can antagonize the myocardiotoxicity induced by doxorubicin (Dox), a most effective anticancer agent. However, the molecular mechanisms are not well-understood. Using a proteomics approach we have detected that major peroxiredoxins (Prxs), an important redox regulating molecule family, may be involved in this process. In the present study, we assessed a link between metallothionein and peroxiredoxins. Wild-type (MT+/+) and MT−/− mice were treated intraperitoneally with doxorubicin at a single dose of 15 mg/kg and sacrificed on the 4th day after treatment. Doxorubicin induced cardiotoxicity in both wild-type and MT−/− mice was manifested with increased serum creatine kinase (CK) and lactate dehydrogenase (LDH) activities, and cardiac morphological changes. These toxic responses were stronger in the hearts of MT−/− mice that were more vulnerable to doxorubicin-induced oxidative injury as exhibited by increased lipid peroxidation and decreased catalase and glutathione peroxidase (GSH-Px) expression. Moreover, in the MT−/− mice, the deficiency of metallothionein inhibited the expression of Cu/Zn Superoxide dismutase (SOD-1) induced by doxorubicin. Doxorubicin significantly increased the mRNA levels and protein expressions of Prx-1, -2, -3, -5, and -6 in the hearts of wild-type but not MT−/− mice. Therefore, the present study suggests that metallothionein provides protection against doxorubicin-induced cardiotoxicity, which possibly involves regulation of peroxiredoxins.