title: Peroxiredoxins are involved in metallothionein protection from doxorubicin cardiotoxicity.
abstract: 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.
authors.affiliation: Evaluation and Research Center for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, 20 Dongdajie Street, Fengtai District, Beijing 100071, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Jing
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Daiying
authors.initials: D
authors.lastname: Zuo
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D054715:Cardiotoxins / Q000009:adverse effects*; D003402:Creatine Kinase / Q000097:blood; D004317:Doxorubicin / Q000009:adverse effects*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008668:Metallothionein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D054464:Peroxiredoxins / Q000235:genetics / Q000378:metabolism*; D017384:Sequence Deletion
chemical_list: D000975:Antioxidants; D054715:Cardiotoxins; D004317:Doxorubicin; D008668:Metallothionein; D007770:L-Lactate Dehydrogenase; D054464:Peroxiredoxins; D003402:Creatine Kinase