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Food Chem Toxicol. 2017 Dec;110:204-213. doi: 10.1016/j.fct.2017.10.035. Epub 2017 Oct 20.

Metallothionein prevents doxorubicin cardiac toxicity by indirectly regulating the uncoupling proteins 2.

Author information

1
School of Public Health, Capital Medical University, 10 Xitoutiao, Fengtai District, Beijing 100069, PR China.
2
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. Electronic address: pengsq@hotmail.com.
3
School of Public Health, Capital Medical University, 10 Xitoutiao, Fengtai District, Beijing 100069, PR China. Electronic address: zwsun@ccmu.edu.cn.

Abstract

Doxorubicin (Dox) is a broad-spectrum anticancer agent, but its clinical use is restricted due to irreversible cardiac toxicity. Metallothionein (MT) can inhibit Dox-induced cardiac toxicity. Applying a proteomics approach we determined that uncoupling proteins (UCPs) may be implicated in this process. This study was designed to examine the mechanisms of MT against Dox cardiac toxicity and the link between MT and UCP2. In vivo, wild-type (MT+/+) and MT-I/II null (MT-/-) mice were given a single dose of Dox (15 mg/kg, i.p.) and sacrificed at 4 days after Dox injection. In vitro, cardiomyocytes were prepared from MT-/- and MT+/+ neonatal mice and cardiomyocytes were pretreated with typical antioxidant NAC or the UCP2 inhibitor genipin followed by exposure to Dox. Based on the results, genipin enhanced Dox-induced oxidative injury, particularly in MT-/- cardiomyocyte. UCP2 levels in MT-/- mice were significantly lower compared to MT+/+ mice treated with Dox. Co-immunoprecipitation demonstrated that MT did not directly bind to UCP2. The NAC and Nrf2 activator oltipraz inhibit the decrease of UCP2 expression induced by Dox. Therefore, attenuating free radical damage with UCP2 help MT antagonize the Dox-induced cardiac toxicity, but does not directly bind MT. MT may regulate UCP2 expression by up-regulating Nrf2.

KEYWORDS:

Doxorubicin; Metallothionein; Nrf2; Uncoupling proteins

PMID:
29061315
DOI:
10.1016/j.fct.2017.10.035
[Indexed for MEDLINE]

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