Abstract
Previous studies have demonstrated that metallothionein functions as an antioxidant that protects against oxidative DNA, protein, and lipid damage induced by superoxide anion, hydrogen peroxide, hydroxyl radical, and nitric oxide. The present study was undertaken to test the hypothesis that metallothionein also protects from DNA and lipoprotein damage induced by peroxynitrite, an important reactive nitrogen species that causes a diversity of pathological processes. A cell-free system was used. DNA damage was detected by the mobility of plasmid DNA in electrophoresis. Oxidation of low density lipoprotein was measured by a thiobarbituric acid-reactive substance, which was confirmed by lipid hydroperoxide assay. Plasmid DNA damage and low density lipoprotein oxidation were induced by 3-morpholinosydnomine, which produces peroxynitrite through the reaction between nitric oxide and superoxide anion or by synthesized peroxynitrite directly. DNA damage by 3-morpholinosydnomine was prevented by both metallothionein and superoxide dismutase, whereas the damage caused by peroxynitrite was prevented by metallothionein only. The oxidation of low density lipoprotein by 3-morpholinosydnomine and peroxynitrite was also significantly inhibited by metallothionein. This study thus demonstrates that metallothionein may react directly with peroxynitrite to prevent DNA and lipoprotein damage induced by this pathological reactive nitrogen species.
Highlights
From the Departments of ‡Medicine and ¶Pharmacology & Toxicology, University of Louisville, §Veterans Affairs Medical Center, and ʈJewish Hospital Heart and Lung Institute, Louisville, Kentucky 40292
We provide, for the first time, direct evidence that MT can react with ONOOϪ to protect DNA and lipoprotein from oxidative damage
The role of ONOOϪ in pathogenesis has been demonstrated to be associated with its interaction with the MAPK signaling pathway
Summary
From the Departments of ‡Medicine and ¶Pharmacology & Toxicology, University of Louisville, §Veterans Affairs Medical Center, and ʈJewish Hospital Heart and Lung Institute, Louisville, Kentucky 40292. The present study was undertaken to test the hypothesis that metallothionein protects from DNA and lipoprotein damage induced by peroxynitrite, an important reactive nitrogen species that causes a diversity of pathological processes. Plasmid DNA damage and low density lipoprotein oxidation were induced by 3-morpholinosydnomine, which produces peroxynitrite through the reaction between nitric oxide and superoxide anion or by synthesized peroxynitrite directly. This study demonstrates that metallothionein may react directly with peroxynitrite to prevent DNA and lipoprotein damage induced by this pathological reactive nitrogen species. It is well known that the cardiac toxicity of doxorubicin (DOX), an important anticancer agent, is mainly due to the formation of ROS and RNS [4] Among these reactive free radicals derived from DOX, ONOOϪ has been considered as the major species that leads to the oxidative damage [15, 16]. Because MT inhibits both DOX-activated p38 MAPK and DOXinduced apoptosis in cardiomyocytes [17], it is possible that MT reacts with ONOOϪ
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