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• W2017501501 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. 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. metallothionein doxorubicin mitogen-activated protein kinase reactive oxygen species reactive nitrogen species peroxynitrite 3-morpholinosydnonimine thiobarbituric acid-reactive substance low density lipoprotein superoxide dismutase supercoiled open circle nitric oxide Oxidative damage to different cellular components makes a major contribution to many pathogeneses (1Gutteridge J.M. Halliwell B. Ann. N. Y. Acad. Sci. 2000; 899: 136-147Crossref PubMed Scopus (795) Google Scholar, 2Spector A. J. Ocul. Pharmacol. Ther. 2000; 16: 193-201Crossref PubMed Scopus (202) Google Scholar). Metallothionein (MT)1 is a ubiquitous, low molecular weight, and highly inducible protein (3Cai L. Satoh M. Tohyama C. Cherian M.G. Toxicology. 1999; 132: 85-98Crossref PubMed Scopus (183) Google Scholar, 4Kang Y.J. Proc. Soc. Exp. Biol. Med. 1999; 222: 263-273Crossref PubMed Scopus (156) Google Scholar, 5Vasak M. Hasler D.W. Curr. Opin. Chem. Biol. 2000; 4: 177-183Crossref PubMed Scopus (368) Google Scholar) that has been shown to function as an antioxidant (3Cai L. Satoh M. Tohyama C. Cherian M.G. Toxicology. 1999; 132: 85-98Crossref PubMed Scopus (183) Google Scholar, 4Kang Y.J. Proc. Soc. Exp. Biol. Med. 1999; 222: 263-273Crossref PubMed Scopus (156) Google Scholar). Several studies have demonstrated that MT is able to quench a wide range of reactive oxygen or nitrogen species (ROS or RNS) including superoxide (O⨪2), hydrogen peroxide (H2O2), hydroxyl radical (HO⋅), and nitric oxide (NO) at a higher efficiency than other well known antioxidants such as GSH, SOD, and catalase (6Thornalley P.J. Vasak M. Biochim. Biophys. Acta. 1985; 827: 36-44Crossref PubMed Scopus (980) Google Scholar, 7Miura T. Muraoka S. Ogiso T. Life Sci. 1997; 60: 301-309Crossref Scopus (110) Google Scholar, 8Quesada A.R. Byrnes R.W. Krezoski S.O. Petering D.H. Arch. Biochem. Biophys. 1996; 334: 241-250Crossref PubMed Scopus (125) Google Scholar). An important RNS is peroxynitrite (ONOO−), which has been shown to play a key role in many pathogeneses. Whether MT reacts with ONOO− is unknown. Many studies have demonstrated that exposure of cells to 3-morpholinosydnomine (SIN-1) or directly to ONOO− caused apoptotic cell death through an activation of p38 MAPK (9Schieke S.M. Briviba K. Klotz L.O. Sies H. FEBS Lett. 1999; 448: 301-303Crossref PubMed Scopus (115) Google Scholar, 10Oh-hashi K. Maruyama W. Yi H. Takahashi T. Naoi M. Isobe K. Biochem. Biophys. Res. Commun. 1999; 263: 504-509Crossref PubMed Scopus (121) Google Scholar, 11Jope R.S. Zhang L. Song L. Arch. Biochem. Biophys. 2000; 376: 365-370Crossref PubMed Scopus (79) Google Scholar). There is also increasing evidence indicating that ONOO− causes mitochondrial structural changes, leading to the release of cytochromec and thereby activating caspase-3 and causing apoptosis (12Gadelha F.R. Thomson L. Fagian M.M. Costa A.D. Radi R. Vercesi A.E. Arch. Biochem. Biophys. 1997; 345: 243-250Crossref PubMed Scopus (109) Google Scholar, 13Borutaite V. Morkuniene R. Brown G.C. Biochim. Biophys. Acta. 1999; 1453: 41-48Crossref PubMed Scopus (118) Google Scholar, 14Cassina A.M. Hodara R. Souza J.M. Thomson L. Castro L. Ischiropoulos H. Freeman B.A. Radi R. J. Biol. Chem. 2000; 275: 21409-21415Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). 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 (4Kang Y.J. Proc. Soc. Exp. Biol. Med. 1999; 222: 263-273Crossref PubMed Scopus (156) Google Scholar). Among these reactive free radicals derived from DOX, ONOO− has been considered as the major species that leads to the oxidative damage (15Vasquez-Vivar J. Martasek P. Hogg N. Masters B.S. Pritchard Jr., K.A. Kalyanaraman B. Biochemistry. 1997; 36: 11293-11297Crossref PubMed Scopus (288) Google Scholar, 16Weinstein D.M. Mihm M.J. Bauer J.A. J. Pharmacol. Exp. Ther. 2000; 294: 396-401PubMed Google Scholar). Because MT inhibits both DOX-activated p38 MAPK and DOX-induced apoptosis in cardiomyocytes (17Kang Y.J. Zhou Z.X. Wang G.W. Buridi A. Klein J.B. J. Biol. Chem. 2000; 275: 13690-13698Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar), it is possible that MT reacts with ONOO−. The present study was undertaken to test the hypothesis that MT directly protects from ONOO−-induced oxidative damage. A cell-free system was used to avoid the influence of other cellular enzymes and antioxidants and the interaction of ONOO− with other ROS and RNS in the cell. DNA damage and oxidation of LDL were determined as indexes of ONOO−-induced oxidative damage, because DNA is a sensitive target (18Szabo C. Zingarelli B. O'Connor M. Salzman A.L. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1753-1758Crossref PubMed Scopus (618) Google Scholar, 19Grace S.C. Salgo M.G. Pryor W.A. FEBS Lett. 1998; 426: 24-28Crossref PubMed Scopus (69) Google Scholar), and lipoproteins are also sensitive to ONOO−-induced oxidative damage (20Radi R. Beckman J.S. Bush K.M. Freeman B.A. Arch. Biochem. Biophys. 1991; 288: 481-487Crossref PubMed Scopus (2024) Google Scholar, 21Hermann M. Kapiotis S. Hofbauer R. Exner M. Seelos C. Held I. Gmeiner B. FEBS Lett. 1999; 445: 212-214Crossref PubMed Scopus (47) Google Scholar). MT, SOD, LDL, pTZ 18U plasmid DNA, agarose, and SIN-1 and all other chemicals were purchased from Sigma. Phosphate buffer was prepared to contain 50 mm sodium phosphate, 10 mm NaCl, 0.1 mm diethylenetriaminepentaacetic acid, pH 7.4 (21Hermann M. Kapiotis S. Hofbauer R. Exner M. Seelos C. Held I. Gmeiner B. FEBS Lett. 1999; 445: 212-214Crossref PubMed Scopus (47) Google Scholar). To eliminate the contamination of transition metals such as copper and iron, the phosphate buffer was treated by Chelex 100 according to the instruction manual from Bio-Rad. Lipid hydroperoxide assay kit was obtained from Cayman Chemical (Ann Arbor, MI). Peroxynitrite was synthesized from nitrite and H2O2 in an acidic medium and rapidly quenched in NaOH as described previously (22Koppenol W.H. Kissner R. Beckman J.S. Methods Enzymol. 1996; 269: 296-302Crossref PubMed Google Scholar). The solution was frozen at −20 °C, and ONOO− concentrated in the upper layer was collected. Its concentration was measured at 302 nm and calculated with a molar extinction coefficient of 1670m−1 cm−1(22Koppenol W.H. Kissner R. Beckman J.S. Methods Enzymol. 1996; 269: 296-302Crossref PubMed Google Scholar). DNA strand breaks in supercoiled DNA were analyzed after agarose gel electrophoresis as described previously (19Grace S.C. Salgo M.G. Pryor W.A. FEBS Lett. 1998; 426: 24-28Crossref PubMed Scopus (69) Google Scholar). pTZ 18U plasmid DNA (0.5 μg) was treated with 0.1–1.0 mm SIN-1 at 37 °C or with 0.05–1.0 mm ONOO− at room temperature (22–23 °C) in phosphate buffer with or without the presence of MT. The solution was immediately mixed after addition of SIN-1 or ONOO− because under these conditions ONOO− spontaneously decays with a half-life of less than 2 s. The reaction solution (30 μl) was mixed with 3 μl of electrophoresis loading buffer and loaded onto a 1.0% agarose gel prepared in TAE buffer (40 mm Tris acetate, 2 mm EDTA). Electrophoresis was carried out for 2 h at 71 mV. After electrophoresis, the gel was stained with 0.5 μg/ml ethidium bromide for 15 min, destained for 30 min, and then visualized under UV light and photographed. To quantitatively analyze DNA damage, the density of supercoiled (SC) DNA band and open circle (OC, see Fig. 1 A) DNA band was measured by Multi-Analysis Software from Bio-Rad. The percentage of density of the OC DNA band to total density of the OC and SC DNA bands was considered the percentage of DNA damage as shown in Fig. 1. LDL (1 mg/ml) was treated with 0.05–1.0 mm SIN-1 at 37 °C or ONOO− at room temperature for 18 h in the phosphate buffer with or without MT. LDL oxidation products were measured by thiobarbituric acid-reactive substance (TBARS). Briefly, a 20-μl LDL sample (1 mg/ml) was added into 20 μl of 8.1% SDS, 150 μl of 20% acetate buffer (pH 3.5), and 210 μl of 0.57% thiobarbituric acid (TBA buffer, made fresh) (23Wang G.W. Schuschke D.A. Kang Y.J. Am. J. Physiol. 1999; 276: H167-H175Crossref PubMed Google Scholar). The mixture was incubated at 90 °C for 70 min. After cooling and addition of 100 μl of deionized water, 500 μl of a butanol/pyridine mixture (15:1) was added. They were centrifuged at 4000 rpm for 15 min at 4 °C. The absorbance was determined by an enzyme-linked immunosorbent assay plate reader at 540 nm. Malondialdehyde concentration was calculated using an extinction coefficient of 1.78 × 105 nmol of TBARS/g of protein. All experiments were performed three times, and results were presented as mean ± S.E. Data were subjected to analysis of variance and multiple comparison. The significant level was accepted at p < 0.05(*). When pTZ 18U plasmid DNA was exposed to SIN-1, the native SC DNA was converted to a relaxed OC DNA with single strand breaks (Fig. 1 A). This effect of SIN-1 was dose-dependent (Fig. 1 B). Although this damage was also time-dependent, it reached a maximum damage level within 3 h of exposure to SIN-1 at 37 °C (Fig. 1, Aand C). In the presence of MT, the extent of SIN-1-mediated DNA damage decreased in a MT dose-dependent manner (Fig. 1,D and E). Because SIN-1 produces NO and O⨪2 simultaneously in physiological solution at 37 °C and the reaction between NO and O⨪2 leads to the formation of ONOO−, DNA damage by SIN-1 is thus assumed to be the effect of ONOO−. To explore the possibility that MT prevents SIN-1-induced DNA damage through the reaction between MT and ONOO−, synthesized ONOO− was added directly to the reaction system. As shown in Fig. 2 A, ONOO− is able to induce DNA damage in a dose-dependent manner, and MT conveyed significant protection from this damage (Fig. 2 B). This suggests that MT is a potent scavenger of the ONOO−radical. To further determine the specificity of MT reaction with ONOO−, the effect of SOD on DNA damage induced by SIN-1 and ONOO− was examined. As shown in Fig. 3, SOD (12.5 units in 30-μl reaction system, which equals about 4.0 μm SOD) is able to prevent DNA damage caused by 0.1 mm SIN-1, but not by ONOO−.Figure 2Effect of MT on ONOO−-induced DNA damage in the presence or absence of MT. Experimental conditions were as described in Fig. 1, except that room temperature (22–23 °C) was used for ONOO−. A, DNA damage induced by different doses of ONOO− with 3-h exposure; B, protection by MT from DNA damage by 0.25 mm ONOO− with 3-h exposure). Theasterisk indicates significant difference at the level ofp < 0.05 from control (A) and from ONOO−-induced DNA damage (B).View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Comparison between the effects of MT and SOD on SIN-1 or on ONOO−-induced DNA damage. Experiments are carried out as described under “Materials and Methods.” Exposure time is 3 h for both SIN-1 and ONOO−, and 37 °C and 25 °C were used for SIN-1 and ONOO−, respectively. N represents no additions other than SC DNA.View Large Image Figure ViewerDownload Hi-res image Download (PPT) When LDL was incubated for 18 h at 37 °C with SIN-1 (1.0 mm), lipid peroxidation was detected by the TBARS assay. The same oxidative damaging effect of the synthesized ONOO− on LDL was also detected. Both SIN-1 and synthesized ONOO− induced a dose-dependent oxidative injury to LDL (Fig. 4 A). MT significantly protected LDL from peroxidation by SIN-1 or ONOO− (Fig. 4 B). The TBARS result was confirmed by a lipid hydroperoxide assay (Cayman Chemical, Ann Arbor, MI), and the same protective effect of MT was observed (data not shown). In the present study, we provide, for the first time, direct evidence that MT can react with ONOO− to protect DNA and lipoprotein from oxidative damage. This further extends our understanding of the characteristics of MT antioxidant action. The reaction of MT with ONOO− is particularly important in preventing oxidative tissue injury because ONOO− has been shown to be highly responsible for pathogenesis under a diversity of disease conditions. These include inflammatory and neurodegenerative disease, myocardial dysfunction, and environmental toxicity (19Grace S.C. Salgo M.G. Pryor W.A. FEBS Lett. 1998; 426: 24-28Crossref PubMed Scopus (69) Google Scholar, 20Radi R. Beckman J.S. Bush K.M. Freeman B.A. Arch. Biochem. Biophys. 1991; 288: 481-487Crossref PubMed Scopus (2024) Google Scholar, 24Mates J.M. Sanchez-Jimenez F.M. Int. J. Biochem. Cell Biol. 2000; 32: 157-170Crossref PubMed Scopus (607) Google Scholar). The role of ONOO− in pathogenesis has been demonstrated to be associated with its interaction with the MAPK signaling pathway. Exposure of cultured cells to SIN-1 or directly to ONOO−caused immediate activation of p38 MAPK with the induction of apoptotic cell death, suggesting the role of ONOO− in activating signaling transduction pathways capable of inducing apoptosis (9Schieke S.M. Briviba K. Klotz L.O. Sies H. FEBS Lett. 1999; 448: 301-303Crossref PubMed Scopus (115) Google Scholar, 10Oh-hashi K. Maruyama W. Yi H. Takahashi T. Naoi M. Isobe K. Biochem. Biophys. Res. Commun. 1999; 263: 504-509Crossref PubMed Scopus (121) Google Scholar, 11Jope R.S. Zhang L. Song L. Arch. Biochem. Biophys. 2000; 376: 365-370Crossref PubMed Scopus (79) Google Scholar). However, an inhibitor of p38 MAPK, SB202190, only partially reduced the activation of caspase-3 and apoptotic cell death caused by ONOO− (10Oh-hashi K. Maruyama W. Yi H. Takahashi T. Naoi M. Isobe K. Biochem. Biophys. Res. Commun. 1999; 263: 504-509Crossref PubMed Scopus (121) Google Scholar). This suggests that the activation of p38 MAPK is only one of the pathways induced by ONOO− for the activation of caspase-3 and induction of apoptosis. Other pathways leading to caspase-3 activation and apoptosis may be involved in ONOO−-induced pathogenesis. Recent studies have shown that ONOO− causes mitochondrial structural and functional alterations through lipid peroxidation and protein sulfhydryl oxidation (12Gadelha F.R. Thomson L. Fagian M.M. Costa A.D. Radi R. Vercesi A.E. Arch. Biochem. Biophys. 1997; 345: 243-250Crossref PubMed Scopus (109) Google Scholar, 13Borutaite V. Morkuniene R. Brown G.C. Biochim. Biophys. Acta. 1999; 1453: 41-48Crossref PubMed Scopus (118) Google Scholar, 14Cassina A.M. Hodara R. Souza J.M. Thomson L. Castro L. Ischiropoulos H. Freeman B.A. Radi R. J. Biol. Chem. 2000; 275: 21409-21415Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). These changes lead to cytochrome c release from mitochondria. This in turn results in activation of caspase-3 through activated caspase-9 by cytochrome c. In addition, it has been shown that ONOO− directly reacts with cytochromec in a cell-free system (14Cassina A.M. Hodara R. Souza J.M. Thomson L. Castro L. Ischiropoulos H. Freeman B.A. Radi R. J. Biol. Chem. 2000; 275: 21409-21415Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). In our recent studies, we have demonstrated that MT prevents DOX-induced cardiomyocyte apoptosis through inhibition of p38 MAPK activation (17Kang Y.J. Zhou Z.X. Wang G.W. Buridi A. Klein J.B. J. Biol. Chem. 2000; 275: 13690-13698Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar). We also have observed that MT inhibited mitochondrial cytochrome c release induced by DOX. 2G. W. Wang, J. B. Klein, and Y. J. Kang, submitted for publication. It has been well known that DOX generates ROS and RNS in the myocardium. However, the species of ROS or RNS responsible for the pathogenesis has not been known until recently. DOX binds to the endothelial isoform of nitric-oxide synthase and undergoes endothelial nitric-oxide synthase-mediated reduction to become the semiquinone radical (15Vasquez-Vivar J. Martasek P. Hogg N. Masters B.S. Pritchard Jr., K.A. Kalyanaraman B. Biochemistry. 1997; 36: 11293-11297Crossref PubMed Scopus (288) Google Scholar). This leads to generation of ONOO− and H2O2. Furthermore, the hypothesis that DOX-induced cardiac toxicity is associated with the accumulation of ONOO− formation has been proven in the intact animals treated with DOX (16Weinstein D.M. Mihm M.J. Bauer J.A. J. Pharmacol. Exp. Ther. 2000; 294: 396-401PubMed Google Scholar). The present study has an important implication of understanding the mechanism of action of MT in preventing DOX-induced cardiotoxicity. The induction of apoptotic cell death is an important mechanism of cardiotoxicity, and the formation of ONOO− plays a critical role in this mechanism. In particular, the protection by MT against DOX-induced apoptosis in cardiomyocytes has been shown to be associated with inhibition of both p38 MAPK activation and mitochondrial cytochrome c release. MT may react with ONOO− to block the activation of p38 MAPK and the release of mitochondrial cytochrome c. This consequently leads to the protection by MT against DOX-induced apoptosis in mouse myocardiumin vivo and cardiomyocytes in vitro. In this study, we observed that ONOO−-induced DNA damage was protected by MT, but the protection was not directly dose-dependent on MT concentrations (Fig. 2 B). It is possible that the kinetics of reactions of ONOO−with MT and DNA define the protective effect of MT rather than its concentration because ONOO− is a very short-lived species in solution (t12 ≈ 2 s). Another explanation is the use of commercial MT, which may contain a limited amount of copper. Copper is a transition metal that generates HO⋅ radical in the presence of reductant such as ascorbate and O⨪2 through the Fenton reaction. DNA is a very sensitive target of HO⋅ (25Cai L. Koropatnick J. Cherian M.G. Chem.-Biol. Interact. 1995; 96: 143-155Crossref PubMed Scopus (72) Google Scholar). The fact that commercial MT contains copper and that RNS can react with MT to release metals from MT have been demonstrated (26Misra R.R. Hochadel J.F. Smith G.T. Cook J.C. Waalkes M.P. Wink D.A. Chem. Res. Toxicol. 1996; 9: 326-332Crossref PubMed Scopus (123) Google Scholar). To explore this possibility in the present study, we have monitored the absorbance at 480 nm in the presence of bathocuproinedisulfonic acid along with MT, ONOO−, and H2O2. If copper is released from MT, a complex of cuprous with bathocuproinedisulfonic acid will be formed (25Cai L. Koropatnick J. Cherian M.G. Chem.-Biol. Interact. 1995; 96: 143-155Crossref PubMed Scopus (72) Google Scholar) and the increase in the absorbance in proportion to MT concentrations will be observed. This phenomenon was indeed apparent (data not shown). Therefore, a balance between MT protection and more DNA damage induced by copper released from MT may be reached, leading to no further protection with increased MT concentrations (Fig. 2 B). Although further study is required to fully understand the characteristics of MT protection against ONOO−-induced DNA damage, the present study provides the first evidence that MT protects from ONOO−-induced DNA and protein damage." @default.
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• W2017501501 title "Metallothionein Inhibits Peroxynitrite-induced DNA and Lipoprotein Damage" @default.
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