Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cu/Zn-superoxide dismutase (SOD)-accelerated oxidation of the benzene metabolite 1,4-hydroquinone (HQ) results in the enhanced formation of semiquinone anion radicals, electrophilic 1,4-benzoquinone (BQ), and H202. We selected bone marrow stromal cells and phiX-174 double stranded plasmid DNA as model systems to investigate the cytotoxicity and DNA cleaving activity of the Cu/Zn-SOD-mediated activation of HQ. The addition of either Cu/Zn-SOD or Min-SOD to the primary bone marrow stromal cell cultures significantly enhanced HQ-induced cytotoxicity, which could be completely prevented by adding reduced glutathione (GSH) or dithiothreitol but not be adding catalase. Incubation of the plasmid DNA with the HQ/Cu/Zn-SOD system resulted in the induction of single- as well as double-strand breaks, which could be inhibited by catalase and the Cu(I) chelators, bathocuproinedisulfonic acid (BCS) and GSH. Although Mn-SOD could enhance HQ-induced cytotoxicity to stromal cells, the activation of HQ by Mn-SOD did not contribute to the induction of DNA strand breaks. Similar to the HQ/Cu(II) and H202/Cu(II) systems, the DNA strand breaks mediated by HQ/Cu/Zn-SOD could not be effectively inhibited by the hydroxyl radical scavengers, including dimethylsulfoxide, mannitol, and 5,5-dimethyl-1-pyrroline N-oxide, but could be protected by sodium azide. Low-temperature electron spin resonance experiments showed that incubation of Cu/Znu-SOD with HQ resulted in the release of copper from the Cu/Zn-SOD, which could be prevented by catalase. Alpha-(4-Pyridyl-1-oxide)-N-tert-butylnitrone (POBN)/spin-trapping studies demonstrated that the interaction of HQ with Cu/Zn-SOD, but not with Mn-SOD, resulted in the significant formation of POBN-CH3 adduct in the presence of dimethylsulfoxide, suggesting the production of hydroxyl radical or its equivalent from this enzyme/xenobiotic interaction. The formation of the POBN-CH3 adduct from the HQ/Cu/Zn-SOD could be inhibited by catalase, BCS or GSH, indicating the important role for H202 and Cu(I) in the production of reactive oxygen species. Addition of human myeloperoxidase to the HQ/Cu/Zn-SOD synergistically enhanced the formation of BQ from HQ. This enhancement could be abolished by catalase. Taken together, these results demonstrate that activation of HQ by either Cu/Zn-SOD or Mn-SOD results in cytotoxicity to primary bone marrow stromal cells through the formation of electrophilic BQ. Interaction of HQ with Cu/Zn-SOD causes oxidative damage to Cu/Zn-SOD, leading to the release of copper from the enzyme. The further reaction between the released copper and H202 generates reactive oxygen species that participate in the induction of strand breaks in plasmid DNA. The H202 generated from the Cu/Zn-SOD-accelerated oxidation of HQ can also be utilized by myeloperoxidase resulting in additional conversion of HQ to BQ.
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PMID:Role of Cu/Zn-superoxide dismutase in xenobiotic activation. II. Biological effects resulting from the Cu/Zn-superoxide dismutase-accelerated oxidation of the benzene metabolite 1,4-hydroquinone. 864 80

4-Vinylcyclohexene diepoxide (VCD) destroys small preantral (25-100 microns) ovarian follicles after repeated dosing in mice and rats. A previous study determined this follicular destruction is via apoptosis (physiological cell death). The purposes of this study were to examine the effects of VCD on amounts of mRNA for several genes that might be involved in this ovotoxic response and to determine the specificity of this response for small preantral follicles. The genes of interest were bax, a cell death gene; three forms of the antioxidant enzyme, superoxide dismutase (mitochondrial manganese-containing or MnSOD, cytosolic copper/zinc-containing or Cu/ZnSOD, and secreted or secSOD); and microsomal epoxide hydrolase (mEH), involved in detoxification of VCD. Female Fischer 344 rats were administered daily doses (10 days) of vehicle control (sesame oil) or VCD (80 mg/kg, ip). Four hours after the last injection, livers and ovaries were removed. Small (25-100 microns) and large (100-250 microns) preantral follicles were separated from the ovaries by gentle dissociation and collected by mouth pipeting. Total RNA was extracted from all tissues, reverse transcribed into first-strand cDNA, and amplified by polymerase chain reaction using oligonucleotide primers specific for each gene. Relative levels of mRNA were visualized by agarose gel electrophoresis and autoradiography and quantified by densitometric analysis. Coamplification of ribosomal protein L19 (constitutively expressed in ovarian tissue) was used for normalization in each sample. Increased levels of mRNA for bax (172 +/- 20% of control, p < 0.05), MnSOD (248 +/- 70% of control, p < 0.05), and mEH (352 +/- 120% of control, p < 0.05) were measured in 25- to 100-microns follicles collected from VCD-treated compared with control rats. Unlike 25- to 100-microns follicles (the targets of ovotoxicity), in 100- to 250-microns follicles (nontargets) there were no changes (p > 0.05) in mRNA levels for bax or MnSOD in VCD-treated rats; however, mRNA levels for mEH were significantly decreased (79 +/- 4% of control, p < 0.05), compared with control. No changes in levels of mRNA for mEH were observed in liver from VCD-treated rats relative to control. Additionally, in liver VCD caused a significant decrease in mRNA levels for bax (31 +/- 5% of control, p < 0.05) and Cu-ZnSOD (56 +/- 17% of control, p < 0.05). In summary, dosing of rats with VCD enhanced expression of mRNA encoding several genes that might respond during the induction of ovotoxicity. The selective increase in bax in the population of follicles destroyed by repeated dosing with VCD may reflect their susceptibility to apoptosis.
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PMID:Enhanced expression of bax in small preantral follicles during 4-vinylcyclohexene diepoxide-induced ovotoxicity in the rat. 880 58

The pathogenesis of diabetic corneal epitheliopathy, one of the ocular complications frequently seen in diabetes patients, still remains to be elucidated. Hyperglycemia causes glycation of various proteins leading to the formation of superoxide radicals (O2.-). Copper, zinc-superoxide dismutase (Cu, Zn-SOD), a scavenger of superoxide radicals, whose function is complementary to manganese-SOD (Mn-SOD), is inactivated during glycation. As a first step to clarify whether depressed antioxidant activity is associated with diabetic corneal epitheliopathy or not, we investigated the expression of Mn-SOD mRNA (messenger ribonuclic acid) in streptozotocin-induced diabetic rat cornea by in situ hybridization using a digoxigenin-labeled Mn-SOD cDNA probe. Mn-SOD mRNA was detected in epithelial cell layer and endothelial cell layer of both diabetic rat cornea and normal rat cornea. However, the expression of Mn-SOD mMRA in the epithelial cell layer of diabetic rat cornea was weaker than that of normal rat cornea. These results suggest that decreased Mn-SOD activity might be one of factors causing diabetic corneal epitheliopathy.
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PMID:[Expression of Mn-SOD mRNA in streptozotocin-induced diabetic rat cornea by in situ hybridization]. 881 Feb 35

Copper/zinc (Cu/ZnSOD) and manganese (MnSOD) superoxide dismutases which catalyze the dismutation of toxic superoxide anion, O(2-)-, to O2 and H2O2, play a major role in protecting cells from toxicity of oxidative stress. However, cells overexpressing either form of the enzyme show signs of toxicity, suggesting that too much SOD may be injurious to the cell. To elucidate the possible mechanism of this cytotoxicity, the effect of SOD on DNA and RNA strand scission was studied. High purity preparations of Cu/ZnSOD and MnSOD were tested in an in vitro assay in which DNA cleavage was measured by conversion of phage phi X174 supercoiled double-stranded DNA to open circular and linear forms. Both types of SOD were able to induce DNA strand scission generating single- and double-strand breaks in a process that required oxygen and the presence of fully active enzyme. The DNA strand scission could be prevented by specific anti-SOD antibodies added directly or used for immunodepletion of SOD. Requirement for oxygen and the effect of Fe(II) and Fe(III) ions suggest that cleavage of DNA may be in part mediated by hydroxyl radicals formed in Fenton-type reactions where enzyme-bound transition metals serve as a catalyst by first being reduced by superoxide and then oxidized by H2O2. Another mechanism was probably operative in this system, since in the presence of magnesium DNA cleavage by SOD was oxygen independent and not affected by sodium cyanide. It is postulated that SOD, by having a similar structure to the active center of zinc-containing nucleases, is capable of exhibiting non-specific nuclease activity causing hydrolysis of the phosphodiester bonds of DNA and RNA. Both types of SOD were shown to effectively cleave RNA. These findings may help explain the origin of pathology of certain hereditary diseases genetically linked to Cu/ZnSOD gene.
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PMID:DNA and RNA strand scission by copper, zinc and manganese superoxide dismutases. 883 54

A major determinant of the level of cellular superoxide anion (O2-.) is the dismutation of O2-. to hydrogen peroxide by the enzyme superoxide dismutase (SOD). Three forms of SOD exist, but in endothelial cells, the major form outside of the mitochondria is the cytosolic copper/zinc-containing superoxide dismutase (Cu/Zn SOD). Since fluid shear stress is an important determinant of the function and structure of endothelial cells in vivo, we examined the effect of laminar shear stress on the expression of Cu/Zn SOD in cultured human aortic endothelial cells. Laminar shear stress of 0.6 to 15 dyne/cm2 increased Cu/Zn SOD mRNA in a time- and dose-dependent manner in human aortic endothelial cells. Shear stress also increased both Cu/Zn SOD protein content and the enzyme activity. Nuclear runon assays showed that nuclei from human aortic endothelial cells exposed to laminar shear stress had a 1.6-fold greater transcriptional activity of the Cu/Zn SOD gene compared with cells not exposed to shear, indicating that an increase in Cu/Zn SOD mRNA induced by laminar shear stress is at least in part mediated by increased transcription. In contrast, shear stress had no effect on Cu/Zn SOD mRNA levels in human aortic smooth muscle cells. These findings show that physiological levels of shear stress increase expression of Cu/Zn SOD in the endothelium. This adaptation to shear stress might augment the effect of locally produced NO. and thereby promote the antiatherogenic and anti-inflammatory properties of the endothelial cell.
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PMID:Shear stress modulates expression of Cu/Zn superoxide dismutase in human aortic endothelial cells. 892 65

Alcohol damage to the liver can, among other factors, be mediated through the action of toxic oxygen radicals generated by ethanol. Major antioxidants in the liver are copper/zinc and manganese superoxide dismutases (Cu/Zn- and Mn-SODs). In order to test whether SODs may be differentially expressed in alcoholic liver disease (ALD), biopsies from 45 patients with ALD were analyzed for qualitative and quantitative immunoreactivity of Cu/Zn- and Mn-SOD in hepatocytes. The overall amount of Cu/Zn-SOD reactivity was significantly lower in ALD than in control biopsies, whereas no difference was found for Mn-SOD. Staining for both enzymes was decreased in ballooned hepatocytes. Low Cu/Zn-SOD was correlated with advanced lattice-like perisinusoidal fibrosis. In hepatocytes forming cirrhotic nodules, SOD reactivity was similar to that of control cells. The results suggest that SODs may be differentially regulated in ALD, and that Mn-SOD, an inducible enzyme, may be involved in recovery and cell protection in ALD.
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PMID:Copper/zinc and manganese superoxide dismutases in alcoholic liver disease: immunohistochemical quantitation. 893 Jun 33

Superoxide dismutases (SODs) protect cells from damage by oxygen free radicals. Manganese (Mn) SOD is preferentially induced in terminally differentiating cells; induction of copper-zinc (CuZn) SOD is more closely associated with postnatal exposure to environmental sources of oxygen free radicals. The purpose of this study was to investigate ontogenetic changes in immunoreactivity for MnSOD and CuZnSOD relative to the expression of markers of neuronal and chemosensory differentiation in olfactory and vomeronasal receptor neurons (ORNs and VRNs, respectively), which mature with different time courses. Immunoreactivity for both SODs was detected in rat ORNs at embryonic day (E) 14, the earliest time point investigated, but not until E16 in vomeronasal neuroblasts. ORNs also expressed the neuronal marker protein gene product (PGP) 9.5 and the chemosensory cell marker olfactory marker protein (OMP) at E14; vomeronasal neuroblasts expressed PGP 9.5 at E16 but were not immunoreactive for OMP until postnatal day (P) 2. Immunoreactivity for MnSOD in ORNs and VRNs generally increased pre- and postnatally to a maximum at P11. Immunoreactivity for CuZnSOD did not increase markedly until after birth, reaching maximal levels at P11-P24. Within ORNs and VRNs, the most intense immunoreactivity was localized in the dendritic and supranuclear regions. The results indicate that in ORNs and VRNs, increases in MnSOD immunoreactivity during ontogeny parallel the ongoing differentiation and maturation of chemosensory receptor neurons; in contrast, the induction of immunoreactivity for CuZnSOD is associated with postnatal exposure to the ambient oxygen and xenobiotic environment.
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PMID:Differential expression of manganese and copper-zinc superoxide dismutases in the olfactory and vomeronasal receptor neurons of rats during ontogeny. 908 17

1. The purpose of the present study was to investigate the changes in superoxide dismutase (SOD) isoenzyme (Mn(2+)-SOD and Cu2+, Zn(2+)-SOD) activities, contents and mRNA expressions in rat skeletal muscle during endurance training and a single bout of exercise. 2. Thirty-eight male Wistar rats were divided into untrained (U) and trained (T) groups. The T group rats were treadmill-trained for 9 weeks. The activity, content and mRNA expression of Mn(2+)-SOD and Cu2+, Zn(2+)-SOD were determined in the soleus muscle of each rat. 3. Mn(2+)-SOD activity and content in the T group were significantly higher than in the U group, both at rest (22 and 21%, respectively) and after exercise (24 and 46%, respectively), while a single bout of exercise affected neither the activity nor content of Mn(2+)-SOD in either group. 4. The content of Cu2+,Zn(2+)-SOD in both groups was not different at rest and after exercise, although its activity at rest was significantly higher in the T group than in the U group (by 29%). 5. After exercise, the expression of Mn(2+)-SOD mRNA was markedly attenuated only in the U group (49%); the expression of Cu2+,Zn(2+)-SOD mRNA was not influenced by exercise. 6. Our results suggest that adequate endurance training increases both the activity and content of Mn(2+)-SOD and that untrained rats are rather susceptible to oxidative stress during physical exercise. It thus appears that Mn(2+)-SOD provides a reliable index of physical training. 7. The results obtained in the present study also suggest that muscle has the capacity of responding to training in such a manner as to reduce the potential harm arising from the accumulation of oxygen free radicals resulting from enhanced metabolic activity.
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PMID:Effects of endurance training on superoxide dismutase activity, content and mRNA expression in rat muscle. 914 82

The enzyme superoxide dismutase (SOD), which catalyzes the dismutation of the superoxide radical, is present in the cytosol and mitochondria of all oxygen-respiring eukaryotes. The cytosolic form contains copper and zinc (CuZnSOD), whereas the mitochondrial form contains manganese (MnSOD). The latter protein is synthesized in the cytosol as a MnSOD precursor, containing an N-terminal mitochondrial-targeting sequence. CuZnSOD is sensitive toward cyanide (CN) and hydrogen peroxide (H2O2), but MnSOD is not. Assays for SOD activity in cytosol from the hepatopancreas of the blue crab, Callinectes sapidus, showed the presence of a CN/H2O2-insensitive form of SOD. No CN/H2O2-sensitive CuZnSOD was found. This unexpected phenomenon was shown to occur in all decapod crustacea (crabs, lobsters, shrimp) examined. The cytosolic and mitochondrial SODs of C. sapidus were purified by means of ion-exchange, size-exclusion, and reverse-phase HPLC. The cytosolic SOD is a homodimeric protein, which exists in a monomer-dimer equilibrium (24 kDa left and right arrow 48 kDa). The protein contains approximately 1 Mn per subunit. No copper or zinc is present. Amino acid sequence analysis identified the novel cytosolic SOD as a MnSOD precursor with an abnormal mitochondrial-targeting sequence. The mitochondrial SOD of C. sapidus is similar to the MnSOD found in other eukaryotes. N-Terminal amino sequences of mitochondrial and cytosolic blue crab MnSOD differ in several positions. The MnSODs are thus encoded for by two different genes. The paradigm that all eukaryotes contain intracellular CuZnSOD and that MnSOD occurs exclusively in the mitochondria appears not to apply to a large group of marine arthropods.
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PMID:The paradigm that all oxygen-respiring eukaryotes have cytosolic CuZn-superoxide dismutase and that Mn-superoxide dismutase is localized to the mitochondria does not apply to a large group of marine arthropods. 934 Dec 31

We have examined the effects of UVB irradiation, oxidative stress and cytokines on the antioxidant enzymes copper/zinc and manganese superoxide dismutase (CuZnSOD and MnSOD) in HeLa cells. A single dose of UVB irradiation regulated dose-dependently the expression of the 4 kb transcript of MnSOD although it did not have any significant effect on MnSOD enzymatic activity. In contrast, UVB irradiation reduced both the enzymatic activity and the expression of the 0.7 and 0.9 kb mRNA transcripts of CuZnSOD. The cytokines TNF-alpha (1 ng ml-1 and 10 ng ml-1) and IL-6 (100 U ml-1) induced MnSOD activity, and TNF-alpha also upregulated MnSOD mRNA expression. Interestingly, genistein, a soy isoflavone and a tyrosine kinase inhibitor, was able to inhibit the induction of Mn-SOD activity and mRNA expression by TNF-alpha. Enzymatic CuZnSOD activity was depressed by a high dose of H2O2 while IL-6 or TNF-alpha had no effect on CuZnSOD activity. Our results demonstrate that, in addition to enzyme activity level, UVB irradiation can regulate the superoxide dismutases at the mRNA level. We also suggest that UVB irradiation, oxidative stress and cytokines regulate differentially CuZnSOD and MnSOD, and that the activities and expression of these antioxidant enzymes are controlled by distinct mechanisms.
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PMID:Regulation of copper/zinc and manganese superoxide dismutase by UVB irradiation, oxidative stress and cytokines. 937 18


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