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)

Although the mechanisms responsible for chemically induced oxidative stress are under intense investigation, little is known about the effects of prooxidant chemicals on the expression of drug-metabolizing enzymes. We examined the effects of diquat (0.1 mmol/kg, ip) and ciprofibrate (0.025% w/w, diet), chemicals which induce oxidative stress via different biochemical mechanisms, on the steady-state messenger RNA (mRNA) levels of six cytochrome P450 enzymes, seven glutathione S-transferase (GST) isoenzymes, UDP-glucuronosyl transferase 1-06 (UGT1*06), gamma-glutamylcysteine synthetase (gamma GCS), NADP(H):quinone oxidoreductase (quinone reductase), Cu/Zn superoxide dismutase (SOD), catalase, and 18S ribosomal RNA in the livers of male Sprague-Dawley rats. Effects of chemical treatments on mRNA levels were compared to changes in catalytic activities for selected enzymes. Ciprofibrate treatment selectively decreased CYP1A2 mRNA expression, whereas both chemicals suppressed CYP3A2 mRNA expression. CYP4A1 mRNA expression and lauric acid hydroxylase activities were induced by ciprofibrate treatment, whereas diquat treatment moderately increased CYP4A1 mRNA levels without affecting lauric acid hydroxylase activities. The steady-state mRNA levels encoding constitutively expressed GST isozymes (Ya1, Ya2, Yb1, Yb2, and Yc1) were decreased by diquat exposure, and the mRNA encoding four of the five constitutively expressed GSTs (Ya1, Ya2, Yb1, and Yc1) were also decreased by ciprofibrate treatment. Nonconstitutively expressed or low constitutively expressed genes (CYP1A1, CYP2B1, CYP2B2, GST Yc2, GST Yf, and UGT1*06) were not induced by exposure to the prooxidants. Changes in isozyme-specific catalytic activities were more consistent with the observed changes in mRNA expression for the GSTs than for the P450s. Both treatments had inhibitory effects on hepatic GSH biosynthesis by decreasing gamma GCS large-subunit mRNA expression, gamma GCS catalytic activities, and hepatic GSH concentrations. Cu/Zn SOD and quinone reductase mRNA levels were increased after ciprofibrate exposure, whereas Cu/Zn SOD mRNA expression was decreased in the diquat-treated animals. The results of this study indicate that diquat and ciprofibrate can decrease the expression profile of a number of phase I, phase II, and antioxidant enzymes and inhibit GSH biosynthesis. These effects may involve the pretranslational loss of hepatic mRNAs, possibly due to accelerated production of reactive oxygen species.
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PMID:The effects of diquat and ciprofibrate on mRNA expression and catalytic activities of hepatic xenobiotic metabolizing and antioxidant enzymes in rat liver. 767 60

Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, SR 4233, WIN 59075) is a bioreductive antitumor agent with a high selective toxicity for hypoxic cells. The selective hypoxic toxicity of TPZ results from the rapid reoxidation of the one-electron reduction product, the TPZ radical, in the presence of molecular oxygen with the concomitant production of superoxide radical. Under hypoxia the TPZ radical kills cells by causing DNA double-strand breaks and chromosome aberrations. However, the mechanism of aerobic cytotoxicity is still a matter of debate. In this study, we investigated the mechanism of aerobic cytotoxicity by adapting human lung adenocarcinoma A549 cells to aerobic TPZ exposure and characterizing the changes associated with drug resistance. The adapted cells were resistant to aerobic TPZ exposures (with dose-modifying factors of up to 9.2), although hypoxic sensitivity was largely unchanged. Relative to the parental A549 cell line, adaptation to continuous aerobic TPZ exposure resulted in increased levels of manganese superoxide dismutase (up to 9.4-fold), moderate increases in glutathione reductase (up to 2.1-fold), and loss of both quinone oxidoreductase (DT-diaphorase) activity and NADPH cytochrome P450 reductase activity. There was essentially no change in the activity of the cytoplasmic form of superoxide dismutase (CuZnSOD), catalase, or glutathione peroxidase. The increased activity of antioxidant enzymes in the resistant cell lines (in particular MnSOD) strongly suggests that reactive oxygen species are, in large part, responsible for the toxicity of TPZ under aerobic conditions, and is consistent with aerobic and hypoxic drug cytotoxicity resulting from different mechanisms.
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PMID:Adaptation of human tumor cells to tirapazamine under aerobic conditions: implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity. 927 29

In previous works we demonstrated that 2-methyl-1,4-naphthoquinone (menadione) causes a marked increase in the force of contraction of guinea pig and rat isolated atria. This inotropic effect was significantly higher in the guinea pig than in the rat and was strictly related to the amount of superoxide anion (O(2)(*-)), generated as a consequence of cardiac menadione metabolism through mitochondrial NADH-ubiquinone oxidoreductase. The present study was designed to further elucidate the basis of these quantitatively different positive inotropic responses. To this purpose, we measured O(2)(*-) and hydrogen peroxide (H(2)O(2)) produced by mitochondria isolated from guinea pig and rat hearts in the presence of 20 microM menadione. Moreover, we evaluated the menadione detoxification activity (DT-diaphorase) and the antioxidant defences of guinea pig and rat hearts, namely their GSH/GSSG content, Cu/Zn- and Mn-dependent superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (Gpx) activities. Our results indicate that DT-diaphorase activity and glutathione levels were similar in both animal species. By contrast, guinea pig mitochondria produced greater amounts of O(2)(*-) and H(2)O(2) than those of rat heart. This is probably due to both the higher Mn-SOD activity (2.93 +/- 0.02 vs. 1.95 +/- 0.06 units/mg protein; P < 0.05) and to the lower Gpx activity (10.09 +/- 0.30 vs. 32.67 +/- 1.02 units/mg protein; P < 0.001) of guinea pig mitochondria. A lower CAT activity was also observed in guinea pig mitochondria (2.40 +/- 0.80 vs. 6.13 +/- 0.20 units/mg protein; P < 0.01). Taken together, these data provide a rational explanation for the greater susceptibility of guinea pig heart to the toxic effect of menadione: because of the greater amount of O(2)(*-) generated by the quinone and the higher mitochondrial Mn-SOD activity, guinea pig heart is exposed to more elevated concentrations of H(2)O(2) that is less efficiently detoxified, because of lower Gpx and CAT levels of mitochondria.
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PMID:Role of antioxidant defences in the species-specific response of isolated atria to menadione. 1210 91

Despite extensive interest in the rodent nasal cavity as a target organ for toxicity, there is very limited information regarding nasal defenses against oxidative stress and xenobiotic-derived oxidants. Using immunohistochemistry, we have examined the distribution of Cu,Zn and Mn superoxide dismutase (SOD), catalase, glutathione (GSH) peroxidase, and DT-diaphorase in rat nasal tissues. In addition, we have determined the concentrations of ascorbate and alpha-tocopherol and the activities of SOD (combined Cu,Zn and Mn forms), catalase, GSH peroxidase, GSH reductase, and DT-diaphorase in nasal respiratory epithelium (RE), olfactory epithelium (OE), and in lung. Immunohistochemistry demonstrated that all four enzymes were similarly distributed, with the greatest staining intensity in dorsal-medial regions of the nasal cavity. In respiratory epithelium, ciliated columnar cells and subepithelial glands stained positively, while in olfactory tissue the enzymes were detected in the sustentacular cells and Bowman's glands. With the exception of SOD, enzyme activities were higher in RE than OE, while concentrations of ascorbate and alpha-tocopherol were higher in OE than RE. With the exception of catalase, nasal activities were either higher than or comparable to those of the lung. Thus, the rat nasal cavity appears to be well protected against oxidative damage.
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PMID:Antioxidant status of the rat nasal cavity. 1261 49

The cytotoxic effects of menadione and hydrogen peroxide were examined in two hepatic stellate cell lines derived from normal or cirrhotic rat liver. The cirrhotic fat-storing cells (CFSC) were found more resistant than the normal fat-storing cells (NFSC) to menadione cytotoxicity. No significant differences were observed in hydrogen peroxide toxicity in these two cell lines. Although protein levels and enzymatic activities of catalase, Cu,Zn-SOD, Mn-SOD, and NADPH cytochrome c reductase were similar in these cell lines, 20-fold increases of NAD(P)H:quinone oxidoreductase 1 (NQO1) enzymatic activity and protein levels were detected in CFSC compared to those of NFSC. Gel mobility shift assays and functional analysis using transient transfection experiments indicated the involvement of the electrophile responsive element (EPRE) in the up-regulation of the NQO1 expression. Antibody supershift analysis revealed that, although Nrf2 is a member of the EPRE-binding complex in both NFSC and CFSC, Nrf1 was identified as a part of the protein/DNA complex only in CFSC. Expression of p53 tumor suppressor gene was found in higher levels in CFSC than in NFSC. We conclude that activation of the EPRE-signaling pathway, which up-regulates several phase II genes and affects p53 stabilization, may offer resistance to hepatic stellate cells against oxidative damage during hepatic injury. This resistance may be a part of the activation process of the hepatic stellate cells and could contribute to their increased proliferation and production of extracellular matrix.
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PMID:Involvement of the electrophile responsive element and p53 in the activation of hepatic stellate cells as a response to electrophile menadione. 1272 13

The cytotoxicity and apoptosis-inducing activity of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and 2-tert-butyl-4-methylphenol (BMP) and the mixture of BHA and BHT (BHA/BHT) (1:1, molar ratio) were investigated, using human promeylocytic leukemia cell lines (HL-60) and human squamous cell carcinoma cell lines (HSC-2). The 50% cytotoxic concentration (CC50) declined in the order of BHA, BHT (0.2-0.3 mM) > BHA/BHT (0.04-0.07 mM) > BMP (0.02-0.05 mM). The addition of antioxidants (N-acetyl-Lcysteine, sodium ascorbate, catalase) reduced the cytotoxicity of BHA/BHT or BMP against HSC-2 cells, but not that of BHA or BHT, whereas the addition of NADH, a quinone reductase to BMP, enhanced the cytotoxicity. These findings suggested that the cytotoxicity of BHA/BHT and BMP might be caused by reactive intermediates. BHA-induced cytotoxicity was enhanced by horseradish peroxidases, suggesting that BHA was oxidizable and produced cytotoxic BHA radicals. Internucleosomal DNA fragmentation of HL-60 cells was preferably induced by BHA/BHT and BMP, followed by BHA. The MnSOD mRNA expression in HL-60 cells assayed by reverse transcriptase-polymerase chain reaction was highly inhibited by BHA/BHT or BMP, accompanied by the change in the electrophoretic mobility of MnSOD on polyacryamide gel. These compounds activated caspase-3, 8 and 9 in HL-60 cells. Activations of caspases, particularly caspase-3, declined in the order of BHA/BHT > BHA > BMP > BHT. The most cytotoxic BMP activated caspase-3 activity to the least extent, possibly in part due to the occurrence of necrosis. The great cytotoxicity and apoptosis induction by BHA/BHT may be due to reactive intermediates derived from the interaction between BHA phenoxyl radical and BHT or BHT phenoxyl radical.
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PMID:Cytotoxicity and apoptosis induction by butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). 1498 15

Lung cancer rates among men and particularly among women, almost all of whom are non-smokers, in Xuan Wei County, China are among the highest in China and have been causally associated with exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). As such, this population provides a unique opportunity to study the pathogenesis of PAH-induced lung cancer that is not substantially influenced by the large number of other carcinogenic constituents of tobacco smoke. Aldo-keto reductases (AKRs) activate PAH dihydrodiols to yield their corresponding reactive and redox-active o-quinones, which can then generate reactive oxygen species that cause oxidative DNA damage. We therefore examined the association between single nucleotide polymorphisms (SNPs) in four genes (AKR1C3-Gln5His, NQO1-Pro187Ser, MnSOD-Val16Ala and OGG1-Ser326Cys) that play a role in the generation, prevention or repair of oxidative damage and lung cancer risk in a population-based, case-control study of 119 cases and 113 controls in Xuan Wei, China. The AKR1C3-Gln/Gln genotype was associated with a 1.84-fold [95% confidence interval (CI) = 0.98-3.45] increased risk and the combined OGG1-Cys/Cys and Ser/Cys genotypes were associated with a 1.93-fold (95% CI = 1.12-3.34) increased risk of lung cancer. Subgroup analysis revealed that the effects were particularly elevated among women who had relatively high cumulative exposure to smoky coal. SNPs in MnSOD and NQO1 were not associated with lung cancer risk. These results suggest that SNPs in the oxidative stress related-genes AKR1C3 and OGG1 may play a role in the pathogenesis of lung cancer in this population, particularly among heavily exposed women. However, due to the small sample size, additional studies are needed to evaluate these associations within Xuan Wei and other populations with substantial exposure to PAHs.
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PMID:Oxidative damage-related genes AKR1C3 and OGG1 modulate risks for lung cancer due to exposure to PAH-rich coal combustion emissions. 1528 79

Loss of antioxidant/oxidant homeostasis perpetuates inflammation in the lungs and may contribute to the development of COPD and lung cancer. Cigarette smoke (CS) is a primary source of airway oxidative stress and recruits inflammatory cells into smokers' lungs. However, whether these consequences are attributable to a specific or the collective fraction of CS is unknown. We investigated whether the particulate or the gas phase of CS would alter expression of the antioxidant enzymes MnSOD and NQO1 or CINC-1. Sprague Dawley rats were exposed to sham (n = 10) or the particulate phase (PP; n = 10) or gas phase (n = 10) of a Kentucky reference cigarette (1R4F) for 2 h/d for 28 d, after which animals were sacrificed and the lower left lobe of the lung was removed. Immunoblots for SOD and NQO1 revealed that lungs exposed to PP had higher MnSOD/actin and NQO1/actin ratios than either sham-or gas phase-treated animals. In contrast, CuZnSOD remained unchanged. In PP-exposed animals, CINC-1 was 3-fold higher than in sham-exposed animals. The increases in MnSOD and NQO1 protein were associated with increases in total SOD, NQO1, and MPO activities. These data provide evidence that the PP of CS alters oxidant/antioxidant homeostasis in the lungs and participates in the pathogenesis of CS-induced lung diseases such as COPD and cancer.
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PMID:Particulate phase cigarette smoke increases MnSOD, NQO1, and CINC-1 in rat lungs. 1547 4

Lawsone is an active naphthoquinone derivative isolated from henna (Lawsonia inermis L.), a widely used hair dye. Previous study on the toxicity of lawsone remains unclear since the involvement of oxidative stress and the kind of ROS (reactive oxygen species) involved have not been fully resolved yet. This present study reports the cytotoxic effects of lawsone and henna. We carried out CAT assay (a zone of inhibition test of bacterial growth and colony-forming efficiency test of transformant Escherichia coli strains that express mammalian catalase gene derived from normal catalase mice (Cs(a)) and catalase-deficient mutant mice (Cs(b))), Ames mutagenicity assay and H(2)O(2) generation assay. Lawsone generated H(2)O(2) slightly in phosphate buffer system and was not mutagenic in Ames assay using TA 98, TA 100 and TA 102, both in the absence and presence of metabolic activation. Lawsone exposure inhibited the growth of both Cs(a) and Cs(b) strains in a dose-dependent manner. Mean zone diameter for Cs(a) was 9.75+/-0.96 mm and 12.75+/-1.5 mm for Cs(b). Natural henna leaves did not show toxic effects, whereas two out of four samples of marketed henna products were shown toxicity effects. Catalase abolished zone of inhibition (ZOI) of marketed henna products, eliminated ZOI of lawsone in a dose-dependent manner and low concentration of exogenous MnSOD and Cu/ZnSOD eliminated the toxicity. Histidine and DTPA, the metal chelator; BHA and low concentration of capsaicin, the inducer of NADH-quinone reductase, effectively protected Cs(a) and Cs(b) against lawsone in this study. We suggest that lawsone cytotoxicity is probably mediated, at least in part, by the release of O(2)(-), H(2)O(2) and OH(-).
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PMID:Cytotoxicity of lawsone and cytoprotective activity of antioxidants in catalase mutant Escherichia coli. 1744 76

Sulforaphane, a cruciferous isothiocyanate compound, upregulates cytoprotective genes in liver, but its effects on antioxidants and phase 2 defenses in vascular cells are unknown. Here we report that incubation of rat aortic smooth muscle A10 cells with sulforaphane (0.25-5 microM) resulted in concentration-dependent induction of a spectrum of important cellular antioxidants and phase 2 enzymes, including superoxide dismutase (SOD), catalase, the reduced form of glutathione (GSH), glutathione peroxidase, glutathione reductase (GR), glutathione S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1). Sulforaphane also increased levels/activities of SOD, catalase, GSH and GST in isolated mitochondria of aortic smooth muscle cells. Time-dependent sulforaphane-induced increases in the mRNA levels for MnSOD, catalase, the catalytic subunit of gamma-glutamylcysteine ligase, GR, GST-A1, GST-P1, and NQO1 were observed. Pretreatment with sulforaphane (0.5, 1, and 5 microM) protected aortic smooth muscle cells from oxidative and electrophilic cytotoxicity induced by xanthine oxidase (XO)/xanthine, H2O2, SIN-1-derived peroxynitrite, 4-hydroxy-2-nonenal, and acrolein. Furthermore, sulforaphane pretreatment prevented intracellular accumulation of reactive oxygen species (ROS) after exposure of the cells to XO/xanthine, H2O2, or SIN-1. Taken together, this study demonstrates that in the aortic smooth muscle cells sulforaphane at physiologically relevant concentrations potently induces a series of total cellular as well as mitochondrial antioxidants and phase 2 enzymes, which is accompanied by dramatically increased resistance of these vascular cells to oxidative and electrophilic stress.
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PMID:Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress. 1860 71


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