Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20020 (adenosine triphosphatase)
 3,299 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acquired resistance to cisplatin (cis-diamminedichloroplatinum (II)) has been generated in vitro in the 41M human ovarian carcinoma cell line, established from a previously untreated patient. Three cisplatin-resistant variants were selected at approximately 2, 4 and 6-fold resistance (in terms of 50% inhibitory concentrations), in order to study the underlying mechanisms of acquired cisplatin resistance. Compared to the parent line, platinum accumulation following exposure to equimolar concentrations of cisplatin was on average (across the entire concentration range) 2.9, 3.6 and 4.8-fold lower in the 41McisR2, 41McisR4 and 41McisR6 cell lines, respectively. Thus the difference in uptake corresponded closely with their resistance factor in the three resistant variants. Moreover, a significant reduction in platinum accumulation was observed as early as 5 min after exposure to cisplatin in the 41M vs 41McisR6 cell lines. Platinum accumulation was similar in all cell lines following exposure to equitoxic concentrations (2 h IC50) of cisplatin. Enhanced efflux of drug was not observed between the 41M and 41McisR6 cells. In addition, there was no difference in intracellular glutathione (GSH) levels. Our previous studies have shown no indication of metallothionein involvement and the decrease in cisplatin uptake in the 41McisR6 cells was reflected by a similar reduction in DNA interstrand cross-links (ISC) formation. These results suggest that the mechanism of acquired resistance to cisplatin in the 41McisR6 cell line may be predominantly due to reduced drug uptake. The 41McisR6 cells were not found to be cross-resistant to ouabain, a postulated specific inhibitor of sodium-potassium adenosine triphosphatase (Na+, K(+)-ATPase), suggesting that decreased cisplatin accumulation in these cells is probably not regulated by alterations in their Na+, K(+)-ATPase levels, and Na+ potential across the plasma membrane. Cellular accumulation of a novel class of platinum (IV) ammine/cyclohexylamine dicarboxylates, which exhibit enhanced cytotoxicity over cisplatin and completely circumvent resistance to cisplatin in the 41McisR line, was also examined. The data suggests that increased accumulation of these compounds, as a result of their enhanced lipophilicity, could account for the dramatic increase in their potency over cisplatin.
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PMID:Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes. 145 52

Glutathione (GSH) and GSH-related enzymes, glutathione reductase (GR), gamma-glutamyl cysteine synthetase (gamma-GCS), gamma-glutamyl transpeptidase (gamma-GTP), glutathione S-transferase (GST) and adenosine triphosphatase (ATPase) enzymes were analysed to study the effect of busulfan on the defence mechanisms of the lens. All these enzymes were found to increase significantly except GSH which showed only 7.9% increase as compared to controls in precataractous stage. These results affirm that busulfan is capable of evoking a response from the enzymes involved in the various pathways of GSH enabling the lens to prolong its clarity. The cataractous lenses showed significant decrease in all these parameters. Here, the impairment of the defense mechanism (GST, GR) and the total ATPase may be attributed to the cumulative action of the drug which can react with -SH groups of these enzymes, ultimately causing opacification.
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PMID:Glutathione and glutathione-related enzymes in busulfan treated rat lens. 191 43

In order to determine the target portion of acetaminophen-induced hepatotoxicity, 750 mg per kg of body weight of acetaminophen was administered to male Wistar strain rats with or without the pretreatment of thiol compounds. In the liver, glutathione content decreased throughout the observation periods, and glutathione S-transferase initially, and later adenosine triphosphatase decreased, followed as elevations of aminotransferases and ornithione carbamoyltransferase in serum. The pretreatment of thiol compounds could not restore hepatic enzyme activities, but partially hepatic glutathione content and serum enzyme elevations. Although distinct time lag existed in biochemical alterations in the liver, hepatic glutathione content was significantly correlated solely with hepatic glutathione S-transferase. The mechanism of acetaminophen hepatotoxicity was discussed from the aspect of biochemical events in cytosol and membrane structure in hepatocytes. The mechanism of acetaminophen induced hepatotoxicity has been extensively investigated, and the hepatotoxicity seems to be related to the toxic metabolites generated by biotransformation process (Gillette et al., 1974, Mitchell et al., 1976). Since the toxic metabolites are conjugated with glutathione (GSH), it is generally accepted that when the hepatocellular GSH content has critically depleted, the metabolites seem to react with hepatocyte macromolecules and/or to produce lipid peroxidation, resulting in biochemical and structural changes leading to cell death (Black, 1980). A hepatotoxic dose of labelled acetaminophen was found throughout the liver and the highest concentration was found in centrilobular area, where considerable disruption and vacuolation of the plasma membrane and of the endoplasmic reticulum also occurred (Jollow et al., 1973, Chiu and Bhakthan, 1978). However remarkably little impairment of several enzyme systems in microsome, such as cytochrome P450 content, arylhydrocarbon hydroxylase and glucuronyl transferase has been reported (Thorgeirsson et al., 1976, Chiu and Bhakthan, 1978: Willson and Hart, 1977, Yamada et al., 1981). To elucidate the exact mechanism of acetaminophen hepatotoxicity, we observed time related biochemical alterations of hepatic GSH content, some marker enzymes in hepatocyte subfractions and serum enzymes. The present results indicated that acetaminophen reduced hepatic GSH content, followed as depletions of glutathione S-transferases (GSTs) and finally adenosine triphosphatase (ATPase), associated with elevations of serum enzymes.
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PMID:The target portion of acetaminophen induced hepatotoxicity in rats: modification by thiol compounds. 666 1

The role of oxidative stress in chronic cadmium (Cd) toxicity and its prevention by cotreatment with beta-carotene was investigated. Adult male rats were intragastrically administered 2 mg CdCl2/kg body weight three times a week intragastrically for 3 and 6 weeks. Brain and testicular thiobarbituric acid reactive substances (TBARS) was elevated after 3 and 6 weeks of Cd administration, indicating increased lipid peroxidation (LPO) and oxidative stress. Cellular damage was indicated by inhibition of adenosine triphosphatase (ATPase) activity and increased lactate dehydrogenase (LDH) activity in brain and testicular tissues. Chronic Cd administration resulted in a decline in glutathione (GSH) content and a decrease of superoxide dismutase (SOD) and glutathione S-transferase (GST) activity in both organs. Administration of beta-carotene (250 IU/kg i.g.) concurrent with Cd ameliorated Cd-induced LPO. The brain and testicular antioxidants, SOD, GST, and GSH, decreased by Cd alone, were restored by beta-carotene cotreatment. Concurrent treatment with beta-carotene also ameliorated the decrease in ATPase activity and the increase in LDH activity in brain and testis of Cd-treated rats, indicating a prophylactic action of beta-carotene on Cd toxicity. Therefore, the results indicate that the nutritional antioxidant beta-carotene ameliorated oxidative stress and the loss of cellular antioxidants and suggest that beta-carotene may control Cd-induced brain and testicular toxicity.
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PMID:Role of beta-carotene in ameliorating the cadmium-induced oxidative stress in rat brain and testis. 1096 95

We tested the hypothesis that ischemia alters sarcoplasmic reticulum (SR) Ca2+ transport by oxidizing regulatory thiols on ryanodine receptors (RyRs), and that membrane-permeable sulfhydryl-containing angiotensin-converting enzyme (ACE) inhibitors protect against ischemia-induced oxidation and explain in part, the therapeutic actions of captopril. Ca2+ uptake and adenosine triphosphatase (ATPase) activity was measured from SR vesicles isolated from control or ischemic dog and human ventricles and compared with or without sulfhydryl reductants. The rate and amount of Ca2+ uptake was lower for canine ischemic SR compared with control (6.5 +/- 0.2 --> 18.5 +/- 1.1 nmol Ca2+/mg/min and 123.1 +/- 4.7 --> 235.0 +/- 17.3 nmol Ca2+/mg; n = 8 each). Captopril, dithiothreitol (DTT), glutathione (GSH), and L-cysteine increased the rate and amount of Ca2+ uptake by canine and human ischemic SR vesicles by approximately 50%. Reducing agents had no effect on Ca2+- ATPase activity in either canine control or ischemic (approximately 40% less than control) SR. Captopril was as potent as DTT at reversing the oxidation of skeletal and cardiac RyRs induced by reactive disulfides (RDSs) or nitric oxide (NO). In neonatal rat myocytes, RDSs or NO triggered SR Ca2+ release and increased cytosolic Ca2+, an effect reversed by captopril and DTT but not GSH or cysteine. Pretreatment of myocytes with captopril (exposure and then wash) inhibited Ca2+ elevation elicited by RDSs or NO, indicating that captopril is an effective, membrane-permeable intracellular reducing agent. Thus, net SR Ca2+ accumulation is reduced by ischemia in part due to the oxidation of thiols that gate RyRs, an effect reversed by captopril.
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PMID:Cardiac ischemia oxidizes regulatory thiols on ryanodine receptors: captopril acts as a reducing agent to improve Ca2+ uptake by ischemic sarcoplasmic reticulum. 1106 27

Membrane injury facilitated the fixation of calcium oxalate crystals and subsequent growth into kidney stones. Oxalate-induced membrane injury was mediated by lipid peroxidation reaction through the generation of oxygen free radicals. In urolithic rat kidney or oxalate exposed cultured cells, both superoxide anion and hydroxyl radicals were generated in excess, causing cellular injury. In hyperoxaluric rat kidney, both superoxide and H2O2-generating enzymes such as glycolic acid oxidase (GAO) and xanthine oxidase (XO) were increased, and hydroxyl radical and transition metal ions, iron, and copper were accumulated. The lipid peroxidation products, thiobarbituric acid-reactive substances (TBARS), hydroperoxides, and diene conjugates were excessively released in tissues of urolithic rats and in plasma of rats as well as stone patients. The accumulation of these products was concomitant with the decrease in the antioxidant enzymes, superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glucose-6 phosphate dehydrogenase (G6PD) as well as radical scavengers, vitamin E, ascorbic acid, reduced glutathione (GSH), and protein thiol. All the above parameters were decreased in urolithic condition, irrespective of the agents used for the induction of urolithiasis. Oxalate binding activity and calcium oxalate crystal deposition were markedly pronounced, along with decreased adenosine triphosphatase (ATPase) activity. Lipid peroxidation positively correlated with cellular oxalate, oxalate binding, gamma-glutamyl carboxylase, and calcium level and negatively correlated with GSH, vitamin E. ascorbic acid, and total protein thiol. Antioxidant therapy to urolithic rats with vitamin E, glutathione monoester, methionine, lipoic acid, or fish oil normalised the cellular antioxidant system, enzymes and scavengers, and interrupted membrane lipid and protein peroxidation reaction, ATPase inactivation, and its associated calcium accumulation. Antioxidant therapy prevented calcium oxalate precipitation in the rat kidney and reduced oxalate excretion in stone patients. Similarly, calcium oxalate crystal deposition in vitro to urothelium was prevented by free radical scavengers such as phytic acid and mannitol by protecting the membrane from free radical-mediated damage. All these observations were suggestive of the active involvement of free radical-mediated lipid peroxidation-induced membrane damage in the pathogenesis of calcium oxalate crystal deposition and retention.
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PMID:Calcium oxalate stone disease: role of lipid peroxidation and antioxidants. 1194 24

The present study was conducted to evaluate the therapeutic effectiveness of chelating agents [glutathione, 2,3 dimercapto propane sulfonic acid (DMPS) and D-penicillamine (DPA)] in combination with antioxidant (sodium selenite) in beryllium induced toxicity in female rats. A bolus dose of 50mg/kg-beryllium nitrate was administered singly followed by chelation therapy with GSH, DMPS + Se and DPA + Se at various durations of 1,3 and 7 days respectively. Results revealed a significant fall in the glycogen content, whereas, a marginal fall in the protein was also observed. The enzymatic activity of alkaline phosphatase and adenosine triphosphatase was depleted; on the contrary, there was a significant rise in the acid phosphatase and glucose-6-phosphatase pattern. A rise in the hepatic lipid peroxidation activity is a direct indication of oxidative damage resulting in free radical generation. The distribution of the metal by atomic absorption spectrophotometry revealed an increased concentration of beryllium in liver and kidney, followed by lung and uterus. The relative ability of three chelating agents to act as antagonists, for acute beryllium poisoning, have been examined in liver, kidney, lungs and uterus. The appreciable change in the beryllium concentration in various organs is duration dependent during the entire period being highly significant at 7 days regimen. Biochemical and distribution studies reveal that DPA + Se was the most effective therapeutic agent followed by DMPS + Se and GSH.
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PMID:Role of chelating agents and antioxidants in beryllium induced toxicity. 1262 5

Wilson disease (WD) is an autosomal recessive disorder due to the defect in ATP7B gene characterized by excessive accumulation of copper in the liver with progressive hepatic damage and subsequent redistribution to various extrahepatic tissues including the brain, kidneys, and cornea. Strikingly, the total serum copper concentration is always low in WD, even though the non-ceruloplasmin copper level is still expected to be high. To assess the role of free radical reactions catalyzed by non-ceruloplasmin copper, we investigated erythrocyte metabolism and oxidative stress as a mechanism for hemolysis in eight WD patients during episodes of acute hemolysis and compared them with eight follow-up cases of WD on d-penicillamine therapy and eight healthy, age-matched children. Elevated levels of non-ceruloplasmin copper were found in all the WD patients during an episode of hemolytic anemia. There was marked inhibition in erythrocyte enzymes, namely, hexokinase, total adenosine triphosphatase (ATPase), and glucose-6-phosphate dehydrogenase (G-6-PD) from WD patients compared with patients on penicillamine and healthy children, indicating altered erythrocyte metabolism during a hemolytic crisis. Antioxidant status was also found to be compromised as is evident from decreased glutathione (GSH) levels, decreased antioxidant enzymes (namely, superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase), increased lipid peroxidation, and deranged plasma antioxidants. Uric acid showed maximum decrease followed by ascorbic acid. These findings suggest that the free radical production by elevated non-ceruloplasmin copper through transition metal catalyzed reactions leads to oxidative injury resulting in altered erythrocyte metabolism and severely compromised antioxidant status of WD patients during hemolytic anemia.
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PMID:Erythrocyte metabolism and antioxidant status of patients with Wilson disease with hemolytic anemia. 1654 36

In the present study, we examined the supplementation of paeonol extracted from Moutan cortex of Paeonia suffruticosa Andrews (MC) or the root of Paeonia lactiflora Pall (PL) on reducing oxidative stress, cognitive impairment and neurotoxicity in d-galactose (D-gal)-induced aging mice. The ICR mice were subcutaneously injected with D-gal (50 mg/(kg day)) for 60 days and administered with paeonol (50, 100 mg/(kg day)) simultaneously. The results showed that paeonol significantly improved the learning and memory ability in Morris water maze test and step-down passive avoidance test in D-gal-treated mice. Further investigation showed that the effect of paeonol on improvement of cognitive deficit was related to its ability to inhibit the biochemical changes in brains of D-gal-treated mice. Paeonol increased acetylcholine (Ach) and glutathione (GSH) levels, restored superoxide dismutase (SOD) and Na(+), K(+)-adenosine triphosphatase (Na(+), K(+)-ATPase) activities, but decreased cholinesterase AChe activity and malondialdehyde (MDA) level in D-gal-treated mice. Furthermore, paeonol ameliorated neuronal damage in both hippocampus and temporal cortex in D-gal-treated mice. These results suggest that paeonol possesses anti-aging efficacy and may have potential in treatment of neurodegenerative diseases.
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PMID:Paeonol attenuates neurotoxicity and ameliorates cognitive impairment induced by d-galactose in ICR mice. 1900 42

Present study investigated the protective role of melatonin (MLT, 5mg/kg body wt., ip) against the long term effects of mercuric chloride (MC; 2 and 4 mg/kg body wt., po) in the thyroid gland of the rats through certain antioxidative indices like superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione (GSH), catalase (CAT) and lipid peroxidation (LPO), other biochemical parameters such as succinate dehydrogenase (SDH), adenosine triphosphatase (ATPase), acid phosphatase (ACPase) and alkaline phosphatase (ALPase) were also measured. Antioxidative enzymes and other parameters showed a significant reduction while LPO and mercury levels increased significantly in a dose dependent manner in MC treated animals as compared to control groups. Co-treatment with MLT revealed no significant effect on antioxidative and metabolic indices in the thyroid gland of rats. The results of present study thus strongly suggest that mercury affected antioxidant defense system and other metabolic enzymes of thyroid. Co-administration of melatonin exerted a protective effect against mercury induced endocrine toxicity.
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PMID:Protective role of melatonin against the mercury induced oxidative stress in the rat thyroid. 1957 59


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