Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species are known to play a key role in the development of acute lung injury, and such injury can be alleviated by pretreating the lung with a suitable antioxidant preparation. In this study, we evaluated and compared the antioxidant efficacy of two liposomal preparations: liposomes containing only alpha-tocopherol versus bifunctional liposomes containing both alpha-tocopherol and glutathione (GSH). alpha-Tocopherol liposomes (2 mg alpha-tocopherol/animal) or liposomes containing both alpha-tocopherol and GSH (2 mg alpha-tocopherol and 10 mumol GSH/animal) were intratracheally instilled into the lungs of rats 30 min prior to a challenge with paraquat dichloride (30 mg/kg, i.p.); animals were killed 24 hr post-paraquat challenge. Lungs of paraquat-challenged animals were damaged extensively as evidenced by increases in lung weight, indicative of edema, and decreases in lung activities of angiotensin converting enzyme (ACE) and alkaline phosphatase (AKP), indicative of endothelial and alveolar type II epithelial cell injuries, respectively. While the pretreatment of rats with alpha-tocopherol liposomes or liposomes containing both alpha-tocopherol and GSH significantly attenuated paraquat-induced changes in lung ACE activity to more or less the same extent, the bifunctional liposomal preparation conferred additional protection to alveolar type II epithelial cells, as evidenced by a significantly higher pulmonary AKP activity. Our results also showed that both liposomal preparations failed to ameliorate paraquat-induced lung edema despite a significant protection of pulmonary endothelial cells, suggesting that paraquat-induced edema formation may be independent of endothelial cell damage. In conclusion, liposome-associated antioxidants can protect the lung against an oxidant challenge, and the extent of protection appears to be related to the characteristics of each antioxidant formulation.
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PMID:Alleviation of paraquat-induced lung injury by pretreatment with bifunctional liposomes containing alpha-tocopherol and glutathione. 893 65

A mouse embryo culture model was used to determine whether embryonic prostaglandin H synthase (PHS)-catalyzed bioactivation and resultant oxidative damage to embryonic protein and DNA may constitute a molecular mechanism mediating phenytoin and benzo[a]pyrene teratogenesis. Embryos were explanted from CD-1 mouse dams on gestational day 9.5 (vaginal plug = day 1) and incubated for either 4 h (biochemistry) or 24 h (embryotoxicity) at 37 degrees C in medium containing either phenytoin (20 micrograms/ml, 80 microM), benzo[a]pyrene (10 microM), or their respective vehicles. As previously observed with phenytoin (Mol. Pharmacol.48: 112-120, 1995), embryos incubated with benzo[a]pyrene showed decreases in anterior neuropore closure, turning, yolk sac diameter, and somite development (p < .05). Addition of the antioxidative enzyme superoxide dismutase (SOD) substantially enhanced embryonic SOD activity (p < .05) and completely inhibited benzo[a]pyrene embryotoxicity (p < .05). Substantial PHS was detected in day 9.5 embryos using SDS/PAGE, anti-PHS antibody, and alkaline phosphatase-conjugated donkey anti-goat IgG. Embryonic protein oxidation was detected by the reaction of 0.5 mM 2,4-dinitrophenylhydrazine with protein carbonyl groups. This method was first validated by using a known hydroxyl radical-generating system consisting of vanadyl sulfate and H2O2, with bovine serum albumin or embryonic protein as the target. Embryonic proteins were characterized by SDS/PAGE, anti-dinitrophenyl antisera, and peroxidase-labeled goat anti-donkey IgG. Using enhanced chemiluminescence, the number and content of oxidized protein bands detected between 25 and 200 kDa were substantially increased by both phenytoin and benzo[a]pyrene. Addition of the reducing agent dithiothreitol, or SOD or catalase, decreased protein oxidation in phenytoin-exposed embryos. Both phenytoin (Mol. Pharmacol.48: 112-120, 1995) and benzo[a]pyrene enhanced embryonic DNA oxidation, determined by the formation of 8-hydroxy-2'-deoxyguanosine, as measured by high-performance liquid chromatography (HPLC) (p < .05). Phenytoin also enhanced the oxidation of embryonic glutathione (GSH) to its GSSG disulfide, as measured by HPLC (p < .05). These results provide direct evidence that, in the absence of maternal or placental processes, embryonic PHS-catalyzed bioactivation and reactive oxygen species-mediated oxidation of embryonic protein, thiols, and DNA may constitute a molecular mechanism mediating phenytoin and benzo[a]pyrene teratogenesis.
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PMID:Evidence for embryonic prostaglandin H synthase-catalyzed bioactivation and reactive oxygen species-mediated oxidation of cellular macromolecules in phenytoin and benzo[a]pyrene teratogenesis. 901 24

Oxygen free radicals have been implicated as mediators of tissue injury in a variety of diseases. We investigated the role of oxidative injury and oxygen free radical scavengers in liver cell injury associated with obstructive jaundice in Wistar rats. Bile duct ligation for 4 or 7 days led to a decrease in both vitamin E and A in the plasma and liver of male Wistar rats, indicating the malabsorption of lipid-soluble vitamins. Serum bilirubin, alkaline phosphatase and gamma-glutamyl transpeptidase activities were increased in the bile-duct-ligated rats. Furthermore, marked increases in lipid peroxide and oxidized glutathione levels indicated cholestatic liver injury. The antioxidant defense system was impaired, as shown by decreases in reduced glutathione and in the activities of glutathione peroxidase (GSH-Px) and superoxide dismutase. Moreover, these high lipid peroxide levels and low levels of antioxidants correlated with the severity of jaundice. After releasing the bile duct ligation, levels of bilirubin, lipid peroxide and oxidized glutathione declined, while the levels of vitamin E and A, reduced glutathione, and the activities of GSH-Px increased, indicating an improvement in liver function. These findings suggest that lipid peroxidation is associated with the pathogenesis of liver damage in animals with bile duct ligation. Meanwhile, free oxygen radical scavengers are reduced in the bile-duct-ligated rats, thereby increasing the susceptibility of the liver to injury by oxygen-derived free radicals.
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PMID:Biochemical events associated with ligation of the common bile duct in Wistar rats. 903 77

In an animal model of hormone-mediated carcinogenesis, male golden Syrian hamsters develop renal carcinoma following prolonged exposure to 17beta-estradiol. The basis for the species and tissue specificity is unclear. Detailed information on the disposition of 17beta-estradiol in this model is lacking. Because catechol estrogens have been implicated in this model of carcinogenesis, we investigated the metabolism and nephrotoxicity of 17beta-estradiol in golden Syrian hamsters, with emphasis on the formation of catechol estrogen thioethers. 17beta-Estradiol (50 micromol/kg, i.p.) is a mild nephrotoxicant, causing significant elevations in the urinary excretion of gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase, glutathione S-transferase (GST) and glucose. Increases in renal protein carbonyls and lipid hydroperoxides, which are markers of oxidative damage, also occur after administration of 17beta-estradiol (50 micromol/kg, i.p.). 17beta-Estradiol-mediated nephrotoxicity is reduced by treating animals with acivicin, an inhibitor of gamma-GT, implying that toxicity is mediated by metabolites requiring metabolism by this enzyme. Following administration of 17beta-[14C]estradiol (100 micromol/kg) to hamsters, 9.7% of the dose is recovered in bile after 5 h, the majority (7.9%) representing aqueous metabolites. Seven catechol estrogen GSH conjugates were identified, 2-hydroxy-1,4-bis-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-17beta-estradiol, 2-hydroxy-4-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-estrone, 2-hydroxy-1-(glutathion-S-yl)-estrone, 4-hydroxy-1-(glutathion-S-yl)-17beta-estradiol, and 2-hydroxy-1-(glutathion-S-yl)-17beta-estradiol. At 5.4 micromol/kg of 17beta-estradiol, a dose-reflective of daily exposure levels in the hamster model of nephrocarcinogenicity, 12% of the dose is recovered within 5 h as a combination of GSH conjugates of 2- and 4-hydroxy-17beta-estradiol and 2- and 4-hydroxyestrone. In summary, oxidation of catechol estrogens, followed by GSH conjugation, occurs in vivo and 17beta-estradiol is a mild nephrotoxicant in a manner dependent on the activity of gamma-GT.
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PMID:Formation of catechol estrogen glutathione conjugates and gamma-glutamyl transpeptidase-dependent nephrotoxicity of 17beta-estradiol in the golden Syrian hamster. 906 57

Although the antioxidant properties of N-acetylcysteine (NAC) in vitro are widely accepted, the efficacy of NAC in the prevention of O2 toxicity in vivo is poorly documented. The aim of our study was to investigate the presumed protective effect of NAC on hyperoxic lung injury, focusing on gamma-glutamyltransferase (gamma-GT) activity and glutathione (GSH) levels in lung tissue, epithelial lining fluid (ELF), and isolated rat type II cells immediately after their isolation and 48 h later when kept in culture in normoxia. Thirty-four male Wistar rats were divided in three groups (n = 10-14) and were exposed to air or to 60 or 85% O2 for 7 days. One-half of the rats in each group received 200 mg/kg NAC intraperitoneally one time per day from 3 days before exposure until the end of the experiment, and the other one-half received the vehicle. In the 85% O2-exposed animals, NAC led to more respiratory distress and weight loss. NAC did not prevent the rise in bronchoalveolar lavage lactate dehydrogenase and alkaline phosphatase, but it did prevent the rise in calculated ELF volume. NAC decreased GSH levels (1.4-fold) and gamma-GT activity (1.8-fold) in the air-exposed type II cells. In the 60% O2-exposed group, no effects of NAC were seen (except for a decrease in gamma-GT mRNA expression), but, in the 85% O2-exposed group, NAC gave rise to higher GSH (2.6-fold) and higher gamma-GT activity (2.9-fold) in the ELF and lower GSH (6.9-fold) and higher gamma-GT activity (3.6-fold) in the type II cells. Even in culture, GSH levels remained 1.5-fold lower than in the cells from the air-exposed animals and 2-fold lower than in the cells from the 85% O2-exposed animals. There was increased DNA damage (as assessed by thymidine incorporation) and apoptosis after hyperoxia, especially after 60% O2, and this effect was amplified after NAC treatment. Although protective at the endothelial side, NAC treatment led to adverse effects at the epithelial side, despite, or probably because of, restoration of the ELF GSH levels in the presence of high O2 levels. Because NAC is rapidly metabolized to cysteine, it is plausible that the effects of NAC are manifested through the toxic effects of cysteine.
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PMID:N-acetylcysteine does not protect against type II cell injury after prolonged exposure to hyperoxia in rats. 931 88

The present study was carried out to find the effects of Pb acetate (10-50 mg/kg body wt) after oral administration on: 1. The distribution of elements, such as Fe, Cu, Zn, and Mn; 2. The activity of 6-amino levulenic acid dehydratase (delta-ALAD) and alkaline phosphatase (PAP); and 3. On the level of reduced glutathione (GSH) in murine placenta. Pb toxicity expressed on a dry-wt basis was reflected in terms of deficiency of delta-ALAD and PAP and enhanced content of GSH. Analysis of trace elements following Pb exposure showed low levels of Mn and Cu. Although Fe composition of placenta remained within normal range with increasing load of endogeneous Pb, Zn decline was not consistent after oral feeding of Pb acetate. Deficiency of PAP after Pb exposure did not correlate with the endogeneous levels of Pb or Zn therein, but correlated with endogeneous levels of Mn. Placental deficiencies of Cu and Mn have been related to the disturbed placental functions by Pb accumulation.
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PMID:Trace metals and metalloenzymes in placenta after oral administration of lead acetate. 940 84

Hydroquinone, an intermediate used in the chemical industry and a metabolite of benzene, is a nephrocarcinogen in the 2-year National Toxicology Program bioassay in male Fischer 344 rats. Current evidence suggests that certain chemicals may induce carcinogenesis by a mechanism involving cytotoxicity, followed by sustained regenerative hyperplasia and ultimately tumor formation. Glutathione (GSH) conjugates of a variety of hydroquinones are potent nephrotoxicants, and we now report on the effect of hydroquinone and 2,3,5-(tris-glutathion-S-yl)hydroquinone, on site-selective cytotoxicity and cell proliferation in rat kidney. Male Fischer 344 rats (160-200 g) were treated with hydroquinone (1.8 mmol/kg or 4.5 mmol/kg, p.o.) or 2,3,5-(tris-glutathion-S-yl)hydroquinone (7.5 micromol/kg; 1.2-1.5 micromol/rat, i.v.), and blood urea nitrogen (BUN), urinary gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase (ALP), glutathione-S-transferase (GST) and glucose were measured as indices of nephrotoxicity. Hydroquinone (1.8 mmol/kg, p.o.) is nephrotoxic in some rats, but not others, but cell proliferation (BrDU incorporation) in proximal tubular cells of the S3M region correlates with the degree of toxicity in individual rats. At 4.5 mmol/kg, hydroquinone causes significant increases in the urinary excretion of gamma-GT, ALP and GST. Pretreatment of rats with acivicin prevents hydroquinone-mediated nephrotoxicity, indicating that toxicity is dependent on the formation of metabolites that require processing by gamma-GT. Consistent with this view, 2,3,5-(tris-glutathion-S-yl)hydroquinone, a metabolite of hydroquinone, causes increases in BUN, urinary gamma-GT and ALP, all of which are maximal 12 h after administration of 2,3,5-(tris-glutathion-S-yl)hydroquinone. In contrast, the maximal excretion of GST and glucose occurs after 24 h. By 72 h, BUN and glucose concentrations return to control levels, while gamma-GT, ALP and GST remain slightly elevated. Examination of kidney slices by light microscopy revealed the presence of tubular necrosis in the S3M segment of the proximal tubule, extending into the medullary rays. Cell proliferation rates in this region were 2.4, 6.9, 15.3 and 14.3% after 12, 24, 48 and 72 h, respectively, compared to 0.8-2.4% in vehicle controls. Together with the metabolic data, the results indicate a role for hydroquinone-thioether metabolites in hydroquinone toxicity and carcinogenicity.
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PMID:Cytotoxicity and cell-proliferation induced by the nephrocarcinogen hydroquinone and its nephrotoxic metabolite 2,3,5-(tris-glutathion-S-yl)hydroquinone. 945 Apr 87

Atractyloside (ATR) causes acute fatal renal and hepatic necrosis in animals and humans. Precision-cut renal cortical and hepatic slices (200 +/- 15 microns) from adult male Wistar rat and domestic pigs, incubated with ATR (0.2-2.0 mM) for 3 h at 37 degrees C, inhibited pyruvate-stimulated gluconeogenesis in a concentration- and time-dependent manner. p-Aminohippurate accumulation was significantly inhibited in both rat and pig renal cortical slices from 0.2 mM ATR (p < 0.05). There was a small decrease in mitochondrial reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium to formazan in both rat and pig kidney slices, which was significant at > or = 2 mM, but no changes in liver slices from either species. However, cellular ATP was significantly depleted at > or = 0.2 mM ATR in kidney and in liver slices from both species. ATR also caused a marked leakage of lactate dehydrogenase and alkaline phosphatase from both pig and rat kidney slices at all concentrations, but only lactate dehydrogenase was significantly elevated in liver slices from both species. ATR > or = 0.5 mM caused a significant increase in lipid peroxidation, but only in liver slices of both species, and > or = 0.2 mM ATR caused a marked depletion of reduced glutathione and significant increase in oxidized glutathione in both kidney and liver slices of both species. However, GSH to GSSG ratio was only significantly altered in the liver slices, indicating that oxidative stress may be the cause of toxicity in this organ. Both rat and pig tissue slices from the same organ responded similarly to ATR, although their basal biochemistry was different. ATR toxicity to both kidney and liver showed similar patterns but it appears that the mechanisms of toxicity are different. While cytotoxicity of ATR in kidney is only accompanied with GSH depletion, that of the liver is linked to both lipid peroxidation and GSH depletion. Striated muscle slices from both species were not affected by the highest ATR concentration. This further strengthens the argument that the molecular basis of ATR, target selective toxicity, is not a measure of the interaction between ATR and mitochondria and that other factors such as selective uptake are involved. Precision-cut tissue slices show organ-specific toxicity in kidney and liver from both rat and pig and suggest different mechanisms of injury for each organ.
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PMID:Toxicity of atractyloside in precision-cut rat and porcine renal and hepatic tissue slices. 946 61

The protective mechanisms operating in the gastrointestinal (GI) tract to counteract the potential oxidizing effects of excess free iron, was tested in rats fed with excess iron. The activities of some antioxidant enzymes, the levels of GSH and the extent of lipid peroxidation at the site of iron absorption were measured. Based on the amount of thiobarbituric acid reactive substances (TBARS) produced, it could be deduced that the duodenal segment of GI tract is resistant to iron mediated lipid peroxidation. The duodenal function as judged from the activities of marker enzymes, namely, alkaline phosphatase and Lys-Ala-dipeptidyl aminopeptidase was normal. There was depletion of GSH possibly due to the increased activities of Cu, Zn SOD and catalase. However, the activity of Gpx was decreased in the Fe fed group. It was also observed that the ratios of SOD/Gpx and Cat/Gpx had significantly increased in the treated group whereas SOD/Cat remained constant suggesting that antioxidative enzymes play a key role in rendering the intestinal mucosal cells resistant to iron induced oxidative damage in rats.
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PMID:Protective effects of antioxidant enzymes and GSH in vivo on iron mediated lipid peroxidation in gastrointestinal tract of rat. 949 52

Cadmium induced lipid peroxidation (LPO) and the activity of antioxidant enzymes after the administration of a single dose of CdCl2 (0.4 mg kg-1 body wt, i.p.) was studied in rat erythrocytes. Cd intoxication increased erythrocyte LPO along with a decrease in superoxide dismutase (SOD) up to three days of Cd treatment. The decrease in erythrocyte catalase (CAT) activity was marked within 9 h of Cd intoxication. After three days of Cd treatment, LPO decreased towards normal, along with an increase in erythrocyte SOC and CAT activity. Blood glutathione (GSH) decreased significantly within 24 h of Cd treatment, followed by an increase towards normal. Erythrocyte glutathione S-transferase (GST) activity increased up to 10 days of Cd intoxication, probably in an attempt to reduce Cd toxicity. Serum glutamate pyruvate transaminase (SGPT), serum alkaline phosphatase (SALP) and serum bilirubin increased up to 10 days of Cd intoxication. Blood urea increased significantly up to three days, followed by a decrease towards normal. The results show that Cd induced LPO was associated with a decrease in antioxidant enzymes and GSH in erythrocytes; as these antioxidants increase in erythrocytes with recovery from Cd intoxication, the Cd induced LPO reversed towards normal. The increase in the SGPT, SALP and serum bilirubin correlated with LPO. The results suggest that Cd intoxication induces oxidative stress and alters the antioxidant system, resulting in oxidative damage to rat erythrocytes.
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PMID:Lipid peroxidative damage on cadmium exposure and alterations in antioxidant system in rat erythrocytes: a study with relation to time. 954 68


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