Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To improve liposome-directed therapy of liver disease and gene delivery, it would be beneficial to selectively target hepatocytes. For this purpose, conventional liposomes (CL) were labeled with asialofetuin (AF), an asialoglycoprotein. The biodistribution of AF-labeled liposomes (AF-L) in mice and their incorporation into rat hepatocytes, and their potential use in acute liver injury, were investigated. AF-L displayed a quicker plasma clearance than CL, and 25.4%, 2.7%, and 1.2% of the injected dose remained in the plasma versus 47.0%, 26.1%, and 9.5% of CL, respectively at 2, 4, and 20 hours after the injection. Total liver uptake of AF-L (73%+/-3.9%) was markedly higher (P < .005) than CL (16.5%+/-1.8%) 4 hours after the injection. Liposomal radioactivity (cpm/mg) was greatly enhanced in the liver (11-fold) during the first 4 hours after the administration of 14C-AF-L, and was much higher than in 14C-CL-injected mice (1.5-fold). In vitro incubation of isolated rat hepatocytes with 14C-AF-L or intravenous injection of 14C-AF-L in rats resulted in higher hepatocyte-bound radioactivity compared with 14C-CL (P < .01-.005). AF-L-associated 1,1'-dilinoleyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) fluorescent signals were not only located in Kupffer cells, but also in hepatocytes, in which bile canaliculus networks were imaged. Intravenous administration of vitamin E (VE)-associated CL (VE-CL, 1 mg/mouse) significantly lowered alanine transaminase (ALT) levels in CCl4-treated mice (196+/-79 vs. 2,107+/-235 U/mL; P < .01). The ALT level in CCl4 + VE-AF-L group was decreased to 38+/-16 units/mL, which was significantly lower than the CC14 + VE-CL group (P < .05). In conclusion, labeling liposomes with AF led to a shortened liposome plasma half-life and greatly enhanced uptake of AF-L liposome by the liver. The enhanced uptake resulted from an increased incorporation of hepatocytes with AF-L liposomes. VE-associated AF liposomes further improved the protective effect of VE liposomes on CC14-induced acute liver injury in mice. Preferential hepatocyte incorporation of AF-L liposomes suggests a useful hepatocyte-targeting approach for drug delivery and gene transfection.
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PMID:Increased liver uptake of liposomes and improved targeting efficacy by labeling with asialofetuin in rodents. 950 Jul 6

Cisplatin [cis-dichlorodiammineplatinum (II)] is a widely used chemotherapeutic drug that is toxic to the kidney. Concurrent administration of cysteine together with vitamin E, Crocus sativus and Nigella sativa reduced the toxicity of cisplatin in rats. When administered i.p. for 5 alternate days with 3 mg/kg cisplatin, cysteine (20 mg/kg) together with vitamin E (2 mg/rat) an extract of Crocus sativus stigmas (50 mg/kg) and Nigella sativa seed (50 mg/kg) significantly reduced blood urea nitrogen (BUN) and serum creatinine levels as well as cisplatin-induced serum total lipids increases. In contrast, the protective agents given together with cisplatin led to an even greater decrease in blood glucose than that seen with cisplatin alone. The serum activities of alkaline phosphatase, lactate dehydrogenase, malate dehydrogenase, aspartate aminotransferase and alanine aminotransferase of cisplatin-treated rats were significantly decreased, whereas the activities of glutathione reductase and isocitrate dehydrogenase were significantly increased. Addition of cysteine and vitamin E, Crocus sativus and Nigella sativa in combination with cisplatin partially prevented many changes in the activities of serum enzymes. In cisplatin-treated rats, the liver activities of isocitrate dehydrogenase and aspartate aminotransferase were significantly increased, whereas much greater changes were found in the kidneys, with increased activity of glucose-6-phosphate dehydrogenase and decreased activities of alkaline phosphatase, isocitrate dehydrogenase, malate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, sorbitol dehydrogenase and gamma-glutamyl transferase, as well as a decreased phosphorylation to oxidation ratio in the mitochondria, indicating reduced adenosine triphosphate production. Also, administration of cysteine and vitamin E, Crocus sativus and Nigella sativa together with cisplatin partially reversed many of the kidney enzymes changes induced by cisplatin. Cysteine together with vitamin E, Crocus sativus and Nigella sativa tended to protect from cisplatin-induced falls in leucocyte counts, haemoglobin levels and mean osmotic fragility of erythrocytes and also prevented the increase in haematocrit. The results of this study indicate a basis for the toxic effects of cisplatin, and suggest a possible way of counteracting the toxicity by introducing protective agents such sulphydryl compounds, other antioxidants and extracts of natural products. It also appears that cells adapt to the effects of cisplatin through the induction of systems that produce NADPH, which in turn compensates the decrease of free sulphydryl groups. We conclude that cysteine and vitamin E, Crocus sativus and Nigella Sativa may be a promising compound for reducing cisplatin-toxic side effects including nephrotoxicity.
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PMID:Protective effect of cysteine and vitamin E, Crocus sativus and Nigella sativa extracts on cisplatin-induced toxicity in rats. 960 69

The antioxidative role of Se-dependent cellular glutathione peroxidase (EC 1.11.1.9, GPX1) in vivo has not been established. Our objective was to determine the effects of GPX1 knockout or overexpression on the susceptibility of mice to paraquat toxicity and the contributions of GPX1, compared with other selenoproteins and vitamin E, to body defenses against such acute oxidative stress. Four experiments were conducted using 111 GPX1 knockout or overexpressing mice and the respective controls. Mice were fed diets supplemented with Se (as sodium selenite) at 0-0.4 mg/kg and/or all-rac-alpha-tocopheryl acetate at 0-75 mg/kg before intraperitoneal injections of 12.5, 50 or 125 mg paraquat/kg body weight. All mice that received 50 or 125 mg paraquat/kg died spontaneously, and the survival time of mice was (independent of dietary levels of Se per se or alpha-tocopheryl acetate) solely a function of tissue GPX1 activity (P < 0.001). Severe acute pulmonary interstitial necrosis was found only in the GPX1 overexpressing mice and the controls that had extended survival time. Thiobarbituric acid reacting substances in postmortem liver inversely correlated with the tissue GPX1 activity and dietary levels of Se and/or alpha-tocopheryl acetate. In contrast, all mice that received 12.5 mg paraquat/kg survived and were killed 2 wk after the injection for tissue collection. Compared with the saline injection, this low dose of paraquat resulted in greater (P < 0.001) liver and lung F2-isoprostanes in both the GPX1 knockout mice and the controls. However, there was no difference in plasma alanine transaminase (EC 2.6.1.2) activity or overt injuries in liver, lung and kidney in either group. Our data indicate that GPX1 is the major, if not the only, metabolic form of body Se that protects mice against the lethal oxidative stress caused by high levels of paraquat; it seems less important, however, in protecting mice against the moderate oxidative stress by the low level of paraquat.
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PMID:Cellular glutathione peroxidase is the mediator of body selenium to protect against paraquat lethality in transgenic mice. 964 87

We showed previously that supplementation for 30 d with 800 IU (727 mg) vitamin E/d did not adversely affect healthy elderly persons. We have now assessed the effects of 4 mo of supplementation with 60, 200, or 800 IU (55, 182, or 727 mg) all-rac-alpha-tocopherol/d on general health, nutrient status, liver enzyme function, thyroid hormone concentrations, creatinine concentrations, serum autoantibodies, killing of Candida albicans by neutrophils, and bleeding time in 88 healthy subjects aged >65 y participating in a double-blind, placebo-controlled trial. No side effects were reported by the subjects. Vitamin E supplementation had no effect on body weight, plasma total proteins, albumin, glucose, plasma lipids or the lipoprotein profile, total bilirubin, alkaline phosphatase, serum aspartate aminotransferase, serum alanine aminotransferase, lactate dehydrogenase, serum urea nitrogen, total red blood cells, white blood cells or white blood cell differential counts, platelet number, bleeding time, hemoglobin, hematocrit, thyroid hormones, or urinary or serum creatinine concentrations. Values from all supplemented groups were within normal ranges for older adults and were not significantly different from values in the placebo group. Vitamin E supplementation had no significant effects on plasma concentrations of other antioxidant vitamins and minerals, glutathione peroxidase, superoxide dismutase, or total homocysteine. There was no significant effect of vitamin E on serum nonspecific immunoglobulin concentrations or anti-DNA and anti-thyroglobulin antibodies. The cytotoxic ability of neutrophils against Candida albicans was not compromised. Thus, 4 mo of supplementation with 60-800 IU vitamin E/d had no adverse effects. These results are relevant for determining risk-to-benefit ratios for vitamin E supplementation.
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PMID:Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults. 970 Nov 88

Oxidant stress has been implicated as playing a role in the pathogenesis of cholestatic liver injury. The objective of this study was to determine whether the xanthine oxidase/xanthine dehydrogenase enzyme system was involved in this oxidant stress. Adult Sprague-Dawley rats were treated with the xanthine oxidase inhibitor, oxypurinol, and randomized to bile duct ligation or sham surgery; vehicle-treated, sham-operated rats served as controls. After 5 d of bile duct ligation, serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and total and direct bilirubin concentrations were significantly elevated, and increased lipid peroxidation of hepatic mitochondria and microsomes was present. Treatment with oxypurinol reduced the aspartate aminotransferase, alanine aminotransferase, and bilirubin values by 26-47% but did not alter the increased lipid peroxidation of mitochondria and microsomes. Serum vitamin E:total lipids ratio was also reduced in both bile duct-ligated groups, consistent with oxidant injury. These data show that inhibition of xanthine oxidase reduces biochemical evidence of hepatocellular injury during bile duct ligation without affecting oxidant damage to intracellular hepatocyte organelles. Thus, in this model a component of cholestatic injury appears to have been caused by oxidant stress from a source outside of the hepatocyte.
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PMID:Effect of oxypurinol, a xanthine oxidase inhibitor, on hepatic injury in the bile duct-ligated rat. 972 20

DEHP [di-(2 ethyl hexyl) phthalate], a widely used plasticizer in blood storage bags, leaches out in appreciable amounts into blood (about 10 mg/100 ml) resulting in exposure of recipients of blood transfusion to this compound. Various reports indicate the toxicity of DEHP, particularly in liver and reproductive organs but all these studies used large doses (up to 2 g or more/Kg body weight) and oral route of administration which are not relevant to the intravenous administration during blood transfusion or the low amounts present in blood. We have studied changes in the activity of some important enzymes-gamma-GT, ALT, CPK, LDH, alkaline phosphatase, acid phosphatase, beta-glucuronidase and few other parameters like vitamin E, glutathione, serum albumin etc in rats administered low doses of DEHP (corresponding to transfusion of 2, 4, 6 and 10 units of blood). Histopathology of the organs has also been carried out. The results obtained indicate no serious toxic effects for DEHP at the level present in blood stored in DEHP plasticized blood bags as evidenced by the lack of any significant alteration in most of the biochemical parameters studied. Even in those cases where there was alteration (for e.g., decrease in the level of vitamin E) 24 hr after administration of DEHP, it returned to near normal level with in 72 hr to 7 days. No histopathological changes were observed in any of the organs at these levels of DEHP. It is concluded that DEHP did not cause any serious toxic effect even at doses corresponding to transfusion of several units of blood in a recipient.
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PMID:Toxic effect of systemic administration of low doses of the plasticizer di-(2-ethyl hexyl) phthalate [DEHP] in rats. 975 59

Aflatoxin B1, a metabolite of Aspergillus flavus is a potent hepatotoxic and hepatocarcinogenic mycotoxin. Lipid peroxidation and oxidative DNA damage are the principal manifestations of aflatoxin B1-induced toxicity which could be mitigated by antioxidants. Many plant constituents, e.g. flavonoids, lignans and spice principles (capsaicin, curcumin, eugenol, etc.) have been reported to prevent liver damage associated with lipid peroxidation. In this study we investigated ternatin, a tetramethoxyflavone isolated from Egletes viscosa, for possible protection against liver injury induced by aflatoxin B1 in rats. Seventy two hours after a single intraperitoneal dose of aflatoxin B1 (1 mg kg(-1)), the concentration of malondialdehyde, the product of lipid peroxidation in liver homogenates, and serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were significantly elevated (P<0.001). Subcutaneous ternatin (25 mg kg(-1)) pretreatment greatly reduced aflatoxin B1-induced increases in the levels of serum enzymes (ALT from 5071+/-763 to 293+/-66 international units L(-1) and AST from 4241+/-471 to 449+/-108 international units L(-1)) and elevated malondialdehyde levels (from 11.37+/-1.27 to 0.79+/-0.22 nmol (mg wet tissue)(-1)) in a manner similar to oral vitamin E (300 mg kg(-1)), a standard antioxidant. Further, histological changes induced by aflatoxin B1 such as hepatocellular necrosis and bile-duct proliferation were markedly inhibited in animals pretreated with ternatin or vitamin E. These data provide evidence that ternatin inhibits lipid peroxidation and affords protection against liver damage induced by aflatoxin B1. Ternatin might, therefore, be a suitable candidate for the chemoprevention of aflatoxicosis associated liver cancer.
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PMID:Inhibition by the bioflavonoid ternatin of aflatoxin B1-induced lipid peroxidation in rat liver. 1021 9

The aim of this work was to determine the role of intraperitoneally-administered vitamin E and selenium on the biochemical and haematological parameters in the blood of rats. Thirty-two adult male Wistar rats were used in this study. All rats were randomly divided into four groups. The first group was used as the control. The second group was intraperitoneally administered with vitamin E (+/-(-)alpha-tocopheroryl acetate, 10 mg day-1), the third group with Se (Na2SeO3 0.2 mg over a day), and the fourth group with vitamin E and Se (vitamin E 10 mg + Na2SeO3 0.2 mg over a day). This administration was done for 5 weeks. Blood samples were taken from animals at the end of the dosage period and biochemical parameters in serum samples and haematological parameters in total blood were determined. The levels of total cholesterol (p < 0.01) and number of white blood cell (p < 0.001) in blood were significantly higher in the vitamin E group than in the control group. The levels of ALP, total cholesterol (p < 0.01) and number of white blood cells (p < 0.01) in blood were significantly higher in the selenium group than in the controls. The levels of glucose (p < 0.05), ALP (p < 0.01), total cholesterol (p < 0.001) and number of white blood cells (p < 0.01) were higher in the vitamin E and selenium combined group than in the controls. Other parameters considered within this trial (ALT, LDH, creatinine, albumin, total protein, amylase, creatine kinase, HDL triglycerides, total lipid, sodium, chloride, uric acids, red blood cell, haemoglobin, packed cell volume, MCV, MCH, MCHC) did not show statistically significant differences between the control and injected groups. The results indicated that blood glucose and total cholesterol levels, ALP activity and white blood cell counts were significantly increased by intraperitoneal administration of vitamin E and selenium in rats.
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PMID:Effects of intraperitoneally-administered vitamin E and selenium on the blood biochemical and haematological parameters in rats. 1037 60

Free radical scavengers have been utilized to prevent the consequences of ischemia, however, results do not seem conclusive. In our study we analyzed the blood flow, function, and histology of rat liver tissue after warm liver ischemia, in order to assess the effect of free radicals in liver reperfusion injury. N-acetyl cysteine (NAC), tocopherol, allopurinol, and superoxide dismutase (SOD), pharmacological agents expected to protect from injury mediated by free radicals, were investigated. Laser Doppler flowmetry and photometry were utilized to measure post-ischemic microcirculatory changes as an expression of ischemia-reperfusion injury in a model of segmental liver ischemia in the rat, with an ischemic time of 45 min. Galactose elimination capacity, ALT and histology were used to assess the functional and morphological consequences of ischemia after 24 h of reperfusion. The overall mean blood flow over 1 hour after reperfusion was of 33.9% (SD 11.2) of the normal, non-ischemic control. NAC (31.2% SD 10.9) did not show any protective effect and in some cases the effect seemed to be negative. Tocopherol (41.7% SD 5.1) marginally improved post ischemic liver tissue blood flow. Treatment with allopurinol did not show any beneficial effects (37.5% SD 14.2). Only animals treated with SOD showed an improvement of the post ischemic liver microcirculation (57.9% SD 14.4)(P < 0.001) and function. Only SOD produced statistically significant differences in galactose elimination capacity, compared with those of the ischemic control group. This moderately protective effect of SOD is encouraging, however, the relevance of all these compounds in a broader pathophysiological setting remains unproven.
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PMID:Free radical scavengers to prevent reperfusion injury following experimental warm liver ischaemia. Is there a real physiological benefit? 1042 60

The aim of this investigation was to determine serum levels of vitamin A, E, beta carotene, glutathione peroxidase (GSHPx), lipid peroxidation (MDA) and biochemical and haematological parameters during enflurane anaesthetised dogs. Ten kangal dogs were used and all animals were anaesthetised with enflurane for two hours and blood samples were taken before and 30, 120 minutes, 24 hours and 7 days during the anaesthesia. Vitamin E and beta carotene content were significantly (p<0.05 and p<0.01) higher before anaesthesia than after whereas serum GSHPx activity was not statistically different. However, serum levels of vitamin A and MDA were significantly (p<0.05) increased during the anaesthesia. In general, serum levels of aspartate aminotransferase, alanine aminotransferase, albumin, glucose, urea and creatinine were significantly (p<0.05 and p<0.01) increased during anaesthesia and returned to near normal values after 7 days of anaesthesia, whereas the white blood cell count was significantly (p<0.05 and p<0.01) decreased during the anaesthesia. However, the red blood cell count, haemoglobin and packed cell volume values, and levels of total cholesterol, triglycerides, total protein and globulin were apparently not influenced by the anaesthesia. In conclusion, we observed that the serum level of vitamin E and beta carotene were significantly decreased, whereas serum MDA and vitamin A levels were significantly increased during the enflurane anaesthesia.
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PMID:The levels of some antioxidant vitamins, glutathione peroxidase and lipoperoxidase during the anaesthesia of dogs. 1045 42


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