Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Propylthiouracil (PTU) has been demonstrated to reduce alcohol-induced hepatocyte damage and severe alcoholic liver disease. Although the mechanism by which the drug operates is yet to be elucidated, there is evidence that PTU may act as an antioxidant. The present study examines the reaction of PTU with oxygen free radicals and the ability of PTU to directly inhibit peroxidation of a model membrane system. PTU reacted directly with hydroxyl radicals produced by gamma-radiolysis. The rate constant for the PTU/hydroxyl radical reaction as determined by steady state competition kinetics with p-nitrosodimethylaniline was 8 x 10(9) L/mol/sec. PTU was less reactive towards superoxide generated by the xanthine/xanthine oxidase system, having a small but significant inhibitory effect on superoxide-induced reduction of cytochrome c only at a concentration of 200 microM. The ability of PTU to protect lipids from peroxidative changes was tested in membranes prepared from linoleic acid. The rate of peroxidation induced by 40 degrees heat decreased from 0.078 to 0.024 mM hydroperoxide/hr in the presence of 0-50 microM PTU. However, this trend was reversed at PTU concentrations above 50 microM. These data suggest that the protective effects of PTU against liver damage may be due to scavenging reactions with hydroxyl radicals in particular and/or its antioxidant potential.
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PMID:Antioxidant activity of propylthiouracil. 131 79

Monitoring of chronic alcoholism would be facilitated by using sensitive biochemical markers in blood cells, mainly to detect differences between alcoholic subjects with or without liver injury. We propose two types of markers: the first one is superoxide dismutase (SOD) activity involved in the conversion of superoxide radicals (O2-.) formed during acetaldehyde oxidation by xanthine oxidase after chronic alcohol consumption; the second one is enolase activity with both isoenzyme forms: nonneuronal enolase (NNE) and neuron specific enolase (NSE) which has been shown to be modified in many injuries related to the glycolytic pathways. For SOD activity we found a significant increase in alcoholic patients with liver injury and mainly in cirrhotic patients with ascitis. Both enolase activities were also found to be significantly increased in alcoholic patients with liver injury but NNE activity was also increased in alcoholics without apparent liver disease. Our results suggest that increased activity of SOD and NSE in blood cells may be related to liver injury mainly in alcoholism while increased NNE activity may also be a marker of alcohol abuse without liver injury.
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PMID:Blood cell superoxide dismutase and enolase activities as markers of alcoholic and nonalcoholic liver diseases. 321 86

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.
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PMID:Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. 889 26

We characterized the effects of an ethanol-extract of the berries of Ampelopsis brevipedunculata (Maxim.) Trautv. (Vitaceae), a plant used in folk medicine to treat liver disease, on rat hepatocyte injury occurring spontaneously, stimulated with ferrous iron and with xanthine oxidase in combination with hypoxanthine or stimulated with ethanol in serum-free culture. Total intracellular and extracellular activities of lactate dehydrogenase (LDH) accumulating during incubation and the percentage of intracellular LDH activity released into culture medium were routinely measured, to evaluate the degree of the injury. The extract decreased a high level of LDH release spontaneously occurring and an elevated level of LDH release stimulated with ferrous iron to approximately the level caused by antioxidants, such as superoxide dismutase, pyruvate and dimethyl sulfoxide. Xanthine oxidase-stimulated LDH release was not decreased by the extract. Ethanol-stimulated LDH release was decreased by the extract when the spontaneous release level was comparatively high. These results indicate that the extract inhibits intact hepatocytes from degrading, by the toxic effect of iron released from primary injured hepatocytes through the generation of reactive oxygen species. The major antitoxic activity of the extract was found in an undialyzable fraction. Sugars were necessary to exert the activity as estimated by periodate oxidation of the extract.
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PMID:An ethanol-extract of Ampelopsis brevipedunculata (Vitaceae) berries decreases ferrous iron-stimulated hepatocyte injury in culture. 950 98

Measurement of salivary clearance and urinary metabolites of caffeine is an excellent noninvasive tool for assessing liver function, particularly the activity of cytochrome P4501A2 (CYP1A2), N-acetyltransferase (NAT), and xanthine oxidase (XO). This study was undertaken to measure the clearance of caffeine using saliva as a biological fluid and to assess the activities of the above-mentioned enzymes in healthy children and pediatric patients with liver diseases using urinary molar ratios of different caffeine metabolites. The well-established two-sample saliva approach was used to measure the clearance of caffeine in nine pediatric patients with liver diseases (LD) and in nine healthy children. The caffeine metabolites were also measured in the urine of these subjects by high-performance liquid chromatography, and urinary molar ratios of 5-acetylamino-6-formylamino-3-methyluracil (AFMU), 1-methylxanthine (1X), 1-methyluric acid (1U), and 1,7-dimethyluric acid (17U) were employed to estimate the activities of CYP1A2, NAT, and XO. The caffeine salivary clearance and the percentage of the dose excreted in the form of various metabolites were significantly (p < 0.035) smaller in the LD patients than those in healthy children. The urinary molar ratio of [AFMU + 1U + 1X]/17U, which reflects the activity of CYP1A2, was also significantly (p < 0.0005) reduced in these patients. However, there were no significant differences between the two groups in the ratios of AFMU/1X and 1U/1X, which estimate the activities of NAT and XO, respectively. In conclusion, the data obtained suggest that liver disease in pediatric subjects significantly reduces the salivary clearance of caffeine and the activity of cytochrome P4501A2, but it has no impact on the activities of NAT and XO.
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PMID:Salivary clearance and urinary metabolic pattern of caffeine in healthy children and in pediatric patients with hepatocellular diseases. 1019 95

Alcohol-induced oxidative stress is linked to the metabolism of ethanol. Three metabolic pathways of ethanol have been described in the human body so far. They involve the following enzymes: alcohol dehydrogenase, microsomal ethanol oxidation system (MEOS) and catalase. Each of these pathways could produce free radicals which affect the antioxidant system. Ethanol per se, hyperlactacidemia and elevated NADH increase xanthine oxidase activity, which results in the production of superoxide. Lipid peroxidation and superoxide production correlate with the amount of cytochrome P450 2E1. MEOS aggravates the oxidative stress directly as well as indirectly by impairing the defense systems. Hydroxyethyl radicals are probably involved in the alkylation of hepatic proteins. Nitric oxide (NO) is one of the key factors contributing to the vessel wall homeostasis, an important mediator of the vascular tone and neuronal transduction, and has cytotoxic effects. Stable metabolites--nitrites and nitrates--were increased in alcoholics (34.3 +/- 2.6 vs. 22.7 +/- 1.2 micromol/l, p < 0.001). High NO concentration could be discussed for its excitotoxicity and may be linked to cytotoxicity in neurons, glia and myelin. Formation of NO has been linked to an increased preference for and tolerance to alcohol in recent studies. Increased NO biosynthesis also via inducible NO synthase (NOS, chronic stimulation) may contribute to platelet and endothelial dysfunctions. Comparison of chronically ethanol-fed rats and controls demonstrates that exposure to ethanol causes a decrease in NADPH diaphorase activity (neuronal NOS) in neurons and fibers of the cerebellar cortex and superior colliculus (stratum griseum superficiale and intermedium) in rats. These changes in the highly organized structure contribute to the motor disturbances, which are associated with alcohol abuse. Antiphospholipid antibodies (APA) in alcoholic patients seem to reflect membrane lesions, impairment of immunological reactivity, liver disease progression, and they correlate significantly with the disease severity. The low-density lipoprotein (LDL) oxidation is supposed to be one of the most important pathogenic mechanisms of atherogenesis, and antibodies against oxidized LDL (oxLDL) are some kind of epiphenomenon of this process. We studied IgG oxLDL and four APA (anticardiolipin, antiphosphatidylserine, antiphosphatidylethanolamine and antiphosphatidylcholine antibodies). The IgG oxLDL (406.4 +/- 52.5 vs. 499.9 +/- 52.5 mU/ml) was not affected in alcoholic patients, but oxLDL was higher (71.6 +/- 4.1 vs. 44.2 +/- 2.7 micromol/l, p < 0.001). The prevalence of studied APA in alcoholics with mildly affected liver function was higher than in controls, but not significantly. On the contrary, changes of autoantibodies to IgG oxLDL revealed a wide range of IgG oxLDL titers in a healthy population. These parameters do not appear to be very promising for the evaluation of the risk of atherosclerosis. Free radicals increase the oxidative modification of LDL. This is one of the most important mechanisms, which increases cardiovascular risk in chronic alcoholic patients. Important enzymatic antioxidant systems - superoxide dismutase and glutathione peroxidase - are decreased in alcoholics. We did not find any changes of serum retinol and tocopherol concentrations in alcoholics, and blood and plasma selenium and copper levels were unchanged as well. Only the zinc concentration was decreased in plasma. It could be related to the impairment of the immune system in alcoholics. Measurement of these parameters in blood compartments does not seem to indicate a possible organ, e.g. liver deficiency.
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PMID:Oxidative stress, metabolism of ethanol and alcohol-related diseases. 1117 77

The establishment of a continuous intragastric enteral feeding protocol in the rat by Tsukamoto and French was a major development in research of alcohol-induced liver disease. Unlike other models which only produce fat, with this model, inflammation, necrosis, and fibrosis can now be studied. However, much of what has been learned to date involves inhibitors or nutritional manipulation which may not be specific. Knockout technology could avoid these potential problems. Therefore, we have adapted a rat long-term intragastric protocol to the mouse so that the knockout technology can be used to study the mechanism of alcohol-induced liver injury. Reactive free radicals are involved in the mechanisms of early alcohol-induced liver injury; however, the key source of these species remains unclear. Cytochrome P450 (CYP) 2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. On the other hand, NADPH oxidase or xanthine oxidase is also a potent source of free radicals. In studies using CYP2E1 and p47phox (NADPH oxidase-deficient) knockout mice with this enteral model, it was reported that oxidants from CYP2E1 play only a small role in the mechanisms of early alcohol-induced liver injury in the mouse. Further, free radicals from NADPH oxidase in Kupffer cells play an important role in early alcohol-induced liver injury. Thus, this new enteral mouse model using knockout technology will provide a powerful tool in alcohol research.
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PMID:Development of an intragastric enteral model in the mouse: studies of alcohol-induced liver disease using knockout technology. 1118 Aug 60

Zhi-Zi-Da-Huang decoction (ZZDHD), a classic traditional Chinese medicine (TCM) formula, has been used for centuries to treat alcoholic liver disease. Reliable therapeutics of ZZDHD has also been validated in clinical practice. In this study, molecular docking and network analysis were carried out to explore the antioxidative mechanism of ZZDHD as an effective therapeutic approach to treat alcoholic liver disease. Multiple active compounds of ZZDHD were screened based on four key original enzymes (cytochrome P450 2E1, xanthine oxidase, inducible nitric oxide synthase, and cyclooxygenase-2) involved in ethanol-induced oxidative stress damage. A drug-target network was constructed through network pharmacology analysis, which predicted the relationships of active ingredients to the targets. Some results had been verified by the previous experimental pharmacological studies; meanwhile, it was first reported that xanthine oxidase and eriocitrin, neoeriocitrin, isorhoifolin, and poncirin had interactions. The network pharmacology strategy used provided a forceful tool for searching the mechanism of action of TCM formula and novel bioactive ingredients.
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PMID:Network pharmacology-based antioxidant effect study of zhi-zi-da-huang decoction for alcoholic liver disease. 2592 10

Autoimmune hepatitis (AIH) is a chronic immune mediated liver disease characterized by elevated transaminases, hyper gammaglobulinemia, presence of autoantibodies and interface hepatitis in the absence of a known etiology of liver disease. Thiopurines (azathioprine [AZA]/6-mercaptopurine [6MP]) and steroids remain the first line of treatment of AIH in both children and adults. However, a small proportion of AIH patients are either non-responders or develop side effects with AZA. The metabolism of AZA is complex and mediated by multiple enzymes. After absorption and getting converted to 6MP, it is converted to 6-thiouric acid, 6-methyl mercaptopurine (6MMP) and 6-thioguanine (6TG) by different enzymes. Elevated 6MMP levels are associated with hepatotoxicity and also poor efficacy due to simultaneous lower levels of 6TG, which is the active drug metabolite related to both efficacy and myelosuppression. Allopurinol, a xanthine oxidase inhibitor shifts the metabolism of AZA away from 6MMP toward 6TG. This combination of allopurinol with reduced dose of AZA is an alternative to more expensive and toxic second line therapy to induce remission in patients with AIH. This article discusses the mechanism of action of allopurinol in inducing response to AZA, reviews the published literature on this combination therapy and gives guidelines on the use of allopurinol in patients with AIH.
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PMID:Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review. 2834 71