Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The worldwide epidemic of metabolic syndrome correlates with an elevation in serum uric acid as well as a marked increase in total fructose intake (in the form of table sugar and high-fructose corn syrup). Fructose raises uric acid, and the latter inhibits nitric oxide bioavailability. Because insulin requires nitric oxide to stimulate glucose uptake, we hypothesized that fructose-induced hyperuricemia may have a pathogenic role in metabolic syndrome. Four sets of experiments were performed. First, pair-feeding studies showed that fructose, and not dextrose, induced features (hyperinsulinemia, hypertriglyceridemia, and hyperuricemia) of metabolic syndrome. Second, in rats receiving a high-fructose diet, the lowering of uric acid with either allopurinol (a xanthine oxidase inhibitor) or benzbromarone (a uricosuric agent) was able to prevent or reverse features of metabolic syndrome. In particular, the administration of allopurinol prophylactically prevented fructose-induced hyperinsulinemia (272.3 vs.160.8 pmol/l, P < 0.05), systolic hypertension (142 vs. 133 mmHg, P < 0.05), hypertriglyceridemia (233.7 vs. 65.4 mg/dl, P < 0.01), and weight gain (455 vs. 425 g, P < 0.05) at 8 wk. Neither allopurinol nor benzbromarone affected dietary intake of control diet in rats. Finally, uric acid dose dependently inhibited endothelial function as manifested by a reduced vasodilatory response of aortic artery rings to acetylcholine. These data provide the first evidence that uric acid may be a cause of metabolic syndrome, possibly due to its ability to inhibit endothelial function. Fructose may have a major role in the epidemic of metabolic syndrome and obesity due to its ability to raise uric acid.
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PMID:A causal role for uric acid in fructose-induced metabolic syndrome. 1623 13

Hyperuricemia is a frequent finding in diseases in which the clinical manifestations are thought to be secondary to a state of generalized vascular endothelial dysfunction and related to the cardiovascular disease present in conditions associated with the metabolic syndrome, such as hypertension or diabetes. Traditionally, uric acid has not been given an active role in the pathologic process underlying these conditions. However, there is now a growing body of experimental and clinical evidence that points to a mechanistic role for uric acid in cardiovascular disease. The mechanisms that are most often thought to link uric acid and endothelial dysfunction involve inflammation and generation of oxidative stress in the vasculature. These observations allowed new clinical applications and formulations of therapies, such as the introduction of xanthine oxidase inhibitors in the management of congestive heart failure.
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PMID:Uric acid and the vasculature. 1667 43

An acute attack of gouty arthritis is one of the most painful experiences reported throughout medical history. Therefore it is paramount to initiate appropriate therapy quickly in order to terminate the acute phase. This goal can be achieved with non-steroidal anti-inflammatory agents, colchicine, or corticosteroid-based therapies. Rarely, because of contraindications to these agents, only symptomatic treatment can be given until the attack subsides. The next step is to lower the serum urate level below the limit of solubility (i.e., below 40.8 mmol/L, or 6.8mg/dL) which reduces recurrences and begins to return the total body urate pool to normal. This equally important goal can be achieved by uricosuric agents or xanthine oxidase inhibitors, although the latter is generally favored. Allopurinol is the agent most commonly preferred because of its safety profile and ease of use, but there are known serious allergic reactions and untoward side effects that occasionally require discontinuation. Febuxostat, a xanthine oxidase inhibitor, and pegylated uricase are new agents under development and may be beneficial in these situations or when other comorbid conditions prevent the use of conventional treatments. Alcohol and dietary consumption are also related to hyperuricemia and acute gout. Recently beer, wine, and liquor were studied and the risk of gout varied according to the alcohol ingested. Furthermore, recent data sheds light on important dietary modifications that may help in the treatment of gout, and dispels certain beliefs about protein ingestion and the occurrence of acute gout. As we learn more about the associated conditions of hypertriglyceridemia, hypertension, and the metabolic syndrome, it may allow the tailoring of medical regimens that directly prevent or reduce recurrent attacks of gouty arthritis. There are specific approved treatments for these common comorbidities that have parallel effects of lowering serum urate levels. These recent findings may be especially important for treating refractory cases. While patient education remains a cornerstone to ensure compliance, other quality indicators for the management of this disease have been reported and should guide the clinician in the treatment of gout and result in improved care.
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PMID:Advances in the management of gout and hyperuricaemia. 1688 87

Hyperuricemia and gout appear to be rapidly increasing worldwide and frequently cause symptoms of metabolic syndrome. Dietary flavonoids have their potential beneficial effects on human health. In the present study, 15 flavonoids (quercetin, morin, myricetin, kaempferol, icariin, apigenin, luteolin, baicalin, silibinin, naringenin, formonoetin, genistein, puerarin, daidzin and naringin dihydrochalcone) were selected to investigate for their hypouricemic action in mice. Oral administration of quercetin, morin, myricetin, kaempferol, apigenin and puerarin at 50 and 100 mg/kg for 3 d was able to elicit hypouricemic actions in hyperuricemic mice induced by potassium oxonate. Luteolin, formonoetin and naringenin showed the significant effects only at 100 mg/kg. Quercetin, puerarin, myricetin, morin and kaempferol significantly reduced liver uric acid level in hyperuricemic animals. In addition, quercetin, morin, myricetin, kaempferol and puerarin exhibited significant inhibition on the liver xanthine oxidase (XOD) activities. It seems to be likely that these flavonoids reduce serum urate levels by mainly inhibiting XOD activity. However, the hypouricemic effect of apigenin observed seemed not to parallel with the changes in liver uric acid level and liver XOD activity, implying that apigenin might act via other mechanisms apart from inhibiting enzyme activity simply. Analysis of the chemical structure showed that a planar structure with the hydroxyl groups played a crucial role in hypouricemic activity of flavonoids. The exact mechanism of the hypouricemic action of flavonoids in vivo should be investigated in the future.
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PMID:Hypouricemic action of selected flavonoids in mice: structure-activity relationships. 1766 19

Increased fructose consumption is associated with hyperuricemia, metabolic syndrome, and renal damage. This study evaluated whether febuxostat (Fx), an investigational nonpurine, and selective xanthine oxidase inhibitor, could alleviate the features of metabolic syndrome as well as the renal hemodynamic alterations and afferent arteriolopathy induced by a high-fructose diet in rats. Two groups of rats were fed a high-fructose diet (60% fructose) for 8 wk, and two groups received a normal diet. For each diet, one group was treated with Fx (5-6 mg.kg(-1).day(-1) in the drinking water) during the last 4 wk (i.e., after the onset of metabolic syndrome), and the other received no treatment (placebo; P). Body weight was measured daily. Systolic blood pressure and fasting plasma uric acid (UA), insulin, and triglycerides were measured at baseline and at 4 and 8 wk. Renal hemodynamics and histomorphology were evaluated at the end of the study. A high-fructose diet was associated with hyperuricemia, hypertension, as well as increased plasma triglycerides and insulin. Compared with fructose+P, fructose+Fx rats showed significantly lowered blood pressure, UA, triglycerides, and insulin (P < 0.05 for all comparisons). Moreover, fructose+Fx rats had significantly reduced glomerular pressure, renal vasoconstriction, and afferent arteriolar area relative to fructose+P rats. Fx treatment in rats on a normal diet had no significant effects. In conclusion, normalization of plasma UA with Fx in rats with metabolic syndrome alleviated both metabolic and glomerular hemodynamic and morphological alterations. These results provide further evidence for a pathogenic role of hyperuricemia in fructose-mediated metabolic syndrome.
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PMID:Effects of febuxostat on metabolic and renal alterations in rats with fructose-induced metabolic syndrome. 1821 51

Increased consumption of fructose may play an important role in the epidemic of metabolic syndrome and may presage the development of diabetes, cardiovascular disease, and chronic kidney disease. Once in the cell, fructose is phosphorylated by ketohexokinase (KHK), leading to consumption of ATP, formation of AMP, and generation of uric acid through xanthine oxidoreductase (XOR). This study aimed to examine the direct effects of fructose in human kidney proximal tubular cells (HK-2) and whether they are mediated by the fructose metabolism via KHK. At a similar concentration to that observed in peripheral blood after a meal, fructose induced production of monocyte chemotactic protein 1 (MCP-1) and reactive oxygen species in HK-2 cells. Knockdown of KHK by stable transfection with small hairpin RNA demonstrated that these processes were KHK dependent. Several antioxidants, including specific inhibitors of NADPH oxidase and XOR, prevented MCP-1 secretion. We detected XOR mRNA in HK-2 cells and confirmed its activity by identifying uric acid by mass spectrometry. Fructose increased intracellular uric acid, and uric acid induced production of MCP-1 as well. In summary, postprandial concentrations of fructose stimulate redox- and urate-dependent inflammatory mediators in proximal tubular cells.
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PMID:Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. 1924 71

The prevalence of gout has been increasing in epidemic proportions over the last several decades. Hyperuricemia has been shown to be associated with metabolic syndrome and to be an independent risk factor for cardiovascular disease. Associations between hyperuricemia, obesity and aging have provided an impetus in recent years to develop alternative methods of treating hyperuricemia and gout. Febuxostat is a new non-purine xanthine oxidase inhibitor indicated for chronic gout. Febuxostat has been shown to quickly and effectively lower serum urate levels in patients with chronic gout. This manuscript will review febuxostat, its pharmacokinetics and pharmacodynamics, efficacy and adverse events and use in patients with comorbid conditions. The review will also summarize the phase III trials leading up to the drug's approval by both the European Commission in 2008 and the U.S. FDA in 2009. Possible implications the medication may have in the future on gout and hyperuricemia will also be discussed.
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PMID:Febuxostat: a new agent for lowering serum urate. 1949 90

Allopurinol is an inhibitor of xanthine oxidoreductase (XOR) and inhibits the generation of uric acid (UA) as the final product of purine catabolism, as well as the resulting generation of superoxide (O2(-)), in humans. Elevation of the serum UA (SUA) level, referred to as hyperuricemia (HU), eventually leads to gout and allopurinol has been used for the treatment of HU and gout. Studies have revealed the role of elevated SUA levels and the associated oxidative stress (OS) in a broad spectrum of pathological conditions and it is anticipated that these findings would also expand the use of allopurinol as a therapeutic drug. This article presents a review of reports, mainly of recent studies, on the efficacy of allopurinol in various diseases and explores novel potential uses of the drug. Important novel and potential uses of great interest include metabolic syndrome (MetS) and related disorders, chronic kidney disease (CKD), nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Ischemia-reperfusion injury and mucositis, encountered as adverse effects of cancer treatment, have also been under investigation as potential targets for allopurinol.
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PMID:Allopurinol, an inhibitor of uric acid synthesis--can it be used for the treatment of metabolic syndrome and related disorders? 1958 65

An abnormal production of reactive oxygen species (ROS) and the subsequent decrease in vascular bioavailability of nitric oxide (NO) have long been proposed to be the common pathogenetic mechanism of the endothelial dysfunction, resulting from diverse cardiovascular risk factors such as hypercholesterolaemia, diabetes mellitus, chronic smoking, metabolic syndrome, and hypertension. Superoxide produced by the nicotinamide dinucleotide phosphate (NADPH) oxidase, mitochondrial sources, or the xanthine oxidase may react with NO, thereby resulting in excessive formation of peroxynitrite, a reactive nitrogen species that has been demonstrated to accelerate the atherosclerotic process by causing direct structural damage and by causing further ROS production. Despite this sound biological rationale and a number of pre-clinical and clinical lines of evidence, studies testing the effects of classical antioxidants such as vitamin C, vitamin E, or folic acid in combination with vitamin E have been disappointing. Rather, substances such as statins, angiotensin-converting enzyme inhibitors, or AT1-receptor blockers, which possess indirect antioxidant properties mediated by the stimulation of NO production and simultaneous inhibition of superoxide production (e.g. from the NADPH oxidase), have been shown to improve vascular function in pre-clinical and clinical studies and to reduce the incidence of cardiovascular events in patients with cardiovascular disease. Today, oxidative stress remains an attractive target for cardiovascular prevention and therapy. However, a deeper understanding of its source, and of its role in vascular pathology, is necessary before new trials are attempted.
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PMID:Is oxidative stress a therapeutic target in cardiovascular disease? 2097 1

Gout is a condition presenting with inflammatory arthritis caused by crystallization and phagocytosis of monosodium urate in synovial fluid. It is the most common form of arthritis in men above the age of 40 years. Four clinical stages of gout have been distinguished: asymptomatic hyperuricemia, acute gouty arthritis, intercritical gout, and chronic gout. Experimental and epidemiologic studies provide growing evidence that hyperuricemia is not only the driving force behind symptoms attributed to the deposition of monosodium urate in the musculoskeletal system but also the important etiological factor in common morbidities of modern societies such as arterial hypertension, cardiovascular disease, chronic kidney disease, and type 2 diabetes mellitus. Today, the majority of gout cases demonstrate clinical features of the metabolic syndrome. Recommendations of the European League Against Rheumatism (EULAR) published in 2006 address key issues in the diagnosis of gout, as well as in the nonpharmacologic and pharmacologic management with regard to the clinical condition and comorbidities of the individual patient. Routinely used antihyperuricemic drugs include allopurinol, colchicine, and uricosuric agents. New agents have recently been introduced into clinical practice, like pegylated uricase and febuxostat, a nonpurine inhibitor analog of xanthine oxidase. Thus, novel therapeutic options are now available to combat this chronic illness which often leads to significant disability.
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PMID:[Gout and comorbidities associated with hyperuricemia]. 2136 38


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