Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The prevalence of gout has increased markedly in the United States in the past two decades, and new treatments for hyperuricemia are being developed. Recent molecular identification of urate transporter-1 (URAT1) as the central mediator of renal urate reabsorption has provided novel understanding of the pathogenesis of hyperuricemia, and the target site for current and possibly future primary uricosuric agents. Recent studies have also highlighted uricosuric effects of several drugs (losartan, atorvastatin, fenofibrate) that are prescribed for primary indications other than hyperuricemia. The niche of these agents in current management of hyperuricemia is discussed. We also review the ongoing development of recombinant uricase preparations and of novel xanthine oxidase inhibitors exemplified by febuxostat. These agents should provide novel options for patients with chronic, refractory gout and hyperuricemia, particularly in association with allopurinol hypersensitivity and renal insufficiency.
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PMID:New developments in clinically relevant mechanisms and treatment of hyperuricemia. 1690 Oct 81

(1) Febuxostat is a selective inhibitor of xanthine oxidase. Its use in the management of hyperuricemia and gout is being studied. (2) In a 52-week, phase III randomized clinical trial, febuxostat was superior to allopurinol for lowering uric acid levels. Its efficacy in preventing gout attacks was similar to that of allopurinol. Despite a similar rate of adverse effects, individuals on febuxostat were more likely to stop treatment than those on allopurinol. (3) The most commonly observed adverse effects with febuxostat include liver function test abnormalities, diarrhea, headache, nausea, vomiting, abdominal pain, and dizziness. (4) Given that renal dysfunction is a risk factor for hyperuricemia and gout, the safety and efficacy of febuxostat in this population should be considered, but only limited data are available. (5) The diffusion of febuxostat may be limited by its price relative to that of allopurinol, regardless of whether febuxostat proves to have advantages in specific populations.
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PMID:Febuxostat for prevention of gout attacks. 1695 89

Mechanistic and therapeutic advances in gout have been moving swiftly in the past decade. Clinically, the disease is changing in character. This review discusses several of the pertinent recent developments in understanding gout and in novel therapeutics for the disease. Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia. We discuss the therapeutic limitations of allopurinol and uricosurics and the potential applications of novel xanthine oxidase inhibitors and of recombinant uricase preparations. Last, we summarize understanding of the central role of the early induced innate immune response in gouty inflammation, which has suggested the potential value of new strategies for treating gouty inflammation by targeting caspase-1 or IL-1beta.
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PMID:Gout in 2006: the perfect storm. 1712 96

Xanthine oxidase (XO) is a key enzyme which can catalyze xanthine to uric acid causing hyperuricemia in humans. By using the fractionation technique and inhibitory activity assay, an active compound that prevents XO from reacting with xanthine was isolated from wheat leaf. It was identified by the Mass and NMR as 6-aminopurine (adenine). A structure-activity study based on 6-aminopurine was conducted. The inhibition of XO activity by 6-aminopurine (IC(50)=10.89+/-0.13 microM) and its analogues was compared with that by allopurinol (IC(50)=7.82+/-0.12 microM). Among these analogues, 2-chloro-6(methylamino)purine (IC(50)=10.19+/-0.10 microM) and 4-aminopyrazolo[3,4-d] pyrimidine (IC(50)=30.26+/-0.23 microM) were found to be potent inhibitors of XO. Kinetics study showed that 2-chloro-6(methylamino)purine is non-competitive, while 4-aminopyrazolo[3,4-d]pyrimidine is competitive against XO.
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PMID:The screening and characterization of 6-aminopurine-based xanthine oxidase inhibitors. 1737 26

Uric acid is the end-product of purine catabolism. Hyperuricaemia is implicated in disorders such as gout and urolithiasis and recent epidemiological evidence suggests an association between increasing uric acid levels and increased cardiovascular morbidity and mortality. A direct causal role remains to be established but recent studies of losartan, atorvastatin and fenofibrate suggest that uric acid reduction contributes to attenuation of cardiovascular risk. Furthermore, several small studies of xanthine oxidase inhibition (the most common method of uric acid reduction) have shown improvements in measures of cardiovascular and endothelial function of a similar magnitude to those of other proven preventative strategies. This review introduces the epidemiological data, discusses strategies to lower uric acid and outlines the available clinical trial data supporting uric acid reduction as a potential and novel method of reducing the burden of cardiovascular disease.
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PMID:Uric acid reduction: a new paradigm in the management of cardiovascular risk? 1762 23

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

Uric acid (UA) is the end product of purine metabolism in humans. Hyperuricemia is often found in patients with chronic heart failure (CHF). The increase of serum UA level is inversely associated with disease severity, cardiac function and prognosis of CHF. Some researchers found that UA had detrimental impact on the cardiovascular system, including mediating immune response upon cell injury, increasing endotoxin-stimulated tumor necrosis factor-alpha production and hence proinflammatory immune activation, increasing blood pressure, and so on. Other researchers found that UA had important antioxidant properties by scavenging various reactive oxygen species. So far, there is no evidence suggest that UA has detrimental effect on the pathophysiology of CHF. Xanthine oxidase (XO) is an enzyme that produces uric acid during purine metabolism. XO activity is up-regulated in failing heart, and serum UA levels reflect the degree of XO activation in CHF. XO plays an important role in the pathophysiology process of CHF, including myocyte apoptosis, endothelial dysfunction and cardiac mechanoenergetic uncoupling. The therapeutic effect of long-term XO inhibition has been confirmed in animal models and partly in human bodies. We hypothesize that UA itself is not a player but a bystander associated with the activation of XO in the pathophysiology of CHF.
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PMID:Is uric acid itself a player or a bystander in the pathophysiology of chronic heart failure? 1768 99

Xanthine oxidoreductase catalyzes the final two steps of purine catabolism and is involved in a variety of pathological states ranging from hyperuricemia to ischemia-reperfusion injury. The human enzyme is expressed primarily in its dehydrogenase form utilizing NAD+ as the final electron acceptor from the enzyme's flavin site but can exist as an oxidase that utilizes O2 for this purpose. Central to an understanding of the enzyme's function is knowledge of purine substrate orientation in the enzyme's molybdenum-containing active site. We report here the crystal structure of xanthine oxidase, trapped at the stage of a critical intermediate in the course of reaction with the slow substrate 2-hydroxy-6-methylpurine at 2.3A. This is the first crystal structure of a reaction intermediate with a purine substrate that is hydroxylated at its C8 position as is xanthine and confirms the structure predicted to occur in the course of the presently favored reaction mechanism. The structure also corroborates recent work suggesting that 2-hydroxy-6-methylpurine orients in the active site with its C2 carbonyl group interacting with Arg-880 and extends our hypothesis that xanthine binds opposite this orientation, with its C6 carbonyl positioned to interact with Arg-880 in stabilizing the MoV transition state.
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PMID:Substrate orientation in xanthine oxidase: crystal structure of enzyme in reaction with 2-hydroxy-6-methylpurine. 1806 85

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


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