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We reviewed lifestyle factors that influence serum uric acid levels and risk of gout flare, and how to improve their deleterious effects. Since obesity increases uric acid and weight gain increases gout risk, weight reduction by daily exercise and limiting intake of excess calories is recommended. However, strenuous exercise, which causes adenine nucleotide degradation; starvation, which decreases uric acid excretion; and dehydration may raise the level of uric acid in serum and trigger gout. Increased intake of purine-rich foods, such as meat and seafood, raise the level of uric acid in serum and is associated with increased risk of gout, whereas dairy products, especially low-fat types, are associated with a lower risk of gout. Also, heavy alcohol drinking raises the uric acid level and increases the risk of gout through adenine nucleotide degradation and lactate production. Sweet fruits and soft drinks containing fructose should be moderated, since fructose may raise uric acid and increase gout risk through uric acid production and/or decreased excretion. On the other hand, the Mediterranean diet is recommended for gout patients, since it may also help prevent hyperuricemia. Furthermore, coffee and vitamin C supplementation could be considered as preventive measures, as those can lower serum uric acid levels as well as the risk of gout.

The effects of tofisopam, a GABA-receptor agonist, following oral administration (300mg) with and without allopurinol pretreatment on the plasma concentration and renal transport of uric acid and oxypurinol were investigated in 5 healthy subjects. Fractional and urinary excretions of uric acid were both significantly increased at 2-3 hours after tofisopam administration (559% and 459%, respectively), while plasma uric acid concentration was significantly decreased (36%) at 2.5 hours, suggesting that tofisopam affects uric acid metabolism via the tubular transport system. The hypouricemic effect of tofisopam was comparable to or greater than that of losartan and/or fenofibrate, which also have uric acid-lowering activity. In addition, with prior administration of allopurinol, the fractional and urinary excretions of oxypurinol were increased at 2-3 hours after tofisopam administration (51% and 33%, respectively), while the plasma oxypurinol concentration was significantly decreased at 1.5 and 2.5 hours (15% and 21%, respectively). Accordingly, tofisopam may be an attractive compound for treatment of hyperuricemia and/or gout, especially in patients complicated with autonomic dysfunction symptoms, though it is possible that the uric acid-lowering effect of oxypurinol is attenuated by tofisopam.

Background Enhancer of zeste homolog 2 is a component of the Polycomb repressive complex 2 that mediates chromatin-based gene silencing through trimethylation of lysine 27 on histone H3. This complex plays vital roles in the regulation of development-specific gene expression. Design and Methods In this study, a comparative microarray analysis of gene expression in primary adult T-cell leukemia/lymphoma samples was performed, and the results were evaluated for their oncogenic and clinical significance. Results Significantly higher levels of Enhancr of zeste homolog 2 and RING1 and YY1 binding protein transcripts with enhanced levels of trimethylation of lysine 27 on histone H3 were found in adult T-cell leukemia/lymphoma cells compared with those in normal CD4+ T cells. Furthermore, there was an inverse correlation between the expression level of Enhancer of zeste homolog 2 and that of miR-101 or miR-128a, suggesting that the altered expression of the latter miRNAs accounts for the overexpression of the former. Patients with high Enhancer of zeste homolog 2 or RING1 and YY1 binding protein transcripts had a significantly worse prognosis than those without it, indicating a possible role of these genes in the oncogenesis and progression of this disease. Indeed, adult T-cell leukemia/lymphoma cells were sensitive to a histone methylation inhibitor, 3-deazaneplanocin A. Furthermore, 3-deazaneplanocin A and histone deacetylase inhibitor panobinostat showed a synergistic effect in killing the cells Conclusions These findings reveal that adult T-cell leukemia/lymphoma cells have deregulated Polycomb repressive complex 2 with over-expressed Enhancer of zeste homolog 2, and that there is the possibility of a new therapeutic strategy targeting histone methylation in this disease.

Epidemiological observations and laboratory studies have suggested that polyphenols possess anti-inflammatory, anti-microbial, anti-carcinogenic, and antioxidant properties. However, studies assessing the effects of polyphenols on uric acid metabolism in vivo are scarce. Herein, we investigated whether a phenolic substance, Oligonol®, has effects on uric acid metabolism. In six healthy male volunteers, Oligonol® significantly decreased 1-h uric acid excretion and fractional uric acid clearance, which was accompanied by a decreased serum concentration of uric acid. In addition, an in vitro experiment showed that Oligonol® inhibited buttermilk xanthine oxidase activity in a dose-dependent manner. Together, these results suggest that Oligonol® lowers serum uric acid through inhibition of xanthine oxidase, and may be effective for prevention and treatment of hyperuricemia and/or gout.

To investigate whether ethanol is able to decrease monosodium urate (MSU) crystal-induced inflammation, differentiated THP1 cells from a human monocyte cell line were cultured in the presence or absence of MSU crystals with and without ethanol. In an in vivo experiment, MSU crystals were administered into subcutaneous air pouches created in mice, following peritoneal injection of ethanol diluted with PBS. MSU crystals (0.75 mg/ml) stimulated the secretion of TNF-α, IL-8, and IL-1β from THP1 cells, while ethanol at a concentration of 0.8% reduced those increases by 1.79-, 1.63-, and 1.75-fold, respectively. In vitro , MSU crystals (0.75 mg/ml) significantly increased the expression of phosphorylated JNK, ERK1/2, and p38 proteins in THP1 cells, while ethanol at a concentration of 0.8% reduced those increased expressions by 1.28-, 1.14-, and 1.68-fold, respectively. In addition, MSU crystals (0.75 mg/ml) significantly increased the expression of phosphorylated NF-κB protein in the nuclear and cytosolic fractions and decreased the expression of IκBα in the cytosolic fraction. Ethanol at a concentration of 0.8% reduced the MSU-increased expression of phosphorylated NF-κB in the nuclear and cytosolic fractions by 1.25- and 1.27-fold, respectively, while it also reduced the MSU-decreased expression of IκBα in the cytosolic fraction by 1.12-fold. In vivo , MSU crystals increased the number of leukocytes, as well as the concentrations of KC, MIP1α, and IL-6 in pouch fluids, while ethanol (5 g/kg body weight) considerably inhibited the MSU crystal-induced inflammation. These results strongly suggest that ethanol suppresses the secretion of inflammatory cytokines induced by MSU crystals via a pathway including MAPK (p38, JNK, and ERK1/2, especially p38) and NF-κB.

Background 1,5-Anhydroglucitol is found in food. We determined factors other than glucosuria that affect serum 1,5-anhydroglucitol (1,5-AG) concentration. Methods The relationships between serum 1,5-AG concentration and metabolic parameters were investigated in 158 males with normal glucose tolerance verified by an oral glucose tolerance test. Results Serum uric acid was positively correlated to 2-h plasma glucose and serum 1,5-AG concentrations. Serum 1,5-AG levels were not different between hyperuricemic and normouricemic subjects, though those with normouricemia had lower 2-h plasma glucose concentrations than subjects with hyperuricemia. The association between 1,5-AG and uric acid in serum was still evident after adjustment with 2-h plasma glucose concentration. Multivariate regression analyses demonstrated that serum uric acid was an independent variable related to serum 1,5-AG and vice versa. Conclusions 1,5-AG and uric acid may share in part a common renal tubular transport system, independent of glucose excretion.

To determine whether an increase in the plasma concentration of uric acid by sucrose intake is ascribable to enhanced purine degradation and/or decreased urinary excretion of uric acid, we measured the plasma concentrations of purine bases (uric acid, hypoxanthine, and xanthine) and uridine, as well as the urinary excretion of purine bases in 7 healthy subjects before and after administering sucrose at 1.5 g/kg of body weight in 2 related experiments, with and without an administration of 300 mg of allopurinol. In addition, in the control experiment without an administration of sugar and with an administration of 300 mg of allopurinol, we measured the same parameters in those 7 subjects. Without added allopurinol, sucrose increased the plasma concentration of uric acid by 11% (P

A 15-year-old boy was referred to our department due to gout. The laboratory findings showed hyperuricemia with a decreased erythrocyte hypoxanthine phosphoribosyl transferase (HPRT) activity. The HPRT cDNA sequence was revealed to be 206A>T, which has not been previously reported. In addition, direct sequencing of genomic DNA showed the patient to possess four variants reported to be associated with hyperuricemia. This is the first case report of partial HPRT deficiency due to a novel HPRT mutation accompanied by variants associated with hyperuricemia. Combination treatment consisting of benzbromarone and febuxostat had a significant effect in reducing the urate level in our patient.

We assessed the efficacy and adverse effects of febuxostat in male hyperuricemia patients.This was a 12-week, multicenter, open-label, uncontrolled study. The enrolled subjects were 89 hyperuricemic male patients (12 overexcretors, 56 normal excretors, and 21 underexcretors). The endpoint was percent change in serum urate level.The concentration of urate in serum before and 12 weeks after beginning administration of febuxostat in the overexcretors was 9.34 ± 1.48 and 5.59 ± 1.17 mg/dl, respectively, while those were 8.59 ± 1.24 and 5.41 ± 1.35 mg/dl, respectively, in the normal excretors, and 8.29 ± 1.01and 5.11 ± 1.71 mg/dl, respectively, in the underexcretors. After 12 weeks, the rate of change in serum urate after beginning administration of febuxostat was - 0.384 ± 0.186 in the overexcretors, - 0.368 ± 0.128 in the normal excretors, and - 0.365 ± 0.217 in the underexcretors, with no significant differences among them. A common adverse event related to febuxostat was gout flare.Febuxostat effectively reduced the concentration of urate in serum in hyperuricemic patients regardless of the level of uric acid excreted in urine without severe adverse effects.

To investigate the effects of exercise on the plasma concentrations and urinary excretion of purine bases and oxypurinol, we performed 3 experiments with 6 healthy male subjects. The first was a combination of allopurinol intake (300 mg) and exercise (VO2max, 70%) (combination experiment), the second was exercise alone (exercise-alone experiment), and the third was allopurinol intake alone (allopurinol-alone experiment). In the combination experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, as well as lactic acid in blood and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and oxypurinol as well as the fractional excretion of hypoxanthine, xanthine, uric acid, and oxypurinol. In the exercise-alone experiment, exercise increased the concentrations of purine bases and noradrenaline in plasma, lactic acid in blood, and the urinary excretion of oxypurines, whereas it decreased the urinary excretion of uric acid and fractional excretion of purine bases. In contrast, in the allopurinol-alone experiment, the plasma concentration, urinary excretion, and fractional excretion of purine bases and oxypurinol remained unchanged. These results suggest that increases in adenine nucleotide degradation and lactic acid production, as well as a release of noradrenaline caused by exercise, contribute to increases in plasma concentration and urinary excretion of oxypurines and plasma concentration of urate, as well as decreases in urinary excretion of uric acid and oxypurinol, along with fractional excretion of uric acid, oxypurinol, and xanthine. In addition, they suggest that oxypurinol does not significantly inhibit the exercise-induced increase in plasma concentration of urate.

A 50-year-old woman was referred to our hospital for shoulder joint stiffness. She had a history of polyclonal hypergammaglobulinemia and an elevated C-reactive protein level. Her laboratory data revealed an elevated serum immunoglobulin G4 (IgG4) level, hypergammaglobulinemia, and rheumatoid factor positivity in the absence of anticyclic citrullinated peptide antibody. [18F]-Fluorodeoxyglucose positron emission tomography showed significant [18F]-fluorodeoxyglucose uptake in multiple lymph nodes (axillary, hilar, para-aortic, and inguinal). Biopsy of the inguinal lymph node showed expansion of the interfollicular areas by heavily infiltrating plasma cells, consistent with multicentric Castleman disease (MCD). Immunohistochemical analysis revealed a 37.3% IgG4-positive:IgG-positive plasma cell ratio, indicating overlapping IgG4-related disease. However, serological cytokine analysis revealed elevated levels of interleukin-6 (9.3 pg/ml) and vascular endothelial growth factor (VEGF) (1210 pg/ml), which are compatible with MCD. Corticosteroid treatment resolved the serological and imaging abnormalities. IgG4-related disease can mimic MCD, and it is crucial to distinguish between these two diseases. Serum interleukin-6 and VEGF levels may help to discriminate MCD from IgG4-related disease.

There are many factors that contribute to hyperuricemia, including obesity, insulin resistance, alcohol consumption, diuretic use, hypertension, renal insufficiency, genetic makeup, etc. Of these, alcohol (ethanol) is the most important. Ethanol enhances adenine nucleotide degradation and increases lactic acid level in blood, leading to hyperuricemia. In beer, purines also contribute to an increase in plasma uric acid. Although rare, dehydration and ketoacidosis (due to ethanol ingestion) are associated with the ethanol-induced increase in serum uric acid levels. Ethanol also increases the plasma concentrations and urinary excretion of hypoxanthine and xanthine via the acceleration of adenine nucleotide degradation and a possible weak inhibition of xanthine dehydrogenase activity. Since many factors such as the ALDH2*1 gene and ADH2*2 gene, daily drinking habits, exercise, and dehydration enhance the increase in plasma concentration of uric acid induced by ethanol, it is important to pay attention to these factors, as well as ingested ethanol volume, type of alcoholic beverage, and the administration of anti-hyperuricemic agents, to prevent and treat ethanol-induced hyperuricemia.

Background: Uric acid is a strong scavenger of reactive oxygen species, which are known to contribute to the development of atherosclerosis, while the incidence of atherosclerotic diseases is rather high in patients with gout. Among the established risk factors for atherosclerosis, oxidized LDL is believed to play a major role in its development and progression. Allopurinol and its active metabolite, oxypurinol, have been suggested to possess an antioxidant ability to scavenge the hydroxyl radical. Therefore, allopurinol may be beneficial in the prevention of LDL oxidation, as well as in the treatment of hyperuricemia. The objective of this work was to determine the degree of LDL oxidation in gout and the effect of allopurinol on LDL oxidation. Methods: Age-matched male patients with primary intercritical gout and healthy male adults were included in the study. The serum concentrations of oxidized LDL autoantibodies and total antioxidant status were measured using an enzyme immunoassay. Results: Serum concentrations of oxidized LDL autoantibodies were significantly higher in patients with gout than the control subjects (p

A 43-year-old xanthinuric female was referred to our department because of hypouricemia. Routine laboratory data showed hypouricemia, a high level of plasma oxypurines, decreased urinary uric acid excretion, and increased urinary oxypurine excretion, with xanthine dehydrogenase activity in the duodenal mucosa below the limits of detection. In addition, allopurinol was not metabolized. From these findings, the patient was diagnosed with xanthinuria type II. To investigate the properties of xanthine dehydrogenase/xanthine oxidase (XDH/XO) deficiency, a cDNA sequence encoding XDH/XO, aldehyde oxidase (AO), and molybdenum cofactor sulferase (MCS), as well as immunoblotting analysis for XDH/XO protein, obtained from duodenal mucosa samples were performed. The XDH/XO cDNA and AO cDNA sequences of the xanthinuric patient were consistent with previously reported ones, whereas the MCS cDNA sequence revealed a point mutation of G to C in nucleotide 466, which changed codon 156 from GCC (Ala) to CCC (Pro). In addition, the MCS genomic DNA sequence including the site of the mutation revealed the same, suggesting that the xanthinuric patient was homozygous for this mutation. Such findings have not been previously reported for patients with xanthinuria type II.

To compare levels of interleukin (IL)-18, tumor necrosis factor-alpha (TNF-alpha), and IL-6 in serum, we studied 151 type 2 diabetes mellitus patients with various degrees of nephropathy, as well as 80 healthy volunteers. IL-18, TNF-alpha, and IL-6 in serum were measured using an enzyme-linked immunosorbent assay (ELISA) with the respective mouse monoclonal antibodies. Significant differences in serum levels of IL-18 and TNF-alpha were observed between the patients and control subjects (IL-18, 278.0 +/- 11.9 pg/mL v 172.8 +/- 7.7 pg/mL, P.0001; TNF-alpha, 2.41 +/- 0.18 pg/mL v 0.46 +/- 0.18 pg/mL, P.0001), whereas that of IL-6 was not different between the two groups (0.73 +/- 0.10 pg/mL v 0.65 +/- 0.08 pg/mL, difference not significant [NS]), although patients with nephropathy showed higher levels. In addition, IL-18 levels were increased in diabetic patients with the development of urinary albumin excretion, with the highest found in those with microalbuminuria (30 micro g/mg creatinine, 252.7 +/- 16.4 pg/mL; 30 to300 micro g/mg creatinine, 352.7 +/- 35.2 pg/mL;300 micro g/mg creatinine, 350.0 +/- 16.0 pg/mL). Similarly, TNF-alpha and IL-6 in diabetic patients with microalbuminuria or clinical albuminuria were significantly increased as compared with those without albuminuria (TNF-alpha, 3.20 +/- 0.41 pg/mL v 1.94 +/- 0.18 pg/mL; IL-6, 1.64 +/- 1.11 pg/mL v 0.51 +/- 0.05 pg/mL, P.05, respectively). These results suggest that serum levels of IL-18, TNF-alpha, and IL-6 may have some etiopathogenic roles in diabetic nephropathy.

To determine the effect of octreotide acetate on urinary excretion of uric acid and plasma concentration of uridine, we subcutaneously administered octreotide acetate (1 microg/kg of body weight) to 5 healthy subjects. Ninety minutes after administration, octreotide acetate increased the plasma concentration of uridine by 15% and decreased the plasma concentration of glucagon by 24% and that of insulin to below the detection limits. In addition, octreotide acetate decreased the urinary excretion of uric acid, sodium, and chloride by 60%, 40%, and 38%, respectively, at 1 hour after administration. However, octreotide acetate did not affect the concentrations of hypoxanthine, xanthine, uric acid, cyclic AMP in plasma, lactic acid and pyruvic acid in blood, urinary excretion of hypoxanthine and xanthine, or creatinine clearance. From these results, we speculated that octreotide acetate decreases the urinary excretion of uric acid by decreasing the concentration of glucagon and/or urinary excretion of sodium, and increases the plasma concentration of uridine via decreased concentrations of glucagon and insulin.

VCAP (vincristine, cyclophosphamide, doxorubicin, and prednisone)-AMP (doxorubicin, ranimustine, and prednisone)-VECP (vindesine, etoposide, carboplatin, and prednisone) is a standard regimen for aggressive adult T cell leukemia-lymphoma (ATL). However, the efficacy of this regimen has not been fully elucidated for patients aged 70 years or older. Here, we retrospectively analyzed elderly patients with aggressive ATL at Nagasaki University Hospital between 1994 and 2010 to assess treatment outcomes. Of 148 evaluable patients, 54 were aged 70 years or older at diagnosis. The median survival time (MST) and overall survival (OS) at 2 years in elderly patients were 10.6 months and 22.1 %, respectively. Thirty-four patients received VCAP-AMP-VECP as the initial treatment, although the doses were reduced for most patients. In these patients, MST and OS at 2 years were 13.4 months and 26.6 %, respectively. Eleven of 34 patients (32 %) received maintenance oral chemotherapy after two or three cycles of VCAP-AMP-VECP, and MST and OS at 2 years were 16.7 months and 32.7 %, respectively. Our results suggest that the VCAP-AMP-VECP regimen may be effective and that maintenance oral chemotherapy may be considered as a therapeutic option for elderly patients with aggressive ATL., International Journal of Hematology, 100(5), pp.464-472; 2014

A number of drugs commonly used in clinical practice can affect the serum concentration of uric acid. Some raise serum uric acid level by an increase in uric acid production or a decrease in uric acid excretion, while others lower serum uric acid level by an increase in uric acid excretion or decrease in uric acid absorption from intestine. In addition, salicylate shows so-called “biphasic effect”. At small doses it raises serum uric acid level, while at higher doses it lowers serum uric acid concentration. To understand the effects of those pharmacological agents on uric acid metabolism will help to avoid unexpected side effect of hyperuricemia and gout flare. In addition, hypouricemic property of some drugs may obviate the need for polypharmacy and improve the medication compliance.

To investigate the properties of xanthine dehydrogenase/xanthine oxidase (XDH/XO) deficiency in a patient with atypical type I xanthinuria, as indicated by oxypurine data, a cDNA sequence encoding XDH, XDH/XO immunoblot analysis and a competitive PCR assay were performed, and the results were compared with those of normal subjects. The xanthine dehydrogenase cDNA sequence of the patient was consistent with the controls, while immunologically reactive 150 kD XDH/XO protein was not present in the xanthinuric duodenal mucosa, unlike the control duodenal mucosa. In addition, a decrease in XDH/XO messenger RNA was found by competitive PCR. These results suggest that atypical type I xanthinuria is due to a decrease in messenger RNA of XDH/XO. Furthermore, it was considered that this decrease could explain the normal plasma level and near normal urinary excretion of hypoxanthine seen in this case of xanthinuria, though XDH/XO activity and protein were not detected spectrophotometrically and immunologically, respectively.

To examine whether furosemide affects the plasma concentration and urinary excretion of purine bases and oxypurinol, we administered allopurinol (300 mg) orally to 6 healthy subjects and then administered furosemide (20 mg) intravenously 10 hours later. Furosemide (20 mg) decreased the urinary excretion of uric acid by 40% (P < .01), oxypurinol by 39% (P < .05), and xanthine by 43% (P < .05) and the fractional clearance of uric acid by 45% (P < .01) and oxypurinol by 34% (P < .05) when measured 1 to 2 hours after administration. Moreover, furosemide increased the plasma concentration of uric acid by 6% at 1.5 hours after administration. These results indicate that furosemide may decrease the urinary excretion of uric acid and oxypurinol by acting on their common renal transport pathway(s). In addition, it is suggested that the effect of furosemide on oxypurinol is clinically important, since the hypouricemic effect of allopurinol may become more potent as a result.

Accurate determination of serum and urinary uric acid concentrations is essential for the diagnosis and classification of gout according to uric acid metabolism derangement. Urine and/or serum samples are often kept at either 4°C or 20°C until assayed, when a large number of samples are handled simultaneously. Our preliminary study indicated a significant decrease in urinary uric acid concentration after preservation, regardless of the storage temperature. Uric acid crystals were often observed in these cases which showed a marked decrease in urinary uric acid concentration after storage. In the present study, we sought the factor(s) that might cause this decrease in urinary uric acid concentration, as well as measures to overcome the problem. High urinary uric acid concentration and low pH proved to play major roles in the decrease in urinary uric acid concentration after storage. In contrast, dilution of the urine samples before storage resulted in no significant change in urinary uric acid concentration. Based on these results, we recommend diluting urine before storage for determination of uric acid concentration and avoiding underestimation.

To determine the effect of amino acids on the plasma level and urinary excretion of uric acid and uridine, 200 mL 12% amino acid solution, and 2 weeks later, 100 mL physiological saline solution containing glucagon (1.2 microg/kg weight), was infused into five healthy men. Both increased the urinary excretion of uric acid and the concentration of glucagon, insulin, and glucose in plasma and pyruvic acid in blood, whereas they decreased the concentration of uridine and inorganic phosphate in plasma. However, neither the amino acid infusion nor glucagon infusion affected the concentration of purine bases (hypoxanthine, xanthine, and uric acid), cyclic adenosine monophosphate (cAMP) in plasma, or lactic acid in blood or the urinary excretion of oxypurines (hypoxanthine and xanthine), uridine, or sodium. These results suggest that glucagon may have an important role in the amino acid-induced increase in urinary excretion of uric acid and decrease in plasma uridine.

To determine whether interferon-gamma affects rat purine catabolic and salvage enzyme activities, rats were injected with interferon-gamma (600000 U/kg, i.p.) and, similarly to a vehicle-injected control group, killed before or after injection at 6, 12, and 24 h. Organ homogenates were prepared and enzymatic reactions with substrates were carried out, after which the products were measured either chromatographically or spectrophotometrically. Western and Northern blotting also were performed. In contrast to the vehicle-injected rats, interferon-gamma-injected rats showed a significant rise in xanthine oxidoreductase activity in the liver, while enzyme activity was unchanged in the spleen, kidney, and lung. Western analysis of hepatic xanthine oxidoreductase showed an increased concentration of this protein 12 and 24 h after interferon-gamma injection. Northern analysis disclosed an enhanced mRNA expression coding for this enzyme, peaking 12 h after injection. Contrastingly, the activities of adenosine deaminase, purine nucleoside phosphorylase, hypoxanthine guanine phosphoribosyltransferase, and adenine phosphoribosyltransferase were not affected by interferon-gamma in any organ tested. While interferon-gamma causes an increased hepatic biosynthesis of xanthine oxidoreductase, the physiologic role of this enzyme induction remains undetermined.

To examine whether fructose and xylitol increase the plasma concentration and urinary excretion of adenosine, as well as uridine and purine bases (hypoxanthine, xanthine, and uric acid), we intravenously administered xylitol and, 2 weeks later, fructose, to five healthy subjects. Analyses of blood and urine samples obtained during these infusion studies demonstrated that fructose increased the urinary excretion of adenosine and uridine 11.9- and 105.5-fold, respectively, and caused only a small increase in the plasma concentrations of uridine and purine bases. It was further demonstrated that xylitol increased the urinary excretion of uridine 58.4-fold, with a marked increase in the plasma concentrations of purine bases and uridine but without an increase in the urinary excretion of adenosine. However, neither infusion increased the plasma concentration of adenosine. These results suggest that in addition to many organs, including the liver, fructose is significantly metabolized by an abrupt adenosine triphosphate (ATP) consumption in the kidney, leading to an increase in the urinary excretion of adenosine and uridine. They also suggest that xylitol is not significantly metabolized in the kidney.

To examine whether glucose increases the plasma concentration of purine bases and uridine, 75 g glucose was administered orally to eight healthy subjects and two patients with hyperuricemia. The plasma concentration of uridine increased by 21%, 25%, and 20% 30, 60, and 90 minutes after administration of glucose, respectively. However, urinary excretion of uridine was not affected, nor were the plasma concentrations and urinary excretion of purine bases (hypoxanthine, xanthine, and uric acid). These results suggest that the glucose-induced increase in plasma uridine was not concomitant with adenosine triphosphate (ATP) consumption—induced purine degradation, but instead was ascribable to a uridine disphosphate (UDP)-glucose consumption—induced pyrimidine degradation (UDP-glucose → UDP → uridine monophosphate [UMP] → uridine).

Sucrose is converted fructose and glucose, which may increase plasma uric acid concentration (pUA) through increased purine degradation and/or decreased uric acid (UA) excretion. To investigate effects of acarbose, an inhibitor of alpha-glucosidase, on the increased pUA from sucrose administration, we measured pUA and urinary UA excretion in 6 healthy subjects before and after administering sucrose, with and without co-administration of acarbose. Sucrose raised pUA by 10% (p < 0.01). However, excretion and fractional clearance of UA were unchanged. Sucrose and acarbose coadministration also increased pUA, but less than did sucrose alone (sucrose: 4.9 to 5.4 mg/dl; sucrose + acarbose, 4.7 to 4.9 mg/dl, p < 0.05) without changes in urinary excretion and fractional clearance of UA. Acarbose appears to attenuate the rise in pUA by sucrose ingestion by inhibiting sucrose absorption.

To determine whether xylitol increases the plasma concentration and urinary excretion of uridine together with purine bases, we administered xylitol (0.6 g/kg weight) intravenously to six normal subjects using a 10% xylitol solution. Xylitol infusion increased the plasma concentration and urinary excretion of uridine, as well as purine bases, while it decreased both the concentrations of inorganic phosphate in plasma and pyruvic acid in blood and increased the blood concentration of lactic acid. These results suggest that an increase in the plasma concentration and urinary excretion of uridine is ascribable to increased pyrimidine degradation following purine degradation induced by xylitol.

We evaluated the effect of accumulation of intraabdominal visceral fat on the metabolism of uric acid in 50 healthy male subjects to elucidate any relationship between such obesity and hyperuricemia. The area of abdominal fat (visceral fat and subcutaneous fat) was measured at the level of the umbilicus by abdominal computed tomographic scanning. Serum and urinary concentrations of uric acid and creatinine were determined with an autoanalyzer. Uric acid clearance and the ratio of urinary uric acid to creatinine excreted in urine were calculated. Univariate and multivariate analyses were used to evaluate the relationship between uric acid metabolism and body fat. The size of the area of visceral fat was significantly correlated with the serum concentration of uric acid (r = .37, P < .01), uric acid clearance (r = -.34, P < .05), and the urinary uric acid to creatinine ratio (r = .65, P < .0001). The size of the area of subcutaneous fat was significantly correlated only with the urinary uric acid to creatinine ratio (r = .38, P < .01). Multivariate analyses, including body mass index (BMI), showed that the size of the visceral fat area was the strongest contributor to an elevated serum concentration of uric acid, a decrease in uric acid clearance, and an increase in the urinary uric acid to creatinine ratio. These results suggest that accumulation of visceral fat may have a greater adverse effect on the metabolism of uric acid than BMI or accumulation of subcutaneous fat. Clearly, patients with hyperuricemia should lose weight to reduce excessive visceral fat stores, to help avoid attacks of gout.

To determine whether the plasma level of uridine can be used to identify patients with gout, the plasma concentration of uridine was determined in patients with gout and normal subjects. Plasma uridine was significantly higher in patients with gout than in normal subjects. It was also significantly higher in patients with gout of the overexcretion (of uric acid) type than in those with gout of the underexcretion type. Plasma uridine was used to classify gout patients into underexcretion and overexcretion types, with a diagnostic accuracy of 92.5%. Results indicate that the plasma uridine concentration may be a marker of uric acid production and can be used to separate hyperuricemia into the overexcretion and underexcretion types.

An assay for human plasma xanthine oxidase activity was developed with pterin as the substrate and the separation of product (isoxanthopterin) by high-performance liquid chromatography with a fluorescence detector. The reaction mixture consists of 60 microliters of plasma and 240 microliters of 0.2 M Tris-HCl buffer (pH 9.0) containing 113 microM pterin. With this assay, the activity of plasma xanthine oxidase could be easily determined despite its low activity. As a result, it could be demonstrated that the intravenous administration of heparin or the oral administration of ethanol did not increase plasma xanthine oxidase activity in normal subjects, and also that plasma xanthine oxidase activity was higher in patients with hepatitis C virus infection than in healthy subjects or patients with gout. In addition, a single patient with von Gierke's disease showed a marked increase in the plasma activity of this enzyme, relative to that apparent in normal subjects.

We evaluated the immunohistochemical localization of xanthine oxidase in various human tissues. Xanthine oxidase was purified from cadaver liver. Polyclonal antibody against xanthine oxidase was raised in a rabbit. Immunoblot analysis showed that the raised antibody reacted specifically with one band whose position corresponded with that of the purified enzyme. Immunostaining of paraffin-embedded tissue sections showed intense reactivity in the following tissues: surface epithelium of tongue, esophagus, and trachea, sweat glands, and mammary glands. Weak, but positive, reactivity was observed in other tissues, such as glandular cells of the small and large intestine and renal tubules, skeletal muscle, gastric epithelial cells, alveoli of the lung, spleen, and liver cytoplasm. Xanthine oxidase staining was observed in infiltrating lymphocytes (probably T-lymphocytes but not in B-lymphocytes) in inflammatory lesions of the small and large intestine. Its ubiquitous localization suggests that xanthine oxidase is involved in cell proliferation/differentiation, the defense mechanisms, and in the pathogenesis of reperfusion tissue injury.

A 29-year-old woman was referred to our department because of gout. Routine laboratory data showed hyperuricemia, a high level of plasma oxypurines, increased urinary uric acid excretion, and increased urinary oxypurine excretion, with decreased hypoxanthine phosphoribosyl transferase (HPRT) activity in the erythrocytes. From these findings, the patient was diagnosed with a partial deficiency of HPRT. To determine its properties, a cDNA sequence encoding HPRT and the androgen receptor AR XIST minimal promoter gene, as well as methylation of the AR gene were investigated. The HPRT cDNA sequence revealed a point mutation of G to A in nucleotide 40, which changed codon 14 from GAA (Glu) to AAA (Lys) in the mutant gene. In addition, the HPRT genomic DNA sequence, including the mutation site, revealed the same point mutation, indicating that the patient was heterozygote. Further analysis of the AR gene on the X chromosome suggested nonrandom X-chromosome inactivation, whereas the AR XIST minimal promoter gene was normal. Such results have not been previously reported in a female with partial HPRT deficiency.

A high-performance liquid chromatographic method was developed for the determination of plasma purine nucleoside phosphorylase activity. In this method, the reaction mixture consisted of 15 microliters of plasma and 285 microliters of 50 mM phosphate buffer (pH 7.4) containing 3.8 mM inosine and 0.15 mM 2-(3-cyano-4-isobutoxyphenyl)-4-methyl-5-thiazolecarboxylic acid (strong xanthine oxidase inhibitor). After the reaction, the hypoxanthine produced was monitored to express plasma purine nucleoside phosphorylase activity. By this method, the activity of purine nucleoside phosphorylase was easily determined even with a small-volume plasma sample and despite its low activity in plasma. In addition, plasma purine nucleoside phosphorylase activity can be accurately determined even if the plasma is turbid. As a result, we were able to measure plasma purine nucleoside phosphorylase activity in patients with gout or asthma and healthy subjects, whereby it was demonstrated that plasma purine nucleoside phosphorylase activity was higher in patients with asthma than in either healthy subjects or patients with gout.

OBJECTIVES--To investigate if serum Lp(a) lipoprotein (Lp(a)), a risk factor for atherosclerotic diseases, increases in patients with gout, who frequently also have atherosclerotic disease. METHODS--Fasting blood samples were taken for measurement of Lp(a) and other variables in 175 male patients with primary gout. Serum concentrations of Lp(a) were measured by enzyme linked immunosorbent assay. The median value and frequency distribution of Lp(a) in gout patients were compared with those in 172 control male subjects. In addition, we examined the effect of niceritorol on serum Lp(a) values in gout patients in whom the Lp(a) concentration was greater than 20 mg/dl. RESULTS--Serum Lp(a) was significantly higher in patients with gout than control subjects (median 15.5 mg/dl upsilon 8.6 mg/dl; p < 0.01). The frequency distribution of Lp(a) in gout was significantly shifted towards greater concentrations compared with control, although skewed distribution was noted in both groups. Serum Lp(a) concentration was not related to age, body mass index, alcohol intake, creatinine, fasting blood sugar or uric acid in patients with gout. Niceritorol decreased the serum concentrations of Lp(a) in gout. CONCLUSIONS--These observations suggest that serum Lp(a) concentrations are increased in patients with gout and may play a role as one of the risk factors for atherosclerotic diseases in gout. Niceritorol seems effective in decreasing high levels of Lp(a) in patients with gout without detrimental influence on serum uric acid concentration.

The effect of glucose infusion on renal handling of purine bases and oxypurinol was examined in 6 normal subjects. Five hundred milliliters of 1.1 M glucose solution were administered intravenously in 1 h. Fractional clearances of uric acid, xanthine and oxypurinol were significantly increased during glucose infusion, but that of hypoxanthine was not changed, while a 1-hour infusion of 500 ml of 1.1 M mannitol had no effect on the fractional clearances of purine bases and oxypurinol. These data indicate that the effect of glucose infusion on the renal clearances of uric acid, xanthine and oxypurinol was not related to osmotic diuresis but induced by glycosuria and/or hyperglycemia. Accordingly, the glycosuria- and/or hyperglycemia-induced decrease in the biological half-life of oxypurinol must be considered in the administration of allopurinol to gouty patients with uncontrolled diabetes mellitus.

BACKGROUND Although hyperuricemia is suggested to increase allantoin production in both pro- and antioxidant manners, it remains undetermined whether it increases the serum concentration of allantoin. In addition, since uric acid has both pro- and antioxidant actions, a decrease in the serum concentration of uric acid may have an effect on the pro-oxidant-antioxidant balance. METHODS To examine whether serum allantoin is correlated with serum urate, we measured those levels as well as other parameters in 63 healthy subjects. In addition, to determine whether serum allantoin is correlated with reactive oxygen species (ROS) biomarkers, we measured 8-hydroxy deoxyguanosine and 15-F2t-isoprostane, markers of ROS, in urine samples from 30 gout patients before and 1 year after benzbromarone treatment (50 mg/d). RESULTS The serum concentration of allantoin was correlated with that of urate in healthy subjects (R = 0.27, p < 0.05). Benzbromarone treatment in the patients decreased the concentrations of allantoin and urate in serum by 17% (p < 0.05) and 49% (p < 0.05), respectively, and the benzbromarone-induced change in serum allantoin was correlated with that in serum urate (R = 0.39, p < 0.05). However, benzbromarone treatment did not change the ratios of 8-hydroxydeoxyguanosine/creatinine or 15-F2t-isoprostane/creatinine in urine. CONCLUSIONS Our findings suggest that hyperuricemia contributes to an increase in serum concentration of allantoin, though they do not indicate that hyperuricemia is a major factor for controlling oxidative stress in vivo.

Objective Although allopurinol is a xanthine oxidase inhibitor, its overall effect may be due to the action of oxypurinol, a metabolite of allopurinol and another xanthine oxidase inhibitor, since the biological half-life of oxypurinol is longer than that of allopurinol. Oxypurinol shares a renal transport pathway with uric acid and ingestion of bovine milk increases the urinary excretion of uric acid. Therefore, we investigated whether its ingestion promotes the urinary excretion of oxypurinol. Subjects/methods Bovine milk (15 ml/kg body weight) was administered to 6 healthy subjects who took allopurinol (300 mg) 12 h prior to ingestion. In addition, a control experiment was performed with the same subjects using the same protocol, except for the ingestion of water instead of bovine milk. Blood and urine samples were collected before and after bovine and water ingestion. Results In the bovine milk ingestion experiment, the urinary excretion values of oxypurinol and uric acid were increased by 18% and 38%, respectively, and the fractional excretion values of oxypurinol and uric acid were increased by 20% and 40%, respectively, whereas those did not change in the control experiment. In addition, the concentration of alanine and sum of concentrations of amino acids were increased by 16% and 20%, respectively, in the bovine milk ingestion experiment. Conclusion These results suggest that bovine milk ingestion promotes the urinary excretion of oxypurinol as well as uric acid by increasing amino acid concentration.

OBJECTIVE C-reactive protein (CRP) is associated with increased risk for myocardial infarction, atherosclerosis, and peripheral artery diseases, while increased serum uric acid level is suggested to be independently associated with an increased risk of cardiovascular mortality. Accordingly, to investigate whether hyperuricemia is associated with serum CRP, we compared serum CRP levels between healthy subjects and patients with gout. In addition, we also examined whether benzbromarone has effects on serum CRP levels in patients with gout and the expression of CRP messenger RNA of CRP in the hepatoma cell line HuH7. METHODS In the first experiment, 40 healthy males and 43 male patients with gout were enrolled, then blood samples were drawn from each after an overnight fast. In the second experiment, 42 male patients with gout were given uric acid-lowering therapy with benzbromarone. Blood samples were drawn after an overnight fast before and 1 year after beginning benzbromarone treatment. In the third experiment, the effects of benzbromarone on IL1beta-induced CRP expression were determined in HuH7 cells. RESULTS Log serum CRP levels were not significantly different between the patients with gout and healthy subjects, while log serum CRP levels were decreased by 11% after benzbromarone treatment, as compared to the values before treatment (p < 0.01). In addition, log serum adiponectin levels were elevated by 2% after treatment (p < 0.01). Furthermore, our in vitro findings demonstrated that benzbromarone down-regulated IL1beta-stimulated CRP gene expression. CONCLUSIONS These results suggest that hyperuricemia may not contribute to an increase in serum CRP level, while benzbromarone may have a favorable effect on CRP.

Uridine is a pyrimidine nucleoside that plays a crucial role in synthesis of RNA, glycogen, and biomembrane. In humans, uridine is present in plasma in considerably higher quantities than other purine and pyrimidine nucleosides, thus it may be utilized for endogenous pyrimidine synthesis. Uridine has a number of biological effects on a variety of organs with or without disease, such as the reproductive organs, central and peripheral nervous systems, and liver. In addition, it is used in clinical situations as a rescue agent to protect against the adverse effects of 5-fluorouracil. Since the biological actions of uridine may be related to its plasma concentration, it is important to examine factors that have effects on that concentration. Factors associated with an increase in plasma concentration of uridine include enhanced ATP consumption, enhanced uridine diphosphate (UDP)-glucose consumption via glycogenesis, inhibited uridine uptake by cells via the nucleoside transport pathway, increased intestinal absorption, and increased 5-phosphribosyl-1-pyrophosphate and urea synthesis. In contrast, factors that decrease the plasma concentration of uridine are associated with accelerated uridine uptake by cells via the nucleoside transport pathway and decreased pyrimidine synthesis.

Allopurinol or pyrazinamide was administered to rats treated with BOF-4272 (a potent xanthine oxidase inhibitor) to investigate to what degree xanthine dehydrogenase participates in the oxidation of these agents. BOF-4272 markedly decreased the plasma concentration and the urinary excretion of both oxypurinol and 5-hydroxypyrazinamide. It also decreased the sum of the urinary excretion of allopurinol and oxypurinol and that of pyrazinamide and its metabolites, although it did not affect the sum of the plasma concentrations of allopurinol and oxypurinol at 105 min after administration of allopurinol or the plasma concentration of pyrazinamide during the period after the administration of pyrazinamide. These results suggested that BOF-4272 almost completely inhibited the oxidation of allopurinol and pyrazinamide and had some effect on the excretion and/or the tissue incorporation of these two compounds. Since the in vitro study demonstrated that BOF-4272 did not inhibit the activity of aldehyde oxidase, which oxidized both allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide, the results suggested that xanthine dehydrogenase was the more important enzyme in converting allopurinol to oxypurinol and pyrazinamide to 5-hydroxypyrazinamide.

Aldehyde oxidase was purified about 120-fold from rat liver cytosol by sequential column chromatography using diethylaminoethyl (DEAE) cellulose, Benzamidine-Sepharose 6B and gel filtration. The purified enzyme was shown as a single band with M(r) of 2.7 x 10(5) on polyacrylamide gel electrophoresis (PAGE) and M(r) of 1.35 x 10(5) on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Using this purified enzyme, in vitro conversion of allopurinol, pyrazinamide and pyrazinoic acid was investigated. Allopurinol and pyrazinamide were oxidized to oxypurinol and 5-hydroxy-pyrazinamide, respectively, while pyrazinoic acid, the microsomal deamidation product of pyrazinamide, was not oxidized to 5-hydroxypyrazinoic acid. The apparent Km value of the enzyme for pyrazinamide was 160 microM and that for allopurinol was 1.1 mM. On PAGE, allopurinol- or pyrazinamide-stained band was coincident with Coomassie Brilliant Blue R 250-stained band, respectively. These results suggest that aldehyde oxidase may play a role in the oxidation of allopurinol to oxypurinol and that of pyrazinamide to 5-hydroxypyrazinamide with xanthine dehydrogenase which can oxidize both allopurinol and pyrazinamide in vivo. The aldehyde oxidase may also play a major role in the oxidation of allopurinol and pyrazinamide in the subgroup of xanthinuria patients (xanthine oxidase deficiency) who can oxidize both allopurinol and pyrazinamide.

The effect of ethanol on nucleotides and glycolytic intermediates in erythrocytes and purine bases in plasma and urine was investigated. Ethanol ingestion (0.45 mL/kg body weight) increased plasma concentrations and urinary excretion of oxypurines (hypoxanthine and xanthine) and concentrations of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and glyceraldehyde 3-phosphate+dihydroxyacetonephosphate in erythrocytes. In an in vitro incubation study using erythrocytes, acetaldehyde increased the concentrations of AMP, ADP, and glyceraldehyde 3-phosphate+dihydroxyacetonephosphate in erythrocytes as well as the concentration of hypoxanthine in the incubation medium. These results suggest that acetaldehyde (a metabolite of ethanol) induces an increase in purine degradation by erythrocytes and then contributes to the ethanol-induced enhanced purine degradation in vivo.

To investigate whether or not lactic acid inhibits the renal transport of oxypurines and oxypurinol, we administered physiological saline containing 0.2 mol sodium lactate to 5 normal subjects intravenously. Lactate infusion decreased the fractional clearance of uric acid, but the fractional clearances of hypoxanthine, xanthine and oxypurinol were not affected. These results suggest that uric acid and lactic acid share the renal transport system of organic acids but hypoxanthine, xanthine and oxypurinol do not. It is further suggested that allopurinol treatment is reasonable in subjects with hyperuricemia accompanied by hyperlactatemia since only the urinary excretion of uric acid and not oxypurines (hypoxanthine and xanthine) was inhibited by lactate infusion.

It has been demonstrated that uridine infusion induces insulin resistance in rats. Furthermore, it was recently reported that plasma uridine is correlated with homeostasis model assessment of insulin resistance (HOMA-R) in hypertensive patients. Therefore, we investigated whether plasma uridine was correlated with HOMA-R in patients with non-insulin-dependent diabetes mellitus (NIDDM).The subjects were 23 male patients with NIDDM (average age 63 years) and 18 healthy males (average age 60 years). Blood samples were drawn after an overnight fast, plasma uridine was then measured using high-performance liquid chromatography.The average plasma uridine concentration in patients with NIDDM was higher than that in healthy subjects (P0.05). Furthermore, plasma uridine values were positively correlated with HOMA-R (r = 0.48, P0.05), serum insulin (r = 0.46, P0.05), and serum C-peptide radioimmunoreactivity (CPR) (r = 0.44, P0.05) values, whereas they were not significantly correlated with fasting blood glucose or hemoglobin A1c values.We found a positive relationship between plasma uridine value and HOMA-R, serum insulin, and CPR, suggesting that plasma uridine is a marker of insulin resistance in patients with NIDDM.

Gout patients are frequently complicated with hypertension, obesity, dyslipidemia, and/or impaired glucose tolerance, which are components of the metabolic syndrome and risks for atherosclerotic diseases.To determine the relationship between metabolic syndrome and gout, as well as plasma concentrations of adipocytokines in gout patients.The frequency of metabolic syndrome as well as its constituents were investigated in 258 male gout patients and 111 males who attended an annual check-up examination. In addition, plasma concentrations of adipocytokines were measured in 107 of the patients.Gout patients had a higher prevalence of metabolic syndrome as compared with the controls (36.4% vs. 15.3%, P0.0001). In addition, frequencies of individual metabolic abnormalities, such as waist circumference85 cm, hypertension, and hypertriglyceridemia, were significantly increased in the gout patients as compared with the controls. Furthermore, uric acid over-production gout had a significantly higher prevalence of metabolic syndrome as compared with uric acid under-excretion gout (48.6% vs. 32.4%, P0.001). The plasma concentrations of leptin and plasminogen activator inhibitor-1 were significantly higher in the patients (P0.05, respectively), while that of adiponectin and the adiponectin/leptin ratio were significantly decreased in the gout patients as compared with the controls (P0.05, respectively).A higher prevalence of metabolic syndrome in gout patients may in part contribute to susceptibility to atherosclerotic diseases. Therefore, more attention should be paid to the presence of metabolic syndrome in gout patients to reduce their risk for cardiovascular disease complications.

We performed mutational analyses of a woman patient with congenital nephrogenic diabetes insipidus referred to us during pregnancy. The diagnosis was made during the neonatal period, after which she was treated with spironolactone and hydrochlorothiazide. Our examination showed the patient to be apparently in good health without definite evidence of dehydration. Serum and urine osmolality were 220 mOsm/L and 50 mOsm/L, respectively, and the serum concentration of AVP was 2.7 pg/mL. Results of a water-deprivation test performed after delivery were compatible with nephrogenic diabetes insipidus. Mutational analyses showed that the patient was a compound heterozygote with point mutations at nucleotide position 298 (G to A; G100R) in exon 1 and nucleotide position 374 (C to T; T125M) in exon 2 of the aquaporin 2 gene, which have been previously described.

As compared with other alcoholic beverages, beer contains considerable amounts of purines, which high-performance liquid chromatography has shown to consist of purine nucleosides and bases. According to that analysis, the nucleoside guanosine was most abundant, as compared with other types of purines. Purine ingestion causes an increased production of uric acid, leading to an increase in the serum concentration of urate. According to the results of a study on nucleic acid ingestion, the serum concentration of urate was increased to a greater degree in patients with hyperuricemia or gout than in normal subjects. In addition, the serum concentration of urate was increased by ingestion of nucleotides (adenosine monophosphate (AMP), guanosine monophosphate, and inosine monophosphate (IMP)) and purine bases (adenine, hypoxanthine, xanthine) in all three subject groups, while it was shown that hypoxanthine, AMP, and IMP had greater hyperuricemic effects on patients with gout than those with hyperuricemia and the normal subjects. The effects of guanosine (the most plentiful purine in beer) on the serum urate levels were not examined in previous human studies. However, since it was found that guanosine was more readily absorbed than other nucleosides, nucleotides, or bases and rapidly converted to uric acid via guanine and xanthine in animals, it is suggested that its ingestion may increase the serum concentration of urate. Since purines in beer have a clinical effect on serum urate and augment hyperuricemic effect in patients with gout, it is important for those patients to refrain from consuming large amounts of beer that contains considerable amounts of purines.

Increased adenosine triphosphate (ATP) degradation and diminished uric acid elimination are considered to be the major causes of alcohol-induced hyperuricemia. In addition, the ingestion of beer, which contains considerable amounts of various purines that might augment the hyperuricemic effect of alcohol, may lead to a greater increase in the plasma concentration of uric acid than other alcoholic beverages. A clinical study of the effects of beer drinking on plasma concentration and urinary excretion of oxypurine (hypoxanthine and xanthine, precursors of uric acid) clearly showed that increased ATP degradation followed beer ingestion. However, freeze-dried beer, which contains no alcohol, and low-malt beer also increased the plasma concentration of uric acid, while purine-free low-malt beer did not, which clearly indicated that the purines present in beer cause an increase in the plasma concentration of uric acid. Further, epidemiological studies and experiments regarding the effects of long-term beer drinking have shown that beer has a deleterious effect on serum uric acid concentration. Therefore, patients with gout should be encouraged to refrain from drinking large amounts of beer regularly.

Urinary excretion of uric acid was found to be extremely low in a 58-year-old female patient with alcaptonuria. This was due to interference with the uricase-peroxidase method used, because analysis using high-performance liquid chromatography (HPLC) showed a normal urinary concentration of uric acid. In vitro experiments demonstrated that a high concentration of homogentisic acid in the patient's urine inhibited the peroxidase reaction, possibly due to inhibition of the colour development of 3-methyl- N-ethyl- N-(β-hydroxyethyl)aniline (MEHA) and 4-aminoantipyrine, via the peroxidase reaction. A homogentisic acid concentration equivalent to that in plasma did not affect the uricase-peroxidase reaction. This result suggests that any assay based on a peroxidase method is affected by a high urinary concentration of homogentisic acid in patients with alcaptonuria.