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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

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 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 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.

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 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).

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.

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.

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.