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PubMed1984

Purine metabolism and urate biosynthesis in isolated chicken hepatocytes.

The metabolism of some purine compounds to urate and their effects on de novo urate synthesis in chicken hepatocytes were investigated. The purines, listed in descending order of rates of catabolism to urate, were hypoxanthine, xanthine, inosine, guanosine, guanine, IMP, GMP, adenosine, AMP, and adenine. During a 1-h incubation period, conversion to urate accounted for more than 80% of the total quantities of guanine, guanosine, and inosine metabolized, but only 42% of the adenosine and 23% of the adenine metabolism. Adenine, adenosine, and AMP inhibited de novo urate synthesis [( 14C]formate incorporation into urate), whereas the other purines, especially guanine, guanosine, and GMP, stimulated de novo urate synthesis. When hepatocytes were incubated with glutamine and adenosine, AMP, guanine, guanosine, or GMP, the rates of de novo urate synthesis were lower than the additive effects of glutamine and the purine in separate incubations. Increasing phosphate concentrations had no effect on urate synthesis in the absence of added purines but, in combination with adenosine, AMP, guanosine, or GMP, increased urate synthesis. These results indicate that the ratio of adenine to guanine nucleotides and the interaction between substrates and purine nucleotides are involved in the regulation of urate biosynthesis in chicken liver.

Adenine↗

PubMed2005

Kinetic studies of copper-induced oxidation of urate, ascorbate and their mixtures.

Urate and ascorbate are the major water-soluble low molecular weight antioxidants in serum. Much attention has been devoted to the effect of these antioxidants on lipoprotein peroxidation in vivo and on their effect on copper-induced peroxidation ex vivo. These studies revealed that urate inhibits ascorbate oxidation in vitro, whereas the effect of ascorbate on urate oxidation has not been systematically studied thus far. The present study addresses mechanistic aspects of the kinetics of copper-induced oxidation of both these antioxidants and their mutual effects in aqueous solutions. We found that: (i) ascorbate becomes oxidized much faster than urate. (ii) Urate inhibits the oxidation of ascorbate but, even in the presence of excess urate, ascorbate becomes oxidized much faster than urate. (iii) Ascorbate, as well as the products of its oxidation (and/or hydrolysis) inhibit the copper-induced oxidation of urate. All these results are consistent with the hypothesis that the rate of ascorbate oxidation is determined by the rate of reoxidation of reduced copper (Cu(I)) to Cu(II) by molecular oxygen, whereas the rate of urate oxidation is governed by the rate of oxidation of urate within a 2:1 urate/copper complex. We think that the mutual effects of urate and ascorbate on each other's oxidation are likely to enhance their inhibitory effect on lipid peroxidation in biologically relevant systems including membranes and lipoproteins.

Antioxidants↗

PubMed2002

Urate homeostasis in polycystic kidney disease: comparison with chronic glomerulonephritic kidney.

Autosomal dominant polycystic kidney disease (ADPKD) might affect urate homeostasis and clearance. Renal tubular urate transport was studied by means of probenecid (PB) and pyrazinamide (PZA) tests in individuals with ADPKD and normal renal function as well as various degrees of renal failure (49 patients). Comparisons were made between polycystic and chronic glomerulonephritic kidney (CGNK), as well as with controls (men with normal renal function). Patients with ADPKD and normal renal function showed plasma urate levels within normal range and normal renal urate handling. In contrast higher plasma urate levels comparing to controls were found in patients with CGNK and normal renal function. During the evolution of renal failure ADPKD patients showed lower urate plasma levels and higher renal clearance as well as, fractional urate excretion, comparing to CGNK patients with the same degree of renal failure. In conclusion patients with ADPKD and normal renal function have normal urate handling and plasma urate levels within normal range. With increasing severity of disease and during evolution of renal failure CGNK patients showed higher urate plasma levels and lower clearances comparing to ADPKD patients. When renal disease becomes more advanced there was no difference in renal urate handling between ADPKD and CGNK patients.

Chronic Disease↗

PubMed2004

Anti- and pro-oxidant effects of quercetin in copper-induced low density lipoprotein oxidation. Quercetin as an effective antioxidant against pro-oxidant effects of urate.

We recently reported that, depending on its concentration, urate is either a pro- or an antioxidant in Cu(2+)-induced low-density lipoprotein (LDL) oxidation. We also previously demonstrated an antioxidant synergy between urate and some flavonoids in the Cu(2+)-induced oxidation of diluted serum. As a result, the effect of the flavonoid quercetin on the Cu(2+)-induced oxidation of isolated LDL has been studied either in the presence or absence of urate. We demonstrate that, like urate, quercetin alone, at low concentration, exhibits a pro-oxidant activity. The pro-oxidant behavior depends on the Cu(2+) concentration but it is not observed at high Cu(2+) concentration. When compared with urate, the switch between the pro- and the antioxidant activities occurs at much lower quercetin concentrations. As for urate, the pro-oxidant character of quercetin is related to its ability to reduce Cu(2+) with the formation of semioxidized quercetin and Cu(+) with an expected yield larger than that obtained with urate owing to a more favorable redox potential. It is also shown that the pro-oxidant activity of urate can be inhibited by quercetin. An electron transfer between quercetin and semioxidized urate leading to the repair of urate could account for this observation as suggested by recently published pulse radiolysis data. It is anticipated that the interactions between quercetin-Cu(2+)-LDL and urate, which are tightly controlled by their respective concentration, determine the balance between the pro- and antioxidant behaviors. Moreover, as already observed with other antioxidants, it is demonstrated that quercetin alone behaves as a pro-oxidant towards preoxidized LDL.

Alkenes↗

PubMed1980

Urate secretion in isolated rabbit renal tubules.

The flux of radioactive urate from bath to lumen was measured in isolated proximal convoluted (PCT), proximal straight (PST), and cortical collecting tubules (CCT). Urate was secreted in the PST as evinced by a) accumulation of urate in the lumen of perfused tubules to levels 2-4 times greater than in the bath, and b) inhibition of urate flux (bath to lumen) by cooling, by probenecid (2.5 X 10(-4) M), and by ouabain (10(-4) M). Urate secretion was strongly dependent on the rate of urinary flow, diminishing as flow rate was reduced below 2 nl/min, and reaching maximal rates when flow exceeded 5 nl/min. The isotopic urate (either [2-14C]urate or [6-14C]urate) was secreted without modification. Luminal urate was not impressively elevated above the concentration of the bath in PCT. Cortical collecting tubules were relatively impermeable to urate. It is concluded that urate secretion occurs predominantly in the PST of this species by a mechanism dependent on the uphill transport of the molecule from the bath into the urine.

Animals↗

PubMed1983

Evidence for an inhibitor of renal urate and PAH secretion in rabbit blood.

Results of previous studies of urate secretion in isolated perfused S2 segments of the rabbit proximal tubule suggested that a bath of rabbit serum may inhibit urate transport in comparison to a synthetic medium. In the current study we tested for a urate transport inhibitor by determining the steady-state tissue-to-medium ratio (T/M) of [14C]urate in nonperfused S2 segments during incubation in synthetic medium (BSA-Burg) and commercial rabbit serum (RS-PF). With 80-120 microM urate in the bath the T/M ratio was 7.66 +/- 0.53 (n = 29) in BSA-Burg and 5.29 +/- 0.40 (n = 29) in RS-PF. RS-PF decreased the influx of urate into the cells but had no effect on urate efflux. Freshly drawn rabbit serum and plasma also inhibited urate accumulation, and the inhibition was reversible. p-Aminohippurate accumulation was inhibited by RS-PF, but tetraethylammonium bromide uptake was not. RS-PF inhibited transepithelial secretion of urate and PAH, but net fluid absorption was not decreased. The inhibitory material in rabbit serum could not be removed by extensive dialysis (14,000-dalton exclusion), by ultrafiltration (50,000-dalton exclusion), or by charcoal or ethanol extraction. Inhibitory activity was detected in both albumin and globulin fractions of rabbit serum. The relation between bath and intracellular urate concentrations of nonperfused tubules in rabbit serum was sigmoidal, whereas the relation in the BSA-Burg medium was more nearly hyperbolic. We conclude that organic anion transport in rabbit S2 segments is inhibited or suppressed by normal serum and suggest that urate secretion and excretion may be subject to allosteric modification by serum proteins.

Aminohippuric Acids↗

PubMed1994

Urate transport in brush-border membrane of human kidney.

Mechanisms of urate transport were investigated in human renal brush-border membrane vesicles. The imposition of an outwardly directed Cl- gradient, in voltage-clamp and pH-clamp conditions, stimulated [14C]urate uptake. Organic anions, including pyrazinoate (PZA), probenecid, lactate, ketone bodies, succinate, and alpha-ketoglutarate in their monovalent forms, cis-inhibited [14C]urate uptake. The affinity order was PZA > urate > probenecid > other anions. Vesicle preloading with these anions trans-stimulated urate uptake. These observations demonstrate the presence of a urate/anion exchanger. p-Aminohippurate and OH- were not substrates for this exchanger. In the presence of an inwardly directed K+ gradient and valinomycin (intravesicular positive potential) [14C]urate uptake was stimulated. Voltage-sensitive [14C]urate uptake was cis-inhibited by organic anions in the following affinity order: urate > probenecid > PZA. The differences in affinity orders for the urate exchanger and the urate voltage-sensitive transport suggest different pathways for apical transport. The anion exchanger might be the main mechanism involved in urate tubular reabsorption in humans.

3-Hydroxybutyric Acid↗

PubMedDate not supplied

Effect of pyrazinamide and probenecid on peritoneal urate transport kinetics during continuous ambulatory peritoneal dialysis.

OBJECTIVE: We administered pyrazinamide (PZA) and probenecid (PB) --two well-known modulators of urate transport via the proximal tubules - to evaluate their impact on urate transport through the peritoneal membrane and to clarify mechanisms affecting peritoneal transport. SETTING: A continuous ambulatory peritoneal dialysis (CAPD) unit in 2nd Hospital of IKA (Social Services Institute), Greece. PATIENTS: In 20 stable CAPD patients, on the study day, a 4-hour, 2-L, 1.36% glucose exchange was performed (control exchange). Pyrazinamide 3 g was given orally and another identical exchange was performed (study exchange). The same protocol was repeated with 2 g PB. KtN, peritoneal clearances of urea, creatinine, and urate for each exchange, and mass transfer area coefficients (MTAC) for the three solutes and their dialysate-to-plasma concentration (D/P) ratios were used to estimate peritoneal transport. RESULTS: Administration of PZA resulted in decreased clearances and MTAC values for the three solutes. The D/P ratio decreased significantly only for urate, indicating a more intense influence of PZA on urate. After PB administration, clearances of urea, creatinine, and urate were increased. MTAC and DIP ratio increased significantly only for urate (p < 0.05), demonstrating an action similar to that exerted on renal tubules. CONCLUSIONS: These findings provide evidence that unrestricted diffusion is not the only transport mechanism in the case of urate, and demonstrate the existence of an active mechanism in peritoneal urate transport with a reabsorptive and, probably, a secretive component that resembles that of renal tubule urate transport. Attention should be given in the case of CAPD patients undergoing antituberculous (PZA) treatment: it might have a negative impact on urea, creatinine, and urate peritoneal transport rates.

Female↗

PubMed1989

Urate oxidase: primary structure and evolutionary implications.

Urate oxidase, or uricase (EC 1.7.3.3), is a peroxisomal enzyme that catalyzes the oxidation of uric acid to allantoin in most mammals. In humans and certain other primates, however, the enzyme has been lost by some unknown mechanism. To identify the molecular basis for this loss, urate oxidase cDNA clones were isolated from pig, mouse, and baboon, and their DNA sequences were determined. The mouse urate oxidase open reading frame encodes a 303-amino acid polypeptide, while the pig and baboon urate oxidase cDNAs encode a 304-amino acid polypeptide due to a single codon deletion/insertion event. The authenticity of this single additional codon was confirmed by sequencing the mouse and pig genomic copies of the gene. The urate oxidase sequence contains a domain similar to the type 2 copper binding motif found in other copper binding proteins, suggesting that the copper ion in urate oxidase is coordinated as a type 2 structure. Based upon a comparison of the NH2-terminal peptide and deduced sequences, we propose that the maturation of pig urate oxidase involves the posttranslational cleavage of a six-amino acid peptide. Two nonsense mutations were found in the human urate oxidase gene, which confirms, at the molecular level, that the urate oxidase gene in humans is nonfunctional. The sequence comparisons favor the hypothesis that the loss of urate oxidase in humans is due to a sudden mutational event rather than a progressive mutational process.

Amino Acid Sequence↗

PubMed1994

Isolation and immunolocalization of a rat renal cortical membrane urate transporter.

Two modalities of urate transport have been reported in rat kidney, a urate/anion exchanger and a potential sensitive, uricase-like uniporter. As an initial attempt to isolate and characterize the responsible transport protein(s), rat renal cortical membranes were harvested, solubilized, and subjected to affinity chromatography with urate or xanthine as the affinity ligand. Pig liver peroxisomal uricase was purified with the same system, and the enzymatically active protein was used to generate polyclonal antibodies in rabbit. Silver stain of SDS-polyacrylamide gel electrophoresis gels of the eluted fraction containing the affinity-purified renal membrane protein(s) demonstrated bands at 25, 32, 36, and 41 kDa. On Western blot, two of these bands (32 and 36 kDa) were immunoreactive to the polyclonal antibody to pig liver uricase. In 6 of 10 studies, the affinity-purified renal membrane protein(s) also oxidized urate. Anti-pig liver uricase produced a selective and dose-dependent inhibition of the uricase-like urate uniporter in renal membrane vesicles, but did not affect the urate/anion exchanger or the sodium-dependent glucose transporter. Immunocytochemical studies of rat renal cortex with the same antibody indicated that the immunoreactivity was localized to proximal tubules. These studies demonstrate that the renal cortical plasma membranes contain urate-binding proteins, which have some functional and immunological homology to the hepatic peroxisomal core protein, uricase. Within the renal cortex, these proteins are localized to proximal tubules, the site of urate transport. Since the antibody that reacts with the affinity-purified urate-binding proteins on Western blot selectively inhibits urate transport in intact membrane vesicles, it is concluded that at least one of the affinity-purified urate-binding proteins is a uricase-like urate transporter.

Animals↗

PubMed1995

Functional expression and peroxisomal targeting of rat urate oxidase in monkey kidney cells.

Humans and hominoid primates lack the enzyme urate oxidase, which catalyzes the oxidation of uric acid to allantoin. In rats and most other mammals, urate oxidase is present as a crystalloid core within the peroxisomes of liver parenchymal cells. To determine whether functionally active recombinantly expressed urate oxidase can be targeted to the peroxisome as well as display the crystalloid core-like structure, we expressed rat urate oxidase cDNA in African green monkey kidney cells (CV-1 cells) under the control of a cytomegalovirus promoter. Cell lines stably expressing urate oxidase were isolated. Northern blot analysis revealed a 1.3-kb transcript and immunoblot analysis confirmed the presence of urate oxidase in the stably transfected cells. The recombinant urate oxidase expressed in CV-1 cells was functionally active. Immunofluorescence microscopy revealed that the expressed protein was visualized as discrete granules in the cytoplasm. Electron microscopy and immunocytochemical localization studies showed that the recombinantly expressed protein formed distinct crystalloid core structures with bundles of tubules within single membrane limited cytoplasmic organelles. On cross section, the recombinant urate oxidase tubular structures are arranged as circles of 10 surrounding a slightly larger circle. This arrangement is reminiscent of urate oxidase-containing cores in rat liver peroxisomes. Immunocytochemical studies confirmed that the recombinantly expressed urate oxidase is correctly targeted to the catalase-containing peroxisomes in these CV-1 cells.

Allantoin↗

PubMed2002

Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout.

OBJECTIVE: The optimal serum urate levels necessary for elimination of tissue deposits of monosodium urate in patients with chronic gout is controversial. This observational, prospective study evaluates the relationship between serum urate levels during therapy and the velocity of reduction of tophi in patients with chronic tophaceous gout. METHOD: Sixty-three patients with crystal-confirmed tophaceous gout were treated with allopurinol, benzbromarone, or combined therapy to achieve serum uric acid levels less than the threshold for saturation of urate in tissues. The tophi targeted for evaluation during followup were the largest in diameter found during physical examination. RESULTS: Patients taking benzbromarone alone or combined allopurinol and benzbromarone therapy achieved faster velocity of reduction of tophi than patients taking allopurinol alone. The velocity of tophi reduction was linearly related to the mean serum urate level during therapy. The lower the serum urate levels, the faster the velocity of tophi reduction. CONCLUSION: Serum urate levels should be lowered enough to promote dissolution of urate deposits in patients with tophaceous gout. Allopurinol and benzbromarone are equally effective when optimal serum urate levels are achieved during therapy. Combined therapy may be useful in patients who do not show enough reduction in serum urate levels with single-drug therapy.

Adult↗

PubMed1985

Effects of SITS on urate transport by isolated, perfused snake renal tubules.

Effects of an inhibitor of membrane anion-exchange transport processes, 4-acetamido-4'-isothiocyano-2,2'-disulfonic stilbene (SITS), on urate transport by isolated, perfused snake (Thamnophis spp.) proximal renal tubules were studied. SITS (10(-4) mol/l) in the luminal perfusate had absolutely no effect on net urate secretion (Jneturate) or on net fluid absorption (JV). This observation is compatible with other data that give no support to the concept of a mediated transport step for urate from the cells to the lumen. SITS (10(-4) mol/l) in the bathing medium reversibly inhibited Jneturate without affecting JV. At the time of maximum inhibition of Jneturate, the concentration of urate in the cell water was increased and the apparent permeability of the luminal membrane to urate was decreased, but the urate efflux across the peritubular membrane and the apparent permeability of the peritubular membrane to urate were unchanged. There was no evidence of significant intracellular binding or trapping of urate. Although an increase in the initial rate of urate transport into the cells across the peritubular membrane could not be demonstrated conclusively in nonperfused tubules, the results still suggest that SITS in the bathing medium may inhibit Jneturate by inhibiting urate movement from the cells to the lumen while actually enhancing transport from the bathing medium into the cells.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed1986

Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate.

The serum urate concentration of adult women, which is lower than in men of a similar age, is thought to be related to a higher renal clearance of urate in women, possibly due to their higher plasma estrogen levels. Intersexual differences in the renal handling of uric acid was assessed in 9 normal adult women and 9 normal age-matched men. Women showed a significantly lower serum urate concentration as compared to men (3.5 +/- 0.3 v 4.9 +/- 0.7 mg/dL, P less than 0.001), higher fractional excretion of urate (9.8 +/- 1.0 v 7.3 +/- 0.8%, P less than 0.001), and significantly lower tubular urate postsecretory reabsorption (67.2 +/- 1.6 v 76.6 +/- 1.4% of secreted urate, P less than 0.01). To test whether plasma E2 has a uricosuric effect we administered estradiol valerate and estradiol benzoate to either oophorectomized or adult women. Plasma E2 levels and urinary total estrogen excretion increased significantly in both groups but the treatment failed to significantly modify serum urate or the fractional excretion of uric acid. Furthermore, in 4 normal adult women, the tubular phases that modulate the renal excretion of urate were not significantly influenced by increased plasma E2 levels. We conclude that in comparison to men of a similar age, the lower tubular urate postsecretory reabsorption of adult women is in accordance with the intersexual differences in uric acid metabolism. Plasma E2 does not influence renal handling of uric acid or serum urate levels.

Absorption↗

PubMed1986

Etiopathogenesis of uric acid and ammonium urate uroliths in non-Dalmatian dogs.

The etiopathogenesis of uric acid, sodium acid urate, and ammonium acid urate uroliths in non-Dalmatian dogs appears to be a complex phenomenon. It may involve one or more pathologic and/or physiologic processes acting independently or in concert to increase urinary concentration of lithogenic substances that result in initiation, growth, and retention of urate uroliths. Increased urine uric acid concentration and/or urinary excretion of uric acid appear to be primary predisposing factors in urate lithogenesis. Specific disorders resulting in hyperuricuria may involve abnormalities of increased synthesis, diminished biodegradation, and/or enhance excretion of uric acid. In addition, ammonium ion, hydrogen ion, and other organic and inorganic urine constituents appear to have major influences on urate urolith formation. Unfortunately, many specific disorders of uric acid metabolism and other factors promoting or inhibiting urate urolith formation remain poorly characterized in the majority of non-Dalmatian dogs with urate urolithiasis. Growing awareness of the significance of urate uroliths in non-Dalmatian dogs should encourage further investigation into the identification, characterization, and quantitation of parameters influencing urate lithogenesis. Results of such studies are required for development of practical and effective strategies for treatment and prevention of canine urate urolithiasis.

Animals↗

PubMed2000

Antioxidative activity of urate in bovine milk.

The antioxidative effects of urate on peroxidase-induced protein oxidation and light-induced riboflavin degradation and lipid oxidation in whole milk were studied. In addition, experiments using ascorbate were conducted to directly compare the antioxidative activity of urate and ascorbate. The presence of urate and/or ascorbate (10-30 mg/L) lowered peroxidase-induced formation of dityrosine by 44-96% in unpasteurized whole milk. No synergistic effect of urate and ascorbate on peroxidase-induced dityrosine formation was registered, but merely an additive effect. Light exposure of pasteurized whole milk showed that ascorbate was oxidized at the expense of urate, which indicated ascorbate-mediated recycling of the urate radical. Moreover, both urate and ascorbate (30 mg/L) retarded light-induced lipid oxidation in pasteurized whole milk as measured by formation of lipid hydroperoxides with urate being the most effective (28% reduction in lipid hydroperoxides) compared with ascorbate (14%). Finally, addition of urate or ascorbate (300 mg/L) to pasteurized whole milk showed a slight protective effect against light-induced degradation of riboflavin with urate being the most effective.

Animals↗

PubMed2002

Effect of urate on nitric oxide microcirculatory response in the rat tail to body heating.

OBJECTIVE: The objective of this study was to determine if nitric oxide (NO)-mediated cutaneous vasodilation depends on urate concentrations. METHODS: Capillary blood cell velocities (BCV) in the tail capillary vessels of anesthetized, heat-stressed Sprague-Dawley rats were measured by the videomicroscopy method, and the femoral mean arterial pressure (MAP) was recorded on a Grass polygraph. The effects of urate or urate and NO production on the above parameters were determined by using specific inhibitors of these compounds, for example, allopurinol (All) or All or N-nitro-L-arginine (NNA), respectively. Urate concentrations were determined by an enzymatic, colorimetric method, and total nitrite levels were measured fluorometrically. RESULTS: During heat stress, All or All and NNA significantly decreased plasma urate or urate and total nitrite concentrations, respectively, and the response of vascular conductance (estimated as a ratio of BCV to MAP). Urate administration, after All and NNA pretreatment, restored plasma urate and total nitrite concentrations and increased BCV/MAP. CONCLUSIONS: Urate at physiological concentration helps to maintain vascular conductance of cutaneous capillaries in the rat tail during body heating. The effect of urate on vascular conductance may be mediated by NO.

Allopurinol↗

PubMed1976

Effect of vasopressin on uric acid excretion: evidence for distal nephron reabsorption of urate in man.

1. When changes in urine flow rate were induced by vasopressin administration in eight subjects, urate excretion decreased by a mean of 14% and was positively correlated with urine flow rate (r = 0.88, P less than 0.01). The effect of vasopressin on urate excretion was not influenced by prior changes in extracellular fluid volume. 2. Mannitol administration in a dose sufficient to prevent vasopressin-induced alterations in urine flow rate blocked the effect of vasopressin on urate excretion. 3. Alterations in urate excretion produced by changes in extracellular fluid volume could be distinguished from the urate-retaining effect of vasopressin-mediated decrease in urine flow. Urate retention after vasopressin was entirely attributed to a decrease in pyrazinamide-suppressible urate excretion, consistent with either decreased secretion or enhanced post-secretory reabsorption of urate. 4. Since diminished urine flow rate in the distal part of the nephron is more likely to lead to enhanced reabsorption of urate, these results provide additional evidence for urate reabsorption in the distal part of the nephron.

Adult↗