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PubMed2004

Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites.

The end product of human purine metabolism is urate, which is produced primarily in the liver and excreted by the kidney through a well-defined basolateral blood-to-cell uptake step. However, the apical cell-to-urine efflux mechanism is as yet unidentified. Here, we show that the renal apical organic anion efflux transporter human multidrug resistance protein 4 (MRP4), but not apical MRP2, mediates ATP-dependent urate transport via a positive cooperative mechanism (K(m) of 1.5 +/- 0.3 mM, V(max) of 47 +/- 7 pmol x mg(-1) x min(-1), and Hill coefficient of 1.7 +/- 0.2). In HEK293 cells overexpressing MRP4, intracellular urate levels were lower than in control cells. Urate inhibited methotrexate transport (IC50 of 235 +/- 8 microM) by MRP4, did not affect cAMP transport, whereas cGMP transport was stimulated. Urate shifted cGMP transport by MRP4 from positive cooperativity (K(m) and V(max) value of 180 +/- 20 microM and 58 +/- 4 pmol x mg(-1) x min(-1), respectively, Hill coefficient of 1.4 +/- 0.1) to single binding site kinetics (K(m) and V(max) value of 2.2 +/- 0.9 mM and 280 +/- 50 pmol x mg(-1) x min(-1), respectively). Finally, MRP4 could transport urate simultaneously with cAMP or cGMP. We conclude that human MRP4 is a unidirectional efflux pump for urate with multiple allosteric substrate binding sites. We propose MRP4 as a candidate transporter for urinary urate excretion and suggest that MRP4 may also mediate hepatic export of urate into the circulation, because of its basolateral expression in the liver.

Adenosine Triphosphate↗
PubMed1987

Tubule urate and PAH transport: sensitivity and specificity of serum protein inhibition.

Macromolecules in rabbit serum inhibit the cellular uptake and transepithelial secretion of [14C]urate and p-[3H]aminohippurate ([3H]PA) in rabbit S2 proximal tubule segments. To understand better the potential role these inhibitors may have in the regulation of renal organic anion excretion, we examined the specificity and relative inhibitory effects on tubule urate and PAH transport of albumin and gamma-globulin, the major inhibitory proteins in rabbit serum. Native rabbit serum markedly inhibited the cellular accumulation of urate and PAH by isolated nonperfused segments [50% inhibition (K0.5) = 0.4 and 0.65 g/dl, respectively]. Urate and PAH transport was also inhibited by bovine serum, human serum, Cohn-fractionated rabbit albumin, and rabbit gamma-globulin, but not by Cohn-fractionated bovine serum albumin. alpha-Lactalbumin and beta-lactoglobulin, derived from milk, also inhibited urate and PAH transport, but to a lesser extent than albumin and gamma-globulin. The transport inhibitory effects of proteins were independent of their binding to urate and PAH. Unidirectional influx and the steady-state intracellular accumulation of urate and PAH in suspensions of proximal tubules were decreased by rabbit serum proteins, suggesting that these inhibitors act on the external face of the cells to diminish the uptake of the organic anions. These studies indicate that the principal plasma proteins (albumin and gamma-globulin) significantly inhibit urate and PAH transporters in the basolateral membranes of S2 proximal tubules. We suggest that circulating plasma proteins that can penetrate the basement membrane of proximal tubules may directly modulate the renal excretion of urate and PAH.

Aminohippuric Acids↗
PubMed1974

Effect of prostaglandins in urate crystal inflammation.

By use of two novel techniques for detecting extremely small amounts of PGs, studies were conducted elucidating the mechanism of urate crystal-induced inflammation. Rats deficient in EFA and thus deficient in PGs received injections of monosodium urate crystals into the footpad. The EFA-deficient animals developed less swelling than did normal animals. However, when a 1-ng dose of PGE-1, PGE-2, PGA-2, or PGF-2-alpha was added along with the urate injection the swelling was enhanced to approximately normal levels. In the second technique the swelling induced by injection of two different urate crystals was compared. Urate crystals heated to 200 degrees C produced less swelling in normal rats than did similar urate crystals heated only to 50 degrees C. However when a 1-ng dose of PGE-1, PGE-2 or PGF-2-alpha was added to the heated urate crystals injection the swelling increased to approximately the swelling in normal controls receiving urate heated to 50 degrees C. Comments are presented suggesting that urate crystal inflammation may be a membrane disease.

Animals↗
PubMed1994

The effects of vitamin C and urate on the oxidation kinetics of human low-density lipoprotein.

Oxidative modification of human low-density lipoprotein (LDL) is believed to play an important role in atherogenesis. Vitamin C (ascorbate) and urate are major water-soluble plasma antioxidants in humans. Urate levels (300-395 microM) in human serum are considerably higher than ascorbate levels (30-50 microM). In this study, we compared the ability of urate to protect human LDL from in vitro oxidation with that of ascorbate. LDL was subjected to in vitro oxidation at 30 degrees C with an O2 saturated solution (0.15 M NaCl/0.25 mM EDTA) and 15 mM of a thermally labile water soluble azo-initiator (ABAP or azobis-2-amidinopropane HCl). In parallel experiments, 50 microM ascorbate or 50 microM urate were present in the oxidation buffer. The consumption of alpha-tocopherol, gamma-tocopherol, urate or ascorbate and the formation of lipid hydroperoxides were measured as a function of time in the in vitro oxidation system. The rate of lipid hydroperoxide formation was found to be significantly increased after the LDL tocopherols (alpha-plus gamma-tocopherol) were totally consumed, i.e., after the lag phase. Urate (50 microM) was more effective than ascorbate (50 microM) in extending the lag phase. Moreover, urate was consumed more slowly than ascorbate under identical oxidation conditions. Urate was not, however, as effective as ascorbate in preventing the formation of lipid hydroperoxides before the lag phase. An empirical mathematical model was also developed to describe the oxidation kinetics of LDL alpha- and gamma-tocopherol in the presence or absence of urate or ascorbate.

Ascorbic Acid↗
PubMed1979

The natural history of urate overproduction in sickle cell anemia.

Serum uric acid and uric acid excretion were studied in 95 patients with sickle cell anemia ranging in age from 17 months to 45 years to ascertain the natural history of urate overproduction. Hyperuricemia was infrequent in children with sickle cell anemia, but was found in 26 of 67 adults (39%). Thirty-six patients studied in a clinical research center had a mean urate clearance of 9.1 +/- 0.8 mL/min. Patients with sickle cell anemia were often normouricemic despite urate overproduction. Normouricemia was maintained by increased urate clearance, which was attributed to increased urate secretion. The hyperuricemic patients had decreased urate clearance with decreased pyrazinamide-suppressible urate clearance. Para-aminohippurate clearance was decreased to 634 mL/min in the hyperuricemic patients with sickle cell anemia compared with 853 mL/min in normouricemic hyperuricosuric subjects with sickle cell anemia. Hyperuricemia occurs only in patients who develop altered renal tubular function with diminished urate clearance secondary to diminished urate secretion.

Adolescent↗
PubMed1992

Two independent mutational events in the loss of urate oxidase during hominoid evolution.

Urate oxidase was lost in hominoids during primate evolution. The mechanism and biological reason for this loss remain unknown. In an attempt to address these questions, we analyzed the sequence of urate oxidase genes from four species of hominoids: human (Homo sapiens), chimpanzee (Pan troglodytes), orangutan (Pongo pygmaeus), and gibbon (Hylobates). Two nonsense mutations at codon positions 33 and 187 and an aberrant splice site were found in the human gene. These three deleterious mutations were also identified in the chimpanzee. The nonsense mutation at codon 33 was observed in the orangutan urate oxidase gene. None of the three mutations was present in the gibbon; in contrast, a 13-bp deletion was identified that disrupted the gibbon urate oxidase reading frame. These results suggest that the loss of urate oxidase during the evolution of hominoids could be caused by two independent events after the divergence of the gibbon lineage; the nonsense mutation at codon position 33 resulted in the loss of urate oxidase activity in the human, chimpanzee, and orangutan, whereas the 13-bp deletion was responsible for the urate oxidase deficiency in the gibbon. Because the disruption of a functional gene by independent events in two different evolutionary lineages is unlikely to occur on a chance basis, our data favor the hypothesis that the loss of urate oxidase may have evolutionary advantages.

Amino Acid Sequence↗
PubMed1979

Degradation of peroxisomal catalase and urate oxidase of rat liver.

Urate oxidase and catalase were purified from rat liver peroxisomes, and respective antibodies were prepared from rabbits by the administration of these enzymes. Although urate oxidase generally precipitates in immunoprecipitation-possible pH ranges (pH 4.5--9.5), the enzyme remained soluble in 50 mM glycine buffer (pH 9.5) containing 50% glycerol up to concentration of 0.3 mg/ml. Anti-urate oxidase reacted with purified urate oxidase as well as with the crude preparation. After [3H]leucine was injected to rats, urate oxidase and catalase were purified from rat liver at certain intervals, and further precipitated by respective antibodies. The half-life of the catalase was 39 h and that of urate oxidase, 20 h. When the sonicated light mitochondrial fraction was incubated at 37 degrees C and at pH 7.0 or 5.6, inactivation of catalase did not seem to differ between these pH values, and approximately 80% of the catalase activity remained even after 8 h. Urate oxidase was inactivated very rapidly at pH 5.6; only 30% of its activity survived incubation for 6 h. This inactivation was found to occur by some proteolytic process. From these findings, the turnover rate of urate oxidase was found to be different from that of catalase, and this distinction seemed to be due to different sensitivity to some degradative enzymes.

Animals↗
PubMed2001

Urate oxidase in the prophylaxis or treatment of hyperuricemia: the United States experience.

Nonrecombinant urate oxidase (Uricozyme, Sanofi-Synthélabo, Inc, Paris, France) is a highly effective uricolytic agent, but its use is associated with hypersensitivity reaction manifested mainly by bronchospasm in approximately 5% of patients. Recently, several multi-institutional studies have evaluated the efficacy and safety of a recombinant urate oxidase (rasburicase). In a phase I/II study, all 131 patients with newly diagnosed acute lymphoblastic leukemia (ALL) or stage III/IV non-Hodgkin's lymphoma (NHL) experienced rapidly decreased plasma uric acid concentrations after receiving recombinant urate oxidase. Serum creatinine levels also decreased significantly. Toxicity was negligible, and none of the patients required dialysis. In a phase III trial, children with newly diagnosed ALL or stage III/IV NHL were stratified and randomized to receive recombinant urate oxidase or allopurinol. Results showed that the 27 patients who received recombinant urate oxidase had a significantly lower plasma uric acid concentration and a more rapid decline in serum creatinine level than did the 25 who took allopurinol. One patient in the recombinant urate oxidase group had hemolysis of unknown cause, and one in the allopurinol group required hemofiltration for hyperphosphatemia. To further assess the safety profile of recombinant urate oxidase, the data on 245 patients (173 children and 72 adults) who received this agent in a compassionate-use program were reviewed retrospectively. The drug produced dramatic decreases in uric acid concentrations in all patients. Nine patients (four children and five adults) had mild adverse reactions that were drug-related or of unknown etiology. These data suggest that recombinant urate oxidase is safe and effective in the prophylaxis and treatment of hyperuricemia associated with malignancy or chemotherapy.

Allopurinol↗
PubMed2026

Urate-lowering effects of losartan: a meta-analysis of randomised controlled trials and target trial emulation.

Common in hypertensive patients, hyperuricaemia is often exacerbated by guideline-recommended antihypertensive therapies such as thiazide diuretics. Losartan is known as an angiotensin II receptor type 1 antagonist with a uricosuric effect, but the magnitude of its efficacy in lowering urate has not been quantified versus a placebo-reference. We sought to quantify the urate-lowering effect of losartan versus placebo using two complementary approaches. We first conducted a meta-analysis of randomised controlled trials (RCTs) to quantify the effect of losartan on serum urate levels versus placebo. We then applied a target trial emulation framework in the UK Biobank as a secondary source of data and a replication experiment. The meta-analysis of six prospective randomised controlled trials (RCTs), including 1119 losartan-treated patients and 1093 controls, demonstrated that losartan reduced serum urate levels by approximately 0.29 mg/dL relative to placebo (95% CI: -0.46 to -0.12, p = 0.0009). In the target trial emulation, 23 losartan-treated individuals showed a reduction in serum urate of approximately 0.35 mg/dL (95% CI: -0.66 to -0.03, p = 0.03) when compared with 92 matched controls, and after accounting for 12 potential confounders including established urate-lowering therapies. Our results provide evidence for a modest yet consistent urate-lowering potential of losartan. This modest biochemical effect (~0.3 mg/dL) may be an attractive option to mitigate the diuretic-induced urate elevation. Thus, losartan can be considered as a favourable antihypertensive choice for patients managed with diuretics or those who are at risk of hyperuricaemia/gout.

Losartan↗
PubMed2000

Evolution of urate-degrading enzymes in animal peroxisomes.

The end product of purine metabolism varies from species to species. The degradation of purines to urate is common to all animal species, but the degradation of urate is much less complete in higher animals. The comparison of subcellular distribution, intraperoxisomal localization forms, molecular structures, and some other properties of urate-degrading enzymes (urate oxidase, allantoinase, and allantoicase) among animals is described. Liver urate oxidase (uricase) is located in the peroxisomes in all animals with urate oxidase. On the basis of the comparison of intraperoxisomal localization forms, mol wt, and solubility of liver urate oxidase among animals, it is suggested that amphibian urate oxidase is a transition form in the evolution of aquatic animals to land animals. Allantoinase and allantoicase are different proteins in fish liver, but the two enzymes form a complex in amphibian liver. The subcellular localization of allantoinase and allantoicase varies among fishes. Hepatic allantoinase is located both in the peroxisomes and in the cytosol in saltwater fishes, and only in the cytosol in freshwater fishes. Hepatic allantoicase is located on the outer surface of the peroxisomal membrane in the mackerel group and in the peroxisomal matrix in the sardine group. Amphibian hepatic allantoinase-allantoicase complex is probably located in the mitochondria. On the basis of previous data, changes of allantoinase and allantoicase in molecular structure and intracellular localization during animal evolution may be as follows: Fish liver allantoinase is a single peptide with a mol wt of 54,000, and is located both in the peroxisomes and in the cytosol, or only in the cytosol. Fish liver allantoicase consists of two identical subunits with a mol wt of 48,000, and is located in the peroxisomal matrix or on the outer surface of the peroxisomal membrane. The evolution of fishes to amphibia resulted in the dissociation of allantoicase into subunits, and in the association of allantoinase with the subunit of allantoicase. This amphibian enzyme was lost by further evolution.

Amidohydrolases↗
PubMed1980

Urate metabolism in a mongrel dog.

(1) We have performed short-term turnover studies in a trained mongrel dog, and found remarkably linear turnover curves for both urate and its principle metabolic product, allantoin. (2) Infusions of Pyrazinamide, Probenecid, and Sodium Salicylate had no apparent effect on urate metabolism. (3) The "uricolytic index" for endogenous urate is consistenely lower than that of infused, isotopic urate. This finding suggests renal synthesis and direct excretion of unlabelled urate. (4) The renal clearance of labelled urate is higher than that of endogenous urate despite apparent renal synthesis. This finding suggests that urate may exist in more than one molecular form.

Allantoin↗
PubMed1984

Lack of effect of low [Ca2+], La3+, and pyrazinoate on urate transport by isolated, perfused snake renal tubules.

Effects of low medium calcium concentration, of lanthanum, and of pyrazinoate on urate transport by isolated, perfused snake (Thamnophis spp.) distal-proximal renal tubules were studied. Removal of calcium from perfusate with 0.18 mmol/l calcium in bathing medium had no effect on net urate secretion (J net urate) or on net fluid absorption (Jv). In the presence of calcium (1.8 mmol/l), lanthanum (2.0 mmol/l) in perfusate alone, in bathing medium alone, or in both perfusate and bathing medium had no effect on J net urate. These findings suggest that urate transport, in contrast to para-aminohippurate (PAH) transport, is not sensitive to calcium entry into the cells and support the concept that urate and PAH are transported by separate mechanisms in these renal tubules. Pyrazinoate (1.0 mmol/l) in the bathing medium had no effect on J net urate or Jv. These findings do not support the idea of a primary urate secretory process uniquely sensitive to pyrazinoate among the vertebrates.

Animals↗
PubMed1975

Peritubular transport of urate in rat kidneys.

Measurement in the rat of renal artery-to-vein transit times permitted evaluation of movement of 14C-labelled urate and of other solutes out of the peritubular inulin spaces in the renal cortex. No interaction between urate and PAH could be demonstrated at this level. Provided the peritubular disappearance may be equated to cellular uptake a mean unidirectional urate flux across peritubular membranes equal to about 1/3 of total renal load may be calculated. This value greatly exceeds the net secretory flux of urate. Such a fact can be explained by the likelihood of significant post-proximal reabsorption of secreted urate, and/or by the conclusion that peritubular urate permeability exceeds that of the luminal side. Assignment of the limiting step in urate secretion to the luminal cell membranes, in contrast to a determining role played by peritubular membranes in PAH transport, can account for the lack of interaction between PAH and urate at the peritubular membrane in rats.

Aminohippuric Acids↗
PubMed1983

Micropuncture study of urate transport by superficial nephrons in avian (Sturnus vulgaris) kidney.

Tubule fluid samples from proximal tubules of superficial, reptilian-type nephrons of the European starling (Sturnus vulgaris) were obtained by micropuncture and, along with plasma samples, were analyzed for urate by high performance liquid chromatography with electrochemical detection, as well as for the elements sodium, chloride, calcium, magnesium, phosphorus and potassium by electron microprobe analysis. All proximal tubules sampled showed net secretion of urate, but the magnitude of transport was highly variable. Mean fractional delivery of urate to the point of micropuncture was 4.04 +/- 0.37 (mean +/- SE, n = 40 tubules). Fractional delivery of urate could not be correlated with fractional delivery of any of the measured elements or with relative fluid absorption. Samples collected from surface segments of cortical collecting ducts suggest that, although much net secretion of urate occurs early within the proximal tubule of superficial nephrons, some additional secretion may occur in more distal segments. Fractional excretion of urate at the level of the cloaca averaged 4.72 +/- 0.97 for nine birds, confirming the result of overall net secretion of urate previously reported for other avian species. These results clearly demonstrate the presence of significant secretory transport of urate in the proximal tubule of superficial reptilian-type nephrons, but do not rule out the possibility of additional secretory or reabsorptive fluxes at other sites.

Animals↗
PubMed1975

Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia.

Seven young adults with uric acid overproduction due to sickle cell anemia were normouricemic with a mean serum uric acid level of 4.9 mg/100 ml. Urate clearance was greater in these patients than in normal subjects or in patients with primary hyperuricemia due to uric acid overproduction. The increase in urate clearance was entirely accounted for by increased pyrazinamide suppressible urate clearance. Pyrazinamide administration abolished the uricosuric response to ribonucleic acid (RNA) feeding in these patients with sickle cell anemia, and maximal uricosuric response to the administration of probenecid was similar in the patients with sickle cell anemia and in normal subjects suggesting that reabsorption of both filtered and secreted urate was not impaired in sickle cell disease. Pyrazinamide suppressible urate clearance at maximal uricosuric response to probenecid was increased in patients with sickle cell disease suggesting increased tubular secretion of urate. This increase in urate secretion permits most young adults with urate overproduction due to sickle cell anemia to remain normouricemic and may account for the low frequency of secondary gout in this disease.

Adolescent↗
PubMed1979

Urate transport in human red blood cells. Activation by ATP.

Urate transport in human erythrocytes were measured and compared to previous observations by other authors regarding inorganic anions, especially chloride. Conclusions wwere as follows: 1. Urate influx as a function of increasing concentrations showed saturation kinetics. 2. The effects of pH and of several passive anion transport inhibitors such as dinitrofluorobenzene, sodium salicylate, sodium benzoate and phenylbutazone suggest that urate and chloride are transported by different mechanisms. 3. Urate influx seems to depend on intracellular glycolysis. The results obtained on red blood cells after glycolysis inhibition agree with those obtained on ghosts where metabolism does not take place. 4. The large drop in urate influxes into erythrocytes in the presence of a glycolysis inhibitor and of a passive ion transport inhibitor seems to argue in favour of a dual urate transport mechanism, one for passive diffusion and the other connected with glycolysis. 5. The drop in the urate influx into ghosts in the absence of ATP suggests that the latter might intervene in urate transport by human red cell membranes.

Adenosine Triphosphate↗
PubMed1990

Uricosurics inhibit urate transporter in rat renal brush border membrane vesicles.

It has been proposed that a urate-anion exchanger system in brush border membrane vesicles (BBMV), which mediates hydroxyl ion (OH-) gradient-dependent urate uptake, is the most likely route for the mediation of urate transport in the first step of urate reabsorption in the proximal tubules. Luminal drugs which inhibit urate reabsorption would inhibit the transport of urate into the cell by blocking the urate-anion exchanger. To confirm this hypothesis, we investigated the inhibitory effects of well-known uricosuric drugs on the OH-/urate exchange in BBMV. The rank order of potency was benzbromarone greater than tienilic acid greater than sulfinpyrazone greater than probenecid, which is consistent with clinical doses in man. AA-193 (5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carb oxylic acid), an excellent candidate for a uricosuric, exerted the most potent inhibition on urate uptake (Ki = 0.12 microM). In contrast with that by stilbene disulfonates, the inhibition by AA-193 or benzbromarone was reversible.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

Substrate specificity of urate transporter in rat renal brush border membranes.

To further demonstrate the substrate specificity of urate-anion exchanger in rat renal brush border membrane vesicles, the hydroxyl ion gradient-dependent [2-14C] urate uptake was studied by a rapid filtration technique. The [2-14C] urate uptake was more sensitive to unlabeled urate than to unlabeled xanthine and hypoxanthine. In addition, urate derivatives which are methylated at the positions 3 and 9 hardly inhibited the urate uptake. Because of the substrate specificity, the urate-anion exchanger in brush border membranes appears to selectively use urate as the endogenous substrate.

Animals↗