Uric Acid Abstracts 4

© 2013

Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes

         (Guggino and Aronson 1985) Download

The effects of pyrazinoate and nicotinate on urate transport in microvillus membrane vesicles isolated from canine renal cortex were evaluated. An outwardly directed gradient of pyrazinoate stimulated uphill urate accumulation, suggesting urate-pyrazinoate exchange. An inside-alkaline pH gradient stimulated uphill pyrazinoate accumulation, which suggested pyrazinoate-OH- exchange. Pyrazinoate-OH- exchange and urate-OH- exchange were similarly sensitive to inhibitors, implying that both processes occur via the same transport system. In addition, an inward Na+ gradient stimulated uphill pyrazinoate accumulation, suggesting Na+-pyrazinoate cotransport. Inhibitor studies demonstrated that Na+-pyrazinoate cotransport takes place via the same pathway that mediates Na+-lactate cotransport in these membrane vesicles. Previously we found that urate does not share this Na+-dependent cotransport pathway. Nicotinate inhibited transport of pyrazinoate by the anion exchange pathway and the Na+ cotransport pathway, suggesting that it is a substrate for both transport systems. Finally, in the presence of an inward Na+ gradient, low doses of pyrazinoate or nicotinate stimulated urate uptake, and higher doses of pyrazinoate or nicotinate inhibited urate accumulation, thereby mimicking in vitro the paradoxical effects of drugs on renal urate excretion that have been observed in vivo. These findings indicate that the paradoxical effect of uricosuric drugs at low doses to cause urate retention may result at least in part from stimulation of urate reabsorption across the luminal membrane of the proximal tubular cell.


Mutations associated with functional disorder of xanthine oxidoreductase and hereditary xanthinuria in humans

         (Ichida, Amaya et al. 2012) Download

Xanthine oxidoreductase (XOR) catalyzes the conversion of hypoxanthine to xanthine and xanthine to uric acid with concomitant reduction of either NAD+ or O(2). The enzyme is a target of drugs to treat hyperuricemia, gout and reactive oxygen-related diseases. Human diseases associated with genetically determined dysfunction of XOR are termed xanthinuria, because of the excretion of xanthine in urine. Xanthinuria is classified into two subtypes, type I and type II. Type I xanthinuria involves XOR deficiency due to genetic defect of XOR, whereas type II xanthinuria involves dual deficiency of XOR and aldehyde oxidase (AO, a molybdoflavo enzyme similar to XOR) due to genetic defect in the molybdenum cofactor sulfurase. Molybdenum cofactor deficiency is associated with triple deficiency of XOR, AO and sulfite oxidase, due to defective synthesis of molybdopterin, which is a precursor of molybdenum cofactor for all three enzymes. The present review focuses on mutation or chemical modification studies of mammalian XOR, as well as on XOR mutations identified in humans, aimed at understanding the reaction mechanism of XOR and the relevance of mutated XORs as models to estimate the possible side effects of clinical application of XOR inhibitors.

Effects of selenium deficiency on aldehyde oxidase 1 in rats

         (Itoh, Adachi et al. 2009) Download

Selenium deficiency has been reported to result in an extraordinary decrease of glutathione peroxidase (GSH-Px) and, reversely, an increase of detoxifying enzymes such as glutathione-S-transferase (GST), uridine-5'-diphosphate glucuronosyltransferase (UGT), nicotinamide-dependent quinine oxidoreductase (NQO1; DT-diaphorase), and epoxide hydrolase without significantly affecting cytochrome P450 activity. However, little is known about the effects on aldehyde oxidase 1 (AOX1) activity towards various kinds of aldehydes and N-heterocyclic aromatic compounds. The aim of this study is to clarify the effects of selenium deficiency on AOX1 in rats. As expected, selenium deficiency was confirmed by the extremely low activity of GSH-Px along with the increased activities of GST and DT-diaphorase. AOX1 activity towards vanillin and (S)-RS-8359 was increased by selenium deficiency, and that corresponded to an increase of AOX1 protein level but not to a decreased AOX1 mRNA level. It has been documented that the assembly of the catalytically active holoenzyme forms of the molybdo-flavoenzyme family is very complex and is controlled through transcriptional and translational events by many gene products. In addition, selenium deficiency has been known to cause oxidative stress that leads to an increase of AOX1 activity. Furthermore, aldehyde oxidase homolog 1 (AOH1) with properties similar to AOX1 is present in rodent liver. All the reports suggest that the mechanisms by which selenium deficiency increases AOX1 activity are highly complicated and investigated from different points of view.

Drug-metabolizing ability of molybdenum hydroxylases

         (Kitamura, Sugihara et al. 2006) Download

Molybdenum hydroxylases, which include aldehyde oxidase and xanthine oxidoreductase, are involved in the metabolism of some medicines in humans. They exhibit oxidase activity towards various heterocyclic compounds and aldehydes. The liver cytosol of various mammals also exhibits a significant reductase activity toward nitro, sulfoxide, N-oxide and other moieties, catalyzed by aldehyde oxidase. There is considerable variability of aldehyde oxidase activity in liver cytosol of mammals: humans show the highest activity, rats and mice show low activity, and dogs have no detectable activity. On the other hand, xanthine oxidoreductase activity is present widely among species. Interindividual variation of aldehyde oxidase activity is present in humans. Drug-drug interactions associated with aldehyde oxidase and xanthine oxidoreductase are of potential clinical significance. Drug metabolizing ability of molybdenum hydroxylases and the variation of the activity are described in this review.

Conjugation of salicylic acid with glycine and its action on uric acid excretion

         (Quick 1933) Download

The action of salicylic acid on uric acid elimination is strikingly augmented by glycine or foods rich in glycine.

While 5 gm. of glycine have practically no effect on the excretion of uric acid, 1.5 gm. when given with 2 gm. of salicylic acid will produce a striking augmentation.        


Cherry consumption and decreased risk of recurrent gout attacks

         (Zhang, Neogi et al. 2012) Download

OBJECTIVE: To study the relationship between cherry intake and the risk of recurrent gout attacks among individuals with gout. METHODS: We conducted a case-crossover study to examine the associations of a set of putative risk factors with recurrent gout attacks. Individuals with gout were prospectively recruited and followed up online for 1 year. Participants were asked to provide the following information regarding gout attacks: the onset date of the gout attack, symptoms and signs, medications (including antigout medications), and exposure to potential risk factors (including daily intake of cherries and cherry extract) during the 2-day period prior to the gout attack. We assessed the same exposure information over 2-day control periods. We estimated the risk of recurrent gout attacks related to cherry intake using conditional logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Our study included 633 individuals with gout. Cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no intake (multivariate OR 0.65 [95% CI 0.50-0.85]). Cherry extract intake showed a similar inverse association (multivariate OR 0.55 [95% CI 0.30-0.98]). The effect of cherry intake persisted across subgroups stratified by sex, obesity status, purine intake, alcohol use, diuretic use, and use of antigout medications. When cherry intake was combined with allopurinol use, the risk of gout attacks was 75% lower than during periods without either exposure (OR 0.25 [95% CI 0.15-0.42]). CONCLUSION: These findings suggest that cherry intake is associated with a lower risk of gout attacks.


References

Guggino, S. E. and P. S. Aronson (1985). "Paradoxical effects of pyrazinoate and nicotinate on urate transport in dog renal microvillus membranes." J Clin Invest 76(2): 543-7. [PMID: 4031062]

Ichida, K., Y. Amaya, et al. (2012). "Mutations associated with functional disorder of xanthine oxidoreductase and hereditary xanthinuria in humans." Int J Mol Sci 13(11): 15475-95. [PMID: 23203137]

Itoh, K., M. Adachi, et al. (2009). "Effects of selenium deficiency on aldehyde oxidase 1 in rats." Biol Pharm Bull 32(2): 190-4. [PMID: 19182374]

Kitamura, S., K. Sugihara, et al. (2006). "Drug-metabolizing ability of molybdenum hydroxylases." Drug Metab Pharmacokinet 21(2): 83-98. [PMID: 16702728]

Quick, A. J. (1933). "Conjugation of salicylic acid with glycine and its action on uric acid excretion." J. Biol. Chem. 101: 475-485. [PMID:

Zhang, Y., T. Neogi, et al. (2012). "Cherry consumption and decreased risk of recurrent gout attacks." Arthritis Rheum 64(12): 4004-11. [PMID: 23023818]