Uric acid

Uric acid

Crystals of urate in polarized light
Names
Systematic IUPAC name
7,9-Dihydro-1H-purine-2,6,8(3H)-trione
Other names
2,6,8-Trioxypurine; 2,6,8-Trihydroxypurine; 2,6,8-Trioxopurine; 1H-Purine-2,6,8-triol
Identifiers
69-93-2 YesY
3DMet B00094
156158
ChEBI CHEBI:27226 N
ChEMBL ChEMBL792 YesY
ChemSpider 1142 YesY
DrugBank DB01696 YesY
EC Number 200-720-7
4731
Jmol 3D model Interactive image
Interactive image
KEGG C00366 N
MeSH Uric+Acid
PubChem 1175
UNII 268B43MJ25 YesY
Properties
C5H4N4O3
Molar mass 168.11 g·mol−1
Appearance White crystals
Melting point 300 °C (572 °F; 573 K)
0.0006g/100 mL (at 20 °C)
log P -1.107
Acidity (pKa) 5.6
Basicity (pKb) 8.4
Thermochemistry
166.15 J K−1 mol−1 (at 24.0 °C)
173.2 J K−1 mol−1
-619.69–617.93 kJ mol−1
-1.9212–1.91956 MJ mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the metabolic breakdown of purine nucleotides. High blood concentrations of uric acid can lead to gout and are associated with other medical conditions including diabetes and the formation of ammonium acid urate kidney stones.

Chemistry

Uric acid is a diprotic acid with pKa1=5.4 and pKa2=10.3.[1] Thus in strong alkali at high pH, it forms the dually charged full urate ion, but at biological pH or in the presence of carbonic acid or carbonate ions, it forms the singly charged hydrogen or acid urate ion, as its pKa1 is lower than the pKa1 of carbonic acid. As its second ionization is so weak, the full urate salts tend to hydrolyze back to hydrogen urate salts and free base at pH values around neutral. It is aromatic because of the purine functional group.

As a bicyclic, heterocyclic purine derivative, uric acid does not protonate as an oxygen [-OH] like carboxylic acids do. X-ray diffraction studies on the hydrogen urate ion in crystals of ammomium hydrogen urate, formed in vivo as gouty deposits, reveal the keto-oxygen in the 2 position of a tautomer of the purine structure exists as a hydroxyl group and the two flanking nitrogen atoms at the 1 and 3 positions share the ionic charge in the six-membered pi-resonance-stabilized ring.[2]

Thus, while most organic acids are deprotonated by the ionization of a polar hydrogen-to-oxygen bond, usually accompanied by some form of resonance stabilization (resulting in a carboxylate ion), uric acid is deprotonated at a nitrogen atom and uses a tautomeric keto/hydroxy group as an electron-withdrawing group to increase the pK1 value. The five-membered ring also possesses a keto group (in the 8 position), flanked by two secondary amino groups (in the 7 and 9 positions), and deprotonation of one of these at high pH could explain the pK2 and behavior as a diprotic acid. Similar tautomeric rearrangement and pi-resonance stabilization would then give the ion some degree of stability. (On the structure shown at the upper-right, the NH at the upper-right on the six-membered ring is "1", counting clockwise around the six-membered ring to "6" for the keto carbon at the top of the six-membered ring. The uppermost NH on the five-membered ring is "7", counting counter-clockwise around this ring to the lower NH, which is "9".)

Uric acid was first isolated from kidney stones in 1776 by the Swedish chemist Carl Wilhelm Scheele.[3] In 1882, the Ukrainian chemist Ivan Horbaczewski first synthesized uric acid by melting urea with glycine.[4]

Solubility

In general, the water solubility of uric acid and its alkali metal and alkaline earth salts is rather low. All these salts exhibit greater solubility in hot water than cold, allowing for easy recrystallization. This low solubility is significant for the etiology of gout. The solubility of the acid and its salts in ethanol is very low or negligible. In ethanol/water mixtures, the solubilities are somewhere between the end values for pure ethanol and pure water.

Compound Cold water Boiling water
Uric Acid 15000 2000
NH4HUrate - 1600
LiHUrate 370 39
NaHUrate 1175 124
KHUrate 790 75
Mg(HUrate)2 3750 160
Ca(HUrate)2 603 276
Na2Urate 77 -
K2Urate 44 35
CaUrate 1500 1440
SrUrate 4300 1790
BaUrate 7900 2700

The figures given indicate what mass of water is required to dissolve a unit mass of compound indicated. The lower the number the more soluble the substance in the said solvent.[5][6][7]

Biology

The enzyme xanthine oxidase catalyzes formation of uric acid from xanthine and hypoxanthine, which in turn are produced from other purines. Xanthine oxidase is a large enzyme whose active site consists of the metal molybdenum bound to sulfur and oxygen.[8] Within cells, xanthine oxidase can exist as xanthine dehydrogenase and xanthine oxireductase, which has also been purified from bovine milk and spleen extracts.[9] Uric acid is released in hypoxic conditions.[10]

In humans and higher primates, uric acid is the final oxidation (breakdown) product of purine metabolism and is excreted in urine. In most other mammals, the enzyme uricase further oxidizes uric acid to allantoin.[11] The loss of uricase in higher primates parallels the similar loss of the ability to synthesize ascorbic acid, leading to the suggestion that urate may partially substitute for ascorbate in such species.[12] Both uric acid and ascorbic acid are strong reducing agents (electron donors) and potent antioxidants. In humans, over half the antioxidant capacity of blood plasma comes from uric acid.[13]

In humans, about 70% of daily uric acid disposal occurs via the kidneys, and in 5-25% of humans, impaired renal (kidney) excretion leads to hyperuricemia.[14]

Other animals

The Dalmatian dog has a genetic defect in uric acid uptake by the liver and kidneys, resulting in decreased conversion to allantoin, so this breed excretes uric acid, and not allantoin, in the urine.[15]

In birds and reptiles, and in some desert dwelling mammals (e.g., the kangaroo rat), uric acid also is the end-product of purine metabolism, but it is excreted in feces as a dry mass. This involves a complex metabolic pathway that is energetically costly in comparison to processing of other nitrogenous wastes such as urea (from urea cycle) or ammonia, but has the advantages of reducing water loss and, hence, reducing the need for water.[16]

Platynereis dumerilii, a marine Polychaete worm, uses uric acid as a sexual pheromone released into the water by females during mating to induce males to release sperm.[17]

Genetics

A proportion of people have mutations in the proteins responsible for the excretion of uric acid by the kidneys. Variants within a number of genes have so far been identified: SLC2A9; ABCG2; SLC17A1; SLC22A11; SLC22A12; SLC16A9; GCKR; LRRC16A; and PDZK1.[18][19] [20] SLC2A9 is known to transport both uric acid and fructose.[14][21]

Medicine

In human blood plasma, the reference range of uric acid is typically 3.4-7.2 mg/dL (200-430 µmol/L) for men (1 mg/dL=59.48 µmol/L), and 2.4-6.1 mg/dL for women (140-360 µmol/L).[22] However, blood test results should always be interpreted using the range provided by the laboratory that performed the test. Uric acid concentrations in blood plasma above and below the normal range are known, respectively, as hyperuricemia and hypouricemia. Likewise, uric acid concentrations in urine above and below normal are known as hyperuricosuria and hypouricosuria. Such abnormal concentrations of uric acid are not medical conditions, but are associated with a variety of medical conditions.

High uric acid

High levels of uric acid is called hyperuricemia and can lead to gout.

Causes of high uric acid

Gout

Excess serum accumulation of uric acid in the blood can lead to a type of arthritis known as gout.[27] This painful condition is the result of needle-like crystals of uric acid precipitating in joints, capillaries, skin, and other tissues.[28] Kidney stones can also form through the process of formation and deposition of sodium urate microcrystals.[29][30]

A study found that men who drink two or more sugar-sweetened beverages a day have an 85% higher chance of developing gout than those who drank such beverages infrequently.[31]

Gout can occur where serum uric acid levels are as low as 6 mg/dL (~357 µmol/L), but an individual can have serum values as high as 9.6 mg/dL (~565 µmol/L) and not have gout.[32]

One treatment for gout, in the 19th century, had been administration of lithium salts;[33] lithium urate is more soluble. Today, inflammation during attacks is more commonly treated with NSAIDs, colchicine, or corticosteroids, and urate levels are managed with allopurinol.[34] Allopurinol, developed over 30 years ago by Elion et al., weakly inhibits xanthine oxidase. It is an analog of hypoxanthine that is hydroxylated by xanthine oxidoreductase at the 2-position to give oxipurinol. Oxipurinol has been supposed to bind tightly to the reduced molybdenum ion in the enzyme and, thus, inhibits uric acid synthesis.[35]

Lesch-Nyhan syndrome

Lesch-Nyhan syndrome, an extremely rare inherited disorder, is also associated with very high serum uric acid levels.[36] Spasticity, involuntary movement, and cognitive retardation as well as manifestations of gout are seen in cases of this syndrome.[37]

Cardiovascular disease

Hyperuricemia may be associated with an increase in risk factors for cardiovascular disease.[38]

Type 2 diabetes

The association of high serum uric acid with insulin resistance has been known since the early part of the 20th century, but the hypothesis that high serum uric acid is a risk factor for diabetes has long been a matter of debate. In fact, hyperuricemia was presumed to be a consequence of insulin resistance rather than its precursor.[39] However, a prospective follow-up study showed high serum uric acid is associated with higher risk of type 2 diabetes, independent of obesity, dyslipidemia, and hypertension.[40]

Metabolic syndrome

Hyperuricemia is associated with components of metabolic syndrome. A study has suggested fructose-induced hyperuricemia may play a pathogenic role in the metabolic syndrome.[41] This is consistent with the increased consumption in recent decades of fructose-containing beverages (such as fruit juices and soft drinks sweetened with sugar and high-fructose corn syrup) and the epidemic of diabetes and obesity.[31]

Uric acid stone formation

Saturation levels of uric acid in blood may result in one form of kidney stones when the urate crystallizes in the kidney. These uric acid stones are radiolucent and so do not appear on an abdominal plain X-ray, and thus their presence must be diagnosed by ultrasound for this reason or stone protocol CT. Very large stones may be detected on X-ray by their displacement of the surrounding kidney tissues.

Uric acid stones, which form in the absence of secondary causes such as chronic diarrhea, vigorous exercise, dehydration, and animal protein loading, are felt to be secondary to obesity and insulin resistance seen in metabolic syndrome. Increased dietary acid leads to increased endogenous acid production in the liver and muscles, which in turn leads to an increased acid load to the kidneys. This load is handled more poorly because of renal fat infiltration and insulin resistance, which are felt to impair ammonia excretion (a buffer). The urine is, therefore, quite acidic, and uric acid becomes insoluble, crystallizes and stones form. In addition, naturally present promoter and inhibitor factors may be affected. This explains the high prevalence of uric stones and unusually acidic urine seen in patients with type 2 diabetes. Uric acid crystals can also promote the formation of calcium oxalate stones, acting as "seed crystals" (heterogeneous nucleation).[42]

Low Uric Acid

Causes of low uric acid

Low uric acid (hypouricemia) can have numerous causes.

Low dietary zinc intakes cause lower uric acid levels. This effect can be even more pronounced in women taking oral contraceptive medication.[43]

Xanthine oxidase is an Fe-Mo enzyme, so people with Fe deficiency (the most common cause of anemia in young women) or Mo deficiency can experience hypouricemia.

Xanthine oxidase loses its function and gains ascorbase function when some of the Fe atoms in XO are replaced with Cu atoms. As such, people with high Cu/Fe can experience hypouricemia and vitamin C deficiency, resulting in oxidative damage. Since estrogen increases the half-life of Cu, women with very high estrogen levels and intense blood loss during menstruation are likely to have a high Cu/Fe and present with hypouricemia.

Sevelamer, a drug indicated for prevention of hyperphosphataemia in patients with chronic renal failure, can significantly reduce serum uric acid.[44]

But the main cause of congenitally low uric acid, sometimes as low as zero, remains the Molybdenum cofactor deficiency.

Multiple sclerosis

Lower serum values of uric acid have been associated with multiple sclerosis (MS). MS patients have been found to have serum levels ~194 µmol/L, with patients in relapse averaging ~160 µmol/L and patients in remission averaging ~230 µmol/L. Serum uric acid in healthy controls was ~290 µmol/L.[45] Conversion factor: 1 mg/dL=59.48 µmol/L[46]

A 1998 study completed a statistical analysis of 20 million patient records, comparing serum uric acid values in patients with gout and patients with multiple sclerosis. Almost no overlap between the groups was found.[47]

Uric acid has been successfully used in the treatment and prevention of the animal (murine) model of MS. A 2006 study found elevation of serum uric acid values in multiple sclerosis patients, by oral supplementation with inosine, resulted in lower relapse rates, and no adverse effects.[48]

Normalizing low uric acid

Correcting low or deficient zinc levels can help elevate serum uric acid.[49] Inosine can be used to elevate uric acid levels.[45] Zn inhibits Cu absorption, helping to reduce the high Cu/Fe in some people with hypouricemia. Fe supplements can ensure adequate Fe reserves (ferritin above 25 ng/dl), also correcting the high Cu/Fe.

Oxidative stress

Uric acid may be a marker of oxidative stress,[50] and may have a potential therapeutic role as an antioxidant.[51] On the other hand, like other strong reducing substances such as ascorbate, uric acid can also act as a prooxidant. Thus, it is unclear whether elevated levels of uric acid in diseases associated with oxidative stress such as stroke and atherosclerosis are a protective response or a primary cause.[52]

For example, some researchers propose hyperuricemia-induced oxidative stress is a cause of metabolic syndrome.[41][53] On the other hand, plasma uric acid levels correlate with longevity in primates and other mammals.[54] This is presumably a function of urate's antioxidant properties.[55]

Sources

Creative output

A relationship may exist between gout with higher levels of blood uric acid and creativity.[59] One study found an association between IQ and serum urate levels, with a stronger correlation between urate levels and scholastic achievement.[60] Another study found a relationship between urate levels and publication rates of university professors, leading to speculation that the similar chemical structure of urate to caffeine may produce a stimulant effect.[60]

See also

References

  1. ↑ McCrudden, Francis H. (2008). Uric Acid. BiblioBazaar.
  2. ↑ European Powder Diffraction Conference, EPDIC-9
  3. ↑ Scheele, V. Q. Examen Chemicum Calculi Urinari, Opuscula, 1776, 2, 73.
  4. ↑ Johann Horbaczewski (1882) "Synthese der Harnsäure" (Synthesis of uric acid), Monatshefte für Chemie und verwandte Teile anderer Wissenschaften … , 3 : 796–797.
  5. ↑ CRC Handbook of Chemistry and Physics (62nd ed.).
  6. ↑ Merck Index (9th ed.).
  7. ↑ Francis H. McCrudden. Uric Acid. p. 58.
  8. ↑ Hille, R (2005). "Molybdenum-containing hydroxylases". Archives of Biochemistry and Biophysics 433 (1): 107–16. doi:10.1016/j.abb.2004.08.012. PMID 15581570.
  9. ↑ Hori, N.; Uehara, K.; Mikami, Y. title = Enzymic synthesis of 5-methyluridine from adenosine and thymine with high efficiency (1992). "Enzymatic Synthesis of 5-Methyluridine from Adenosine and Thymine with High Efficiency". Biosci., Biotechnol., Biochem 56 (4): 580–582. doi:10.1271/bbb.56.580.
  10. ↑ Baillie, J.K.; M.G. Bates; A.A. Thompson; W.S. Waring; R.W. Partridge; M.F. Schnopp; A. Simpson; F. Gulliver-Sloan; S.R. Maxwell; D.J. Webb (May 2007). "Endogenous urate production augments plasma antioxidant capacity in healthy lowland subjects exposed to high altitude". Chest 131 (5): 1473–1478. doi:10.1378/chest.06-2235. PMID 17494796.
  11. ↑ Angstadt, Carol N. (1997-12-04). Purine and Pyrimidine Metabolism: Purine Catabolism. NetBiochem, 4 December 1997. Retrieved from http://library.med.utah.edu/NetBiochem/pupyr/pp.htm#Pu%20Catab.
  12. ↑ Proctor P (November 1970). "Similar functions of uric acid and ascorbate in man?". Nature 228 (5274): 868. doi:10.1038/228868a0. PMID 5477017.
  13. ↑ Maxwell, S. R. J.; Thomason, H.; Sandler, D.; Leguen, C.; Baxter, M. A.; Thorpe, G. H. G.; Jones, A. F.; Barnett, A. H. (1997). "Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus". European Journal of Clinical Investigation 27 (6): 484–90. doi:10.1046/j.1365-2362.1997.1390687.x. PMID 9229228.
  14. 1 2 Vitart V, Rudan I, Hayward C, et al. (April 2008). "SLC2A9 is a newly identified urate transporter influencing serum urate concentration, urate excretion and gout". Nature Genetics 40 (4): 437–42. doi:10.1038/ng.106. PMID 18327257.
  15. ↑ Friedman, Meyer; and Byers, Sanford O. (1 September 1948). "Observations concerning the causes of the excess excretion of uric acid in the Dalmatian dog". The Journal of Biological Chemistry 175 (2): 727–35. PMID 18880769.
  16. ↑ Hazard, Lisa C. (2004). Sodium and Potassium Secretion by Iguana Salt Glands. Iguanas: Biology and Conservation (University of California Press). pp. 84–85. ISBN 978-0-520-23854-1.
  17. ↑ Zeeck, Erich; Harder, Tilman; Beckmann, Manfred (1998). "Uric acid: the sperm-release pheromone of the marine polychaete Platynereis dumerilii". Journal of Chemical Ecology 24 (1): 13–22. doi:10.1023/A:1022328610423.
  18. ↑ Aringer M, Graessler J (December 2008). "Understanding deficient elimination of uric acid". Lancet 372 (9654): 1929–30. doi:10.1016/S0140-6736(08)61344-6. PMID 18834627.
  19. ↑ Kolz M, Johnson T, et al. (June 2009). Allison DB, ed. "Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations". PLoS Genet 5 (6): e1000504. doi:10.1371/journal.pgen.1000504. PMC 2683940. PMID 19503597.
  20. ↑ Köttgen, A; et al. (February 2013). "Genome-wide association analyses identify 18 new loci associated with serum urate concentrations". Nature Genetics 45 (2): 145–54. doi:10.1038/ng.2500. PMC 3663712. PMID 23263486.
  21. ↑ Döring A, Gieger C, Mehta D, et al. (April 2008). "SLC2A9 influences uric acid concentrations with pronounced sex-specific effects". Nature Genetics 40 (4): 430–6. doi:10.1038/ng.107. PMID 18327256.
  22. ↑ "Harmonisation of Reference Intervals" (PDF). Pathology Harmony (UK). Retrieved 13 August 2013.
  23. ↑ Cirillo P, Sato W, Reungjui S, et al. (December 2006). "Uric acid, the metabolic syndrome, and renal disease". J. Am. Soc. Nephrol. 17 (12 Suppl 3): S165–8. doi:10.1681/ASN.2006080909. PMID 17130256.
  24. ↑ Theodore J. Angelopoulos, Joshua Lowndes, Linda Zukley, Kathleen J. Melanson 5, Von Nguyen 3, Anik Huffman 4, and James M. Rippe. (June 2009). "The Effect of High-Fructose Corn Syrup Consumption on Triglycerides and Uric Acid". J. Nutr. 139 (6): 1242S–1245S. doi:10.3945/jn.108.098194. PMID 19403709.
  25. ↑ Mayo Clinic staff. (September 11, 2010). High uric acid level. Mayo Clinic. Retrieved April 24, 2011.
  26. ↑ "Diuretic-Related Side Effects: Development and Treatment". Medscape. Retrieved 17 May 2013.
  27. ↑ Heinig M, Johnson RJ (December 2006). "Role of uric acid in hypertension, renal disease, and metabolic syndrome". Cleveland Clinic Journal of Medicine 73 (12): 1059–64. doi:10.3949/ccjm.73.12.1059. PMID 17190309.
  28. ↑ Richette P, Bardin T (January 2010). "Gout". Lancet 375 (9711): 318–28. doi:10.1016/S0140-6736(09)60883-7. PMID 19692116.
  29. ↑ Banach, K.; Bojarska, E.; Kazimierczuk, Z.; Magnowska, L.; Bzowska, A. Kinetic Model of Oxidation Catalyzed by Xanthine Oxidase—The Final Enzyme in Degradation of Purine Nucleosides and Nucleotides. Nucleic Acids 2005; 24, 465-469.
  30. ↑ "What is Gout: What Causes Gout?". MedicalBug. 6 January 2012. Retrieved 6 May 2012.
  31. 1 2 Malik, VS; Popkin, BM; Bray, GA; Després, JP; Willett, WC; Hu, FB. (2010). "Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis". Diabetes Care 33 (11): 2477–2483. doi:10.2337/dc10-1079. PMC 2963518. PMID 20693348.
  32. ↑ Tausche AK, Unger S, Richter K, et al. (May 2006). "Hyperurikämie und Gicht" [Hyperuricemia and gout: diagnosis and therapy]. Der Internist (in German) 47 (5): 509–20; quiz 521. doi:10.1007/s00108-006-1578-y. PMID 16586130.
  33. ↑ Gerhard N. Schrauzer (2002). "Lithium: Occurrence, Dietary Intakes, Nutritional Essentiality". Journal of the American College of Nutrition 21 (1): 14–21. doi:10.1080/07315724.2002.10719188. PMID 11838882.
  34. ↑ "NHS Clinical Knowledge Summaries". Archived from the original on 17 May 2013.
  35. ↑ Okamoto, K; Eger, BT; Nishino, T; Pai, EF; Nishino, T (2008). "Mechanism of inhibition of xanthine oxidoreductase by allopurinol: Crystal structure of reduced bovine milk xanthine oxidoreductase bound with oxipurinol". Nucleosides, nucleotides & nucleic acids 27 (6): 888–93. doi:10.1080/15257770802146577. PMID 18600558.
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  37. ↑ Nyhan WL (March 2005). "Lesch-Nyhan Disease". Journal of the History of the Neurosciences 14 (1): 1–10. doi:10.1080/096470490512490. PMID 15804753.
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  40. ↑ Dehghan A, van Hoek M, Sijbrands EJ, Hofman A, Witteman JC (February 2008). "High serum uric acid as a novel risk factor for type 2 diabetes". Diabetes Care 31 (2): 361–2. doi:10.2337/dc07-1276. PMID 17977935.
  41. 1 2 Nakagawa T, Hu H, Zharikov S, et al. (March 2006). "A causal role for uric acid in fructose-induced metabolic syndrome". American Journal of Physiology. Renal Physiology 290 (3): F625–31. doi:10.1152/ajprenal.00140.2005. PMID 16234313.
  42. ↑ Pak CY (September 2008). "Medical stone management: 35 years of advances". The Journal of Urology 180 (3): 813–9. doi:10.1016/j.juro.2008.05.048. PMID 18635234.
  43. ↑ Hess FM, King JC, Margen S (1 December 1977). "Effect of low zinc intake and oral contraceptive agents on nitrogen utilization and clinical findings in young women". The Journal of Nutrition 107 (12): 2219–27. PMID 925768.
  44. ↑ Garg JP, Chasan-Taber S, Blair A, et al. (January 2005). "Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial". Arthritis and Rheumatism 52 (1): 290–5. doi:10.1002/art.20781. PMID 15641045.
  45. 1 2 Toncev G, Milicic B, Toncev S, Samardzic G (May 2002). "Serum uric acid levels in multiple sclerosis patients correlate with activity of disease and blood–brain barrier dysfunction". European Journal of Neurology 9 (3): 221–6. doi:10.1046/j.1468-1331.2002.00384.x. PMID 11985629.
  46. ↑ SI Units for Clinical Data
  47. ↑ Hooper DC, Spitsin S, Kean RB, et al. (January 1998). "Uric acid, a natural scavenger of peroxynitrite, in experimental allergic encephalomyelitis and multiple sclerosis". Proceedings of the National Academy of Sciences of the United States of America 95 (2): 675–80. doi:10.1073/pnas.95.2.675. PMC 18479. PMID 9435251.
  48. ↑ Toncev G (October 2006). "Therapeutic value of serum uric acid levels increasing in the treatment of multiple sclerosis". Vojnosanitetski Pregled 63 (10): 879–82. doi:10.2298/VSP0610879T. PMID 17121380.
  49. ↑ Umeki S, Ohga R, Konishi Y, Yasuda T, Morimoto K, Terao A (November 1986). "Oral zinc therapy normalizes serum uric acid level in Wilson's disease patients". The American Journal of the Medical Sciences 292 (5): 289–92. doi:10.1097/00000441-198611000-00007. PMID 3777013.
  50. ↑ Becker BF (June 1993). "Towards the physiological function of uric acid". Free Radical Biology & Medicine 14 (6): 615–31. doi:10.1016/0891-5849(93)90143-I. PMID 8325534.
  51. ↑ Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA (2005). "Uric acid and oxidative stress". Current Pharmaceutical Design 11 (32): 4145–51. doi:10.2174/138161205774913255. PMID 16375736.
  52. ↑ Proctor PH (May 2008). "Uric acid: neuroprotective or neurotoxic?". Stroke 39 (5): e88; author reply e89. doi:10.1161/STROKEAHA.107.513242. PMID 18369163.
  53. ↑ Hayden MR, Tyagi SC (2004). "Uric acid: A new look at an old risk marker for cardiovascular disease, metabolic syndrome, and type 2 diabetes mellitus: The urate redox shuttle". Nutrition & Metabolism 1 (1): 10. doi:10.1186/1743-7075-1-10. PMC 529248. PMID 15507132.
  54. ↑ Cutler RG (December 1984). "Urate and ascorbate: their possible roles as antioxidants in determining longevity of mammalian species". Archives of Gerontology and Geriatrics 3 (4): 321–48. doi:10.1016/0167-4943(84)90033-5. PMID 6532339.
  55. ↑ Ames BN; et al. (November 1981). "Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis". Proc Natl Acad Sci U S A 78 (11): 6858–62. doi:10.1073/pnas.78.11.6858. PMC 349151. PMID 6947260.
  56. ↑ Gout Causes: List of Diet/Food Sources High or Low in Purine Content
  57. ↑ Gout Diet / Low Purine Diet - Limit High Purine foods
  58. ↑ Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G (March 2004). "Purine-rich foods, dairy and protein intake, and the risk of gout in men". The New England Journal of Medicine 350 (11): 1093–103. doi:10.1056/NEJMoa035700. PMID 15014182.
  59. ↑ Arthur Jensen (1996). "Giftedness ≠ Genius". In Camilla Perrson Benbow, David Lubinski. Intellectual talent: From Psychometrics to Giftedness. Hopkins. pp. 403–404. ISBN 9780801853012.
  60. 1 2 Arthur Jensen; SN Sinha (1993). "Physical correlates of human intelligence". In Philip A. Vernon. Biological approaches to the study of human intelligence. Norwood, NJ: Ablex Publ. Corp. ISBN 9780893917982.

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