Uric Acid

URIC ACID (acidum uricum), 2, 6, 8-trioxypurine C₅H₄N₄O₃. Uric acid was discovered by Scheele in 1776 and synthesized in 1882 by Horbaczewski by heating glycocoll and urea, or urea and trichlorolactic acid. Uric acid was also obtained by splitting off water from pseudouric acid (Fischer).

Uric acid is contained in small amounts in the urine of most mammals, including humans; in significant amounts, in the urine of birds, scaled amphibians, insects, and other invertebrates; it often forms part of urinary calculi and is the main component of gouty deposits. In human blood, uric acid is contained in trace amounts; however, its quantity can strongly increase in gout, leukemia, pneumonia, nephritis (delayed excretion), and other diseases. Uric acid has also been found in human milk, saliva, sweat, transudates, ascitic fluid, and meconium; it is contained in large quantities in pigeon droppings, guano (accumulations of seabird droppings on the Chilean coast and in other places in South America), and in snake excrement; it has not been found in human excrement. Uric acid was detected in the spores of Aspergillus oryzae.

Uric acid is a diureide (contains 2 urea residues in the molecule) and can exist in two tautomeric forms: the oxo form (lactam form) and the oxy form (lactim form). Uric acid is a weak dibasic acid, very sparingly soluble in cold water (1 : 39,500 at 18°), sparingly in boiling water (1 : 1,600), more easily in blood serum, and insoluble in alcohol and ether. It dissolves easily, especially upon heating, in caustic and carbonate alkalis, in many organic bases, and in concentrated H₂SO₄ (precipitating from it upon dilution with water). Salts of uric acid and alkali metals (urates): neutral ones (Na₂C₅H₂N₄O₃) are easily soluble in water; acid ones are less soluble (NaC₅H₃N₄O₃ is the main component of sedimentum lateritium, and often enters into the composition of urinary calculi), especially acid ammonium urate, which, in view of its difficult solubility, is quite often found in urine sediments and urinary calculi and serves for the isolation of uric acid in its quantitative determination by the Folin and Shaffer method; neutral salts of uric acid are never found in the organism, only acid ones or free uric acid.

Pure uric acid is a colorless crystalline powder under the microscope. Crystals of uric acid isolated from urine are colored yellow-red or sandy by urine pigment and have a very diverse shape; rhomboidal forms and whetstones predominate. Uric acid possesses reducing ability: for example, upon boiling in an alkaline medium, it reduces copper hydroxide to cuprous oxide. Uric acid gives sparingly soluble double salts with silver and alkali or alkaline-earth metals; the isolation of uric acid from solutions during its quantitative determination by the Ludwig and Salkowski method occurs in the form of the silver-magnesium salt. Sparingly soluble mixtures (or perhaps chemical compounds) of acid urates with free uric acid (so-called quadriurates) have been found in the excrement of birds and snakes, and in sedimentum lateritium.

Both uric acid itself and its acid salts are capable of forming colloidal solutions with a higher substance content in solution than corresponds to the true solubility of uric acid or its salt; the excess dissolved substance gradually precipitates upon standing of the solution. This property is important in the formation of gouty deposits. A characteristic reaction for uric acid is the murexide test, which is used to detect uric acid in urinary stones: to a small amount of dry uric acid on a porcelain lid or dish, 1-2 drops of concentrated HNO₃ are added and carefully evaporated to dryness on a bare flame; if the red residue, containing oxidation and hydration products of uric acid including alloxantin, is moistened with ammonia, a purple-red coloration is obtained (formation of murexide—the ammonium salt of purpuric acid).

If instead of ammonia the residue is moistened with caustic soda or potash, a blue-violet coloration is obtained. Upon oxidation of uric acid in an acidic medium, the main reaction product is alloxan and urea; in an alkaline or neutral medium, it is allantoin (see). These substances, as well as oxaluric acid (NH₂.CO.NH.CO.COOH) and oxalic acid, which are also formed upon the oxidation of uric acid, have been found in the organism. Upon the reduction of uric acid, xanthine and hypoxanthine are formed. When heated, dry uric acid chars, decomposing to form urea, cyanuric acid, ammonium carbonate, and hydrocyanic acid. Ulpiani isolated bacteria that decompose uric acid into urea and CO₂. Under the influence of other bacteria (Liebert), uric acid is split with the formation of allantoin, urea, oxalic acid, CO₂, and NH₃. The conversion of uric acid into allantoin also occurs under the influence of the uricolytic enzyme (uricase), found in the organism of many animals and apparently absent in humans and birds.

To isolate uric acid from urine, the latter is acidified with HCl and left for a day—crystals of uric acid form at the bottom and along the walls of the vessel, often floating on the surface as well. Bird droppings or urinary stones are extracted by heating with caustic soda, the extract is saturated with carbonic acid, the precipitated acid sodium urate is filtered off, and it is decomposed with HCl.

Nucleoproteins → Polynucleotides → Nuclease → Mononucleotides → Nucleotidase → Nucleosides → Desamidase (guanosine, adenosine). Xanthosine, Inosine → Nucleosidase → Xanthine, Hypoxanthine → Xanthine oxidase → Uric acid ⇄ Xanthine → Uric acid.

Uric acid is the main product of purine metabolism in the human body. Under the influence of enzymes found in various organs, the nucleic bases of cell nucleus nucleoproteins are converted into uric acid upon exposure to air. The process can be represented by a schema (see art. 110). On average, an adult human excretes 0.5 g of uric acid per day, which corresponds to 1-3% of the total urinary nitrogen. The amount of uric acid excreted in the urine varies depending on the amount of purines in food (exogenous uric acid) and in the body itself (endogenous uric acid). According to some authors, the amount of endogenous uric acid is constant for a given individual, but differs among different persons. When feeding on a diet rich in ready-made purines or cell nuclei, in febrile states, and in leukemia, the formation and excretion of uric acid increases. In children, uric acid is excreted in relatively greater amounts than in adults, and they frequently exhibit deposits of uric acid and its salts in the kidneys—uric acid infarcts. Among medicinal substances, quinine and atropine decrease, while pilocarpine and salicylic acid increase the excretion of uric acid from the organism. Uric acid is of particular importance in gout (see). In the dog, cat, rabbit, and some other animals, the main product of purine metabolism is not uric acid, but allantoin, whereas in humans the formation of allantoin is negligible. This difference is apparently related to the presence in the liver and other organs of these animals of the uricolytic enzyme, which is absent in humans. However, a significant portion of intravenously administered uric acid is also broken down in humans. There are indications of partial breakdown of uric acid in the human body with the formation of urea. Consequently, the magnitude of daily uric acid excretion cannot serve as an exact measure of its formation in the body. The formation of uric acid in mammals (experiments on dogs) occurs in many organs (liver, spleen, muscles). In birds, the bulk of nitrogen is excreted in the form of uric acid, and only 2-4% accounts for urea. The chemistry of uric acid formation in birds also differs from that in humans and other mammals: the main part of uric acid is formed synthetically from proteins that yield ammonium lactate, which is subsequently converted into uric acid in the liver via synthesis, the liver being the main site of uric acid formation in birds. It is possible that part of the uric acid is also formed by synthesis in the mammalian organism. (On methods for the quantitative determination of uric acid, see Urine, Blood.) To determine the amount of uric acid in any organ, the latter is comminuted and heated (50-500 g) with 2 l of water and 10 cm³ of concentrated H₂SO₄ for 12 hours without bringing to a boil; it is left to stand for 12 hours, the residue is filtered off and extracted 2 more times with 0.5% H₂SO₄ upon heating for 2-3 hours each time. The combined filtrates are mixed with an amount of barium hydroxide equivalent to the amount of H₂SO₄ used; the BaSO₄ precipitate is allowed to settle upon heating for several hours, and then filtered. The filtrate is neutralized with lithium carbonate and left at 30-40°, maintaining a neutral reaction of the liquid by adding acetic acid; the liquid becomes alkaline as the precipitate forms. The settled liquid should give no turbidity with either barium hydroxide or Li₂CO₃. The precipitate is filtered off and washed repeatedly with hot water. The filtrate is evaporated on a water bath, filtered from the albumose precipitate, and uric acid is precipitated in the form of a double silver-magnesium compound (see Urine). The uric acid content in serous fluids is determined in a similar manner. Among the derivatives of uric acid, human and other mammalian erythrocytes contain small amounts of uric acid riboside, a compound formed by the elimination of 1 molecule of water from a molecule of uric acid and a molecule of d-ribose (Davis, Newton, Benedict); it represents crystals that are very sparingly soluble in water, does not reduce Fehling's solution, and is not precipitated from solutions by silver-magnesium mixture. Upon the action of methyl iodide (CH₃I) or other methylating agents on uric acid and its salts, products of the successive substitution of H atoms at nitrogen by methyl are obtained—methyluric acids. Upon the action of POCl₃ on uric acid or methyluric acids, a successive substitution of hydroxyl groups (uric acid reacts here in the oxy-form) with Cl occurs, which can be replaced by hydrogen upon reduction. Thus, the transition is accomplished from uric acid and methyluric acids to purine derivatives containing less oxygen than uric acid: xanthine and methylxanthines, among which the alkaloids caffeine and theobromine are of great pharmaceutical importance.

L. Broude. The question of whether uric acid in the human organism is the end product of purine metabolism has not yet received a final resolution despite the abundance of experimental data in this field. In all mammals except man and the anthropoid ape, under the action of the so-called uricolytic enzyme, uric acid undergoes further decomposition, the most important product of which is allantoin. The fact that upon feeding nucleoproteins only a portion of the purines can be detected in the urine in the form of uric acid is interpreted in various ways. Thannhauser and Dorfmuller believe that the purine ring is cleaved in the intestine due to the activity of the intestinal flora, and by no means in intermediate metabolism, as believed by Schittenhelm, Harpuder, and others. Chantraine found complete excretion of uric acid in self-experiments a long time after its administration. Bass, Griesbach, and others explain the insignificant amount of uric acid in the blood detected shortly after administration not by uricolysis, but by the fact that the main part of uric acid is retained in the tissues. A. Jung observed a varying degree of uric acid excretion depending on whether it was administered in an alkaline or acidic solution; in the second case, a larger amount was excreted. E. Steinitz obtained double amounts of uric acid in human blood upon its prolonged standing in a thermostat. Along with this, the excretion of uric acid upon its injection into healthy individuals has been repeatedly observed. Thus, the facts on which certain authors base themselves to resolve the question of the existence of uricolysis are clearly insufficient, especially since neither the uricolytic enzyme nor the decomposition products of uric acid (allantoin) have been found in the human organism. The amount of excreted uric acid and the duration of its stay in the organism depend on the state not only of the kidneys, but also of the tissues. There is every reason to assume that uric acid salts entering the bloodstream travel a complex path before reaching the kidneys and, as has already been proved with respect to water and NaCl, are preliminarily retained by the tissues; depending on the state of the latter, they remain there for a longer or shorter period and are only then excreted by the kidneys. Certain clinicians (Gudzent) adhere to the opinion that the deposition of uric acid in tissues can take place only as a result of their pathological "affinity" for uric acid. The site of excretion of almost all uric acid excreted by the organism is the kidney. True, the fact of uric acid excretion by other organs, mainly the liver, can be considered established. Proceeding from this, attempts were made to substantiate the treatment of patients with delayed uric acid excretion with cholagogic mineral waters. An increased amount of uric acid was also found in the gastric juice of uremics. Uric acid was detected in sweat and saliva (in men 2.1 mg%, in women 1.11 mg%); observations indicate that the amount of uric acid is directly related to the rate of saliva secretion and the nature of the stimulus. As a result of studies conducted on humans and animals, it can be considered established that the kidneys prevail so much in relation to uric acid excretion over all other excretory organs that the latter can be practically neglected. The presence of the two types of uric acid mentioned above (endogenous and exogenous uric acid) cannot yet explain all phenomena of uric acid metabolism. Thus, for example, it has been noted that during starvation, the amount of excreted uric acid is significantly lower than with purine-free nutrition. On the other hand, after meat food, the uric acid content in the urine is greater than that which would be expected from a simple summation of endogenous and exogenous uric acid. To explain these phenomena, it is assumed (Maresch) that there is a third type of uric acid (Reizharnsaure of German authors) and it is considered the result of increased activity of the digestive glands due to their irritation by food. Abl's studies reveal that not only food, but also certain pharmacological irritants causing hyperemia and intestinal hypersecretion thereby enhance uric acid production. Abl came to this conclusion by studying the effect of atophan, nucleic acid, and thymus on a patient with an anus praeternaturalis. Thus, the uric acid excreted after taking purine-containing food consists of exo-, endo-, and Reiz-uric acid. The very mechanism of increased uric acid excretion under the action of food or pharmacological substances can be imagined in one of the following forms: 1) enhancement of nucleic acid metabolism, 2) mobilization of purines retained anywhere in the organism, 3) increase in renal secretion in relation to uric acid. Accelerated uric acid excretion under the influence of adrenaline and slowed down after the administration of ergotamine suggest that both the mobilization of reserve purines and the deposition of uric acid are under the influence of the autonomic nervous system. In the blood, uric acid is in the form of monosodium urate salts. The solubility of uric acid, and hence the greater or lesser tendency to precipitate from solution, depends on which form of uric acid we are dealing with—the lactam or the lactim form. Gudzent established that the readily soluble lactam form transforms into the less soluble lactim form. It has not yet been clarified in which of the two forms uric acid circulates in the blood. In 1860, Garrod claimed that the retention of uric acid in tissues is exclusively due to pathological changes in the kidneys. Since Garrod's assertion was not supported by either anatomical changes in the kidney or impairment of its remaining functions, this theory was subsequently abandoned. Only recently have Thannhauser and Lichtwitz come to the conviction that impairments of individual kidney functions can occur independently of each other and not be accompanied by anatomical changes. In any case, it can be considered established that primary damage to the renal tissue, especially its glomerular part (nephritis, nephrosclerosis, pyelonephritis), is accompanied by the retention of uric acid in the blood (Thannhauser, Lichtwitz, Dubnova, and Itsigson). Kraus, Lichtwitz, Mendel, and others assert that in renal diseases, the earliest and most serious symptom is an increase in blood uric acid, which rises earlier than other nitrogenous slags. At the autopsy of renal patients in various stages of the disease, uric acid deposits are often found in the tissues, which do not make themselves felt during life. Observations and experiments indicate that merely an increase in blood uric acid is insufficient for its deposition in tissues. Thus, in certain forms of leukemias, in croupous pneumonia, malignant neoplasms, Banti's disease, and other diseases, a large amount of uric acid is observed in the blood, yet cases of its deposition in the tissues are very rare. Also, in the blood itself, no precipitation of excess uric acid is detected despite the fact that in some cases its content far exceeded (400 mg %) the solubility limit. In the presence of excess uric acid in the blood, an essential condition for the deposition of uric acid in the tissues is apparently, if not anatomical or histological changes of the latter, at least changes in their colloids. By injecting renal poisons (chromic salt) into birds, Epstein managed to cause uric acid deposits in the tissues; however, the possibility is not excluded that the latter were subjected to the direct action of these poisons. While many consider tissue necrosis a necessary condition for the precipitation of uric acid in them, Riehl found its deposits precisely in healthy tissues and not in adjacent necrotic ones. The conclusions that Riehl draws from this observation are objected to by Lichtwitz, Freudweiler, His, and many others. However, the experience of many researchers indicates that the appearance of uric acid crystals in cartilage after its injection takes place only in those cases when alcohol, which precipitates proteins, is simultaneously administered. From this point of view, deep tissue damage such as necrosis is by no means required for uric acid deposition; minor changes in the protein substance are sufficient. Thus, there is an opinion that an increased NaCl content in cartilage serves as a favorable moment for the deposition of uric acid in them. The special attention paid to all these questions is due to the role of uric acid in gouty diseases. There are indications in the literature, albeit few, on the curative effect of uric acid in exudative and inflammatory processes.