Alloxan

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Alloxan [1]
Alloxan, skeletal formula.svg
Alloxan
Alloxan hydrate structure.png
Alloxan hydrate
Names
Preferred IUPAC name
5,5-Dihydroxypyrimidine-2,4,6(1H,3H,5H)-trione
Other names
5,5-Dihydroxybarbituric acid
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.057 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-062-0
MeSH Alloxan
PubChem CID
UNII
  • InChI=1S/C4H2N2O4/c7-1-2(8)5-4(10)6-3(1)9/h(H2,5,6,8,9,10) Yes check.svgY
    Key: HIMXGTXNXJYFGB-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H2N2O4/c7-1-2(8)5-4(10)6-3(1)9/h(H2,5,6,8,9,10)
    Key: HIMXGTXNXJYFGB-UHFFFAOYAQ
  • C1(=O)C(=O)NC(=O)NC1=O
Properties
C4H4N2O5
Molar mass 160.07 g/mol
Appearancepale yellow solid
Density 1.639 g/cm3 (anhydrous)
Melting point 254 °C (489 °F; 527 K) (decomposition)
0.29 g/100 mL [2]
Hazards
Safety data sheet (SDS) MSDS
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Alloxan, sometimes referred to as alloxan hydrate, is an organic compound with the formula OC(N(H)CO)2C(OH)2. It is classified as a derivative of pyrimidine. The anhydrous derivative OC(N(H)CO)2CO is also known, as well as a dimeric derivative. These are some of the earliest known organic compounds. They exhibit a variety of biological activities.

Contents

History and literature

The compound was discovered by Justus von Liebig and Friedrich Wöhler. It is one of the oldest named organic compounds. It was originally prepared in 1818 by Luigi Valentino Brugnatelli (1761-1818) [3] [4] and was named in 1838 by Wöhler and Liebig. [5] The name "Alloxan" emerged from an amalgamation of the words "allantoin" and "Oxalsäure" (oxalic acid). The alloxan model of diabetes was first described in rabbits by Dunn, Sheehan and McLetchie in 1943. [6] The name is derived from allantoin, a product of uric acid excreted by the fetus into the allantois, and oxaluric acid derived from oxalic acid and urea, found in urine.

Alloxan was used in the production of the purple dye murexide, discovered by Carl Wilhelm Scheele in 1776. Murexide is the product of the complex in-situ multistep reaction of alloxantin and gaseous ammonia.[ citation needed ] Murexide results from the condensation of the unisolated intermediate uramil with alloxan, liberated during the course of the reaction.

Murexide dye (right) from reaction of alloxantin (left) Murexide dye.png
Murexide dye (right) from reaction of alloxantin (left)

Scheele sourced uric acid from human calculi (such as kidney stones) and called the compound lithic acid. William Prout investigated the compound in 1818 and he used boa constrictor excrement with up to 90% ammonium acid urate.

In the chapter "Nitrogen" of his memoir The Periodic Table, Primo Levi tells of his futile attempt to make alloxan for a cosmetics manufacturer who has read that it can cause permanent reddening of the lips. Levi considers the droppings of pythons as a source for uric acid for making alloxan, but he is turned down by the director of the Turin zoo because the zoo already has lucrative contracts with pharmaceutical companies, so he is obliged to use chickens as his source of uric acid. The synthesis fails, however, "and the alloxan and its resonant name remained a resonant name." [7]

Synthesis

It was originally obtained by oxidation of uric acid by nitric acid. It is prepared by oxidation of barbituric acid by chromium trioxide. [8]

A dimeric derivative alloxantin can be prepared by partial reduction of alloxan with hydrogen sulfide. [2]

Alloxane (left) with dialuric acid (center) and alloxantin (right) Alloxane chemistry.png
Alloxane (left) with dialuric acid (center) and alloxantin (right)

Biological effects

Alloxan is a toxic glucose analogue, which selectively destroys insulin-producing cells in the pancreas (that is, beta cells) when administered to rodents and many other animal species. This causes an insulin-dependent diabetes mellitus (called "alloxan diabetes") in these animals, with characteristics similar to type 1 diabetes in humans. Alloxan is selectively toxic to insulin-producing pancreatic beta cells because it preferentially accumulates in beta cells through uptake via the GLUT2 glucose transporter. Alloxan, in the presence of intracellular thiols, generates reactive oxygen species (ROS) in a cyclic reaction with its reduction product, dialuric acid. The beta cell toxic action of alloxan is initiated by free radicals formed in this redox reaction. Studies suggests that alloxan does not cause diabetes in humans. [9] Others found a significant difference in alloxan plasma levels in children with and without diabetes Type 1. [10]

Impact upon beta cells

Because it selectively kills the insulin-producing beta-cells found in the pancreas, alloxan is used to induce diabetes in laboratory animals. [11] [12] This occurs most likely because of selective uptake of the compound due to its structural similarity to glucose as well as the beta-cell's highly efficient uptake mechanism (GLUT2). In addition, alloxan has a high affinity to SH-containing cellular compounds and, as a result, reduces glutathione content. Furthermore, alloxan inhibits glucokinase, a SH-containing protein essential for insulin secretion induced by glucose. [13]

Most studies have shown that alloxan is not toxic to the human beta-cell, even in very high doses, probably because of differing glucose uptake mechanisms in humans and rodents. [14] [15]

Alloxan is, however, toxic to the liver and the kidneys in high doses.

See also

Related Research Articles

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Insulin is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (INS) gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood into liver, fat and skeletal muscle cells. In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both. Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood. Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat.

<span class="mw-page-title-main">Pancreas</span> Organ of the digestive system and endocrine system of vertebrates

The pancreas is an organ of the digestive system and endocrine system of vertebrates. In humans, it is located in the abdomen behind the stomach and functions as a gland. The pancreas is a mixed or heterocrine gland, i.e., it has both an endocrine and a digestive exocrine function. 99% of the pancreas is exocrine and 1% is endocrine. As an endocrine gland, it functions mostly to regulate blood sugar levels, secreting the hormones insulin, glucagon, somatostatin and pancreatic polypeptide. As a part of the digestive system, it functions as an exocrine gland secreting pancreatic juice into the duodenum through the pancreatic duct. This juice contains bicarbonate, which neutralizes acid entering the duodenum from the stomach; and digestive enzymes, which break down carbohydrates, proteins and fats in food entering the duodenum from the stomach.

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The following is a glossary of diabetes which explains terms connected with diabetes.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

Drugs used in diabetes treat diabetes mellitus by decreasing glucose levels in the blood. With the exception of insulin, most GLP-1 receptor agonists, and pramlintide, all diabetes medications are administered orally and are thus called oral hypoglycemic agents or oral antihyperglycemic agents. There are different classes of hypoglycemic drugs, and selection of the appropriate agent depends on the nature of diabetes, age, and situation of the person, as well as other patient factors.

<span class="mw-page-title-main">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Alpha cell</span> Glucagon secreting cell

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<span class="mw-page-title-main">Pramlintide</span> Diabetes medication

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<span class="mw-page-title-main">Murexide</span> Chemical compound

Murexide (NH4C8H4N5O6, or C8H5N5O6·NH3), also called ammonium purpurate or MX, is the ammonium salt of purpuric acid. It is a purple solid that is soluble in water. The compound was once used as an indicator reagent. Aqueous solutions are yellow at low pH, reddish-purple in weakly acidic solutions, and blue-purple in alkaline solutions.

<span class="mw-page-title-main">Streptozotocin</span> Chemical compound

Streptozotocin or streptozocin (STZ) is a naturally occurring alkylating antineoplastic agent that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the islets of Langerhans and used in medical research to produce an animal model for hyperglycemia and Alzheimer's in a large dose, as well as type 2 diabetes or type 1 diabetes with multiple low doses.

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<span class="mw-page-title-main">Biguanide</span> Chemical compound

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<span class="mw-page-title-main">Luigi Valentino Brugnatelli</span> Italian chemist and inventor

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References

  1. Merck Index , 11th Edition, 281.
  2. 1 2 Tipson, R. S. (1953). "Alloxantin dihydrate". Organic Syntheses . 33: 3; Collected Volumes, vol. 4, p. 25.
  3. Luigi Valentino Brugnatelli; also cited as: Luigi Gaspari Brugnatelli and Luigi Vincenzo Brugnatelli.
  4. See:
  5. F. Wöhler und J. Liebig (1838) "Untersuchungen über die Natur der Harnsäure" (Investigations into the nature of uric acid), Annalen der Chemie und Pharmacie, 26 : 241-340. Alloxan is named on p. 252 and its preparation and properties appear on pp. 256 ff.
  6. Dunn, J. S.; Sheehan, H. L.; McLetchie, N. G. B. (1943). "Necrosis of Islets of Langerhans Produced Experimentally". Lancet. 241 (6242): 484–487. doi:10.1016/S0140-6736(00)42072-6.
  7. Primo Levi, The Periodic Table (New York: Schocken, 1984), translated by Raymond Rosenthal, 183.
  8. Holmgren, A. V.; Wenner, W. (1952). "Alloxan monohydrate". Organic Syntheses . 32: 6; Collected Volumes, vol. 4, p. 23.
  9. Lenzen, S. (2008). "The Mechanisms of Alloxan- and Streptozotocin-induced Diabetes". Diabetologia. 51 (2): 216–226. doi: 10.1007/s00125-007-0886-7 . PMID   18087688.
  10. Mrozikiewicz, A.; Kielstrokczewska-Mrozikiewicz, D.; Lstrokowicki, Z.; Chmara, E.; Korzeniowska, K.; Mrozikiewicz, P. M. (1994). "Blood Levels of Alloxan in Children with Insulin-dependent Diabetes Mellitus". Acta Diabetologica. 31 (4): 236–237. doi:10.1007/bf00571958. PMID   7888696. S2CID   12726659.
  11. Danilova I.G.; Sarapultsev P.A.; Medvedeva S.U.; Gette I.F.; Bulavintceva T.S.; Sarapultsev A.P. (2014). "Morphological Restructuring of Myocardium During the Early Phase of Experimental Diabetes Mellitus". Anat. Rec. 298 (2): 396–407. doi:10.1002/ar.23052. hdl: 10995/73117 . PMID   25251897. S2CID   205412167.
  12. Alfredo Rigalli; Loreto, Veronica Di, eds. (2009-05-12). Experimental Surgical Models in the Laboratory Rat. Boca Raton: CRC Press. doi:10.1201/9781420093278. ISBN   978-0-429-14721-0.
  13. Szkudelski T (2001). "The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas". Physiol Res. 50 (6): 536–546. PMID   11829314.
  14. Tyrberg, B.; Andersson, A.; Borg, L. A. (2001). "Species Differences in Susceptibility of Transplanted and Cultured Pancreatic Islets to the β-Cell Toxin Alloxan". General and Comparative Endocrinology. 122 (3): 238–251. doi:10.1006/gcen.2001.7638. PMID   11356036.
  15. Eizirik, D. L.; Pipeleers, D. G.; Ling, Z.; Welsh, N.; Hellerström, C.; Andersson, A. (1994). "Major Species Differences between Humans and Rodents in the Susceptibility to Pancreatic β-Cell Injury". Proceedings of the National Academy of Sciences of the United States of America. 91 (20): 9253–9256. Bibcode:1994PNAS...91.9253E. doi: 10.1073/pnas.91.20.9253 . PMC   44790 . PMID   7937750.