Cantharidin

From Wikipedia, the free encyclopedia

This is an old revision of this page, as edited by AnomieBOT (talk | contribs) at 06:38, 14 December 2015 (Dating maintenance tags: {{Full}} {{What?}} {{Expand section}} {{Cn}}). The present address (URL) is a permanent link to this revision, which may differ significantly from the current revision.

Cantharidin
Names
IUPAC names
2,6-Dimethyl-4,10-dioxatricyclo-
[5.2.1.02,6]decane-3,5-dione
Other names
Cantharidin, Spanish Fly
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.000.240 Edit this at Wikidata
KEGG
UNII
  • InChI=1S/C10H12O4/c1-9-5-3-4-6(13-5)10(9,2)8(12)14-7(9)11/h5-6H,3-4H2,1-2H3/t5-,6+,9-,10+ checkY
    Key: DHZBEENLJMYSHQ-YUMGAWCOSA-N checkY
  • O=C2OC([C@@]1(C)[C@@H]3CC[C@@H](O3)[C@]12C)=O
Properties
C10H12O4
Molar mass 196.20 g/mol
Density 1.41 g/cm3
Melting point 212 °C (414 °F; 485 K)
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Highly toxic
GHS labelling:
GHS06: Toxic
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 4: Very short exposure could cause death or major residual injury. E.g. VX gasFlammability 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilInstability 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
4
1
1
Lethal dose or concentration (LD, LC):
0.03–0.5 mg/kg (human)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Cantharidin is a terpene secreted by many species of blister beetles, and most notably by the Spanish fly, Lytta vesicatoria. The false blister beetles, cardinal beetles, and soldier beetles also produce cantharidin. It can be poisonous if taken internally, and externally it is a vesicant (blistering agent), exposure to which can cause severe chemical burns. Properly dosed and applied, the same properties can be used to make it an effective topical medication for some conditions.[clarification needed]

Chemistry and nomenclature

Cantharidin, from the Greek kantharis, for beetle,[1][full citation needed] is a monoterpene, and so contains in its framework two isoprene units derived by biosynthesis from two equivalents of isopentenyl pyrophosphate.[citation needed] Its skeleton is tricyclic, formally, a tricyclo- [5.2.1.02,6]decane skeleton. Its functionalities include an carboxylic acid anydride (-CO-O-CO-) substructure in one of its rings, as well as a cyclic ether in its bicyclic ring system.[citation needed]

History

Hycleus lugens, an aposematically colored beetle, secretes cantharidin.

Cantharidin was first isolated in 1810 by Pierre Robiquet,[2] a French chemist then living in Paris, from Lytta vesicatoria. Robiquet demonstrated that cantharidin was the actual principle responsible for the aggressively blistering properties of the coating of the eggs of that insect, and established that cantharidin had definite toxic properties comparable in degree to those of the most virulent poisons known in the 19th century, such as strychnine.[3] It is an odorless and colorless solid at room temperature. It is secreted by the male blister beetle and given to the female as a copulatory gift during mating. Afterwards, the female beetle covers her eggs with it as a defense against predators. The complete mechanism of the biosynthesis of cantharidin is currently unknown.

The level of cantharidin in blister beetles can be quite variable. Among blister beetles of the genus Epicauta in Colorado, E. pennsylvanica contains about 0.2 mg, E. maculata contains 0.7 mg, and E. immaculata contains 4.8 mg per beetle; males also contain higher levels than females.[4]

There are are many examples in historical sources that reference preparations of this natural product:[citation needed]

  • In Roman times, Livia, the scheming wife of Augustus Caesar slipped it into food, hoping to inspire her guests to some indiscretion with which she could later blackmail them.[5]
  • Henry IV (1050–1106) is said to have consumed Spanish fly.[6]
  • In 1572, Ambroise Paré wrote an account of a man suffering from "the most frightful satyriasis" after taking a potion composed of nettles and cantharides.[7]
  • In the 1670s, Spanish fly was mixed with dried mole's and bat's blood for a love charm made by the magician La Voisin.[8]
  • It was slipped into the food of Louis XIV to secure the king's lust for Madame de Montespan.[dubious – discuss][citation needed]
  • In the 18th century, cantharides became fashionable, known as pastilles Richelieu in France.[citation needed]
  • Marquis de Sade is said to have given aniseed-flavored pastilles that were laced with Spanish fly to prostitutes at an orgy in 1772. He was sentenced to death for poisoning and sodomy, but later reprieved on appeal.[9]

Medical uses

Diluted solutions of cantharidin can be used as a topical medication to remove warts[10][11] and tattoos and to treat the small papules of Molluscum contagiosum.[12]

Medical risks for humans

As a blister agent, cantharidin has the potential to cause adverse effects when used medically; for this reason, it has been included in a list of "problem drugs" used by dermatologists[13] and emergency personnel.[14] However, when compounded properly and applied in the clinic topically by a medical provider familiar with its effects and uses, cantharidin can be safely and effectively used to treat some benign skin lesions like warts and molluscum.[15]

When ingested by humans, the LD50 is around 0.5 mg/kg, with a dose of as little as 10 mg being potentially fatal. Ingesting cantharidin can initially cause severe damage to the lining of the gastrointestinal and urinary tracts, and may also cause permanent renal damage. Symptoms of cantharidin poisoning include blood in the urine, abdominal pain, and rarely prolonged erections.[13]

Aphrodisiac

Main article: Spanish fly

Cantharidin has been used since ancient times as an aphrodisiac, possibly because its physical effects were perceived to mimic those of sexual arousal,[16] and because it can cause priapism.[17] According to Tacitus, it was used by the empress Livia to entice members of the imperial family to commit sexual indiscretions (giving her information to hold over them). The Marquis de Sade inadvertently poisoned two prostitutes, nearly killing them, by giving them cantharidin.[18]

The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.[19][20] As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.[14]

Medical risks for animals

Horses are highly sensitive to cantharidin: the LD50 for horses is roughly 1 mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them.[21] Cantharidin has activity against parasites of great bustards, a strongly polygynous bird species.[22] These birds are not immune to the toxicity of cantharidin; they become intoxicated after ingesting some blister beetles.[23]

Research

Mechanism of action

Cantharidin is absorbed by the lipid membranes of epidermal cells, causing the release of serine proteases, enzymes that break the peptide bonds in proteins. This causes the disintegration of desmosomal plaques, cellular structures involved in cell-to-cell adhesion, leading to detachment of the tonofilaments that hold cells together. The process leads to the loss of cellular connections (acantholysis) and ultimately blistering of the skin. Lesions heal without scarring.[15][24]

Bioactivities

Topical treatment with cantharidin appears to have some effect in an animal model of cutaneous leishmaniasis.[25] In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells.[26][27][28] Laboratory studies with cultured tumor cells suggest that this activity may be the result of PP2A inhibition.[29][30]

Popular culture

Natural products preparations containing cantharidin appear frequently in popular media. Examples include:

Further reading

  • Dupuis, Gérard & Berland, Nicole (2004). "Cantharidin: Origin and synthesis," Lille, FR: Lycée Faidherbe, see [1], accessed 13 December 2015.

References

  1. ^ Medical Dictionary, 2009, 2012, Farlex and Partners.[full citation needed]
  2. ^ Wolter, H. (1995). Kompendium der Tierärztlichen Homöopathie. Enke. ISBN 978-3432978925.
  3. ^ Robiquet, P. J. (1810). "Expériences sur les cantharides". Annales de Chimie. 76: 302–322.
  4. ^ Capinera, J. L.; Gardner, D. R.; Stermitz, F. R. (1985). "Cantharidin Levels in Blister Beetles (Coleoptera: Meloidae) Associated with Alfalfa in Colorado". Journal of Economic Entomology. 78 (5): 1052–1055.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ James, Peter (1995). Ancient Inventions. Ballantine Books. p. 177. ISBN 0-345-40102-6.
  6. ^ Eplett, Layla (13 March 2012). "When Sparks Fly: Aphrodisiacs and the Fruit Fly". Scientific American. Retrieved 18 November 2014.
  7. ^ (Milsten 2000, p. 170)
  8. ^ (Cavendish 1968, p. 333)
  9. ^ Ford, Peter; Howell, Michael (1985). The beetle of Aphrodite and other medical mysteries. New York: Random House. ISBN 0-394-54797-7.{{cite book}}: CS1 maint: multiple names: authors list (link)
  10. ^ Epstein, W. L.; Kligman, A. M. (1958). "Treatment of warts with cantharidin". AMA Archives of Dermatology. 77 (5): 508–511. doi:10.1001/archderm.1958.01560050014003. PMID 13519856.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Bacelieri, R.; Johnson, S. M. (2005). "Cutaneous warts: An evidence-based approach to therapy". American Family Physician. 72 (4): 647–652. PMID 16127954.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ "Molluscum contagiosum". Merck Manuals. November 2005. Retrieved 2007-10-21.
  13. ^ a b Binder, R. (1979). "Malpractice--in dermatology". Cutis; Cutaneous Medicine for the Practitioner. 23 (5): 663–666. PMID 456036.
  14. ^ a b Karras, D. J.; Farrell, S. E.; Harrigan, R. A.; Henretig, F. M.; Gealt, L. (1996). "Poisoning from "Spanish fly" (cantharidin)". The American Journal of Emergency Medicine. 14 (5): 478–483. doi:10.1016/S0735-6757(96)90158-8. PMID 8765116. While most commonly available preparations of Spanish fly contain cantharidin in negligible amounts, if at all, the chemical is available illicitly in concentrations capable of causing severe toxicity. Symptoms of cantharidin poisoning include burning of the mouth, dysphagia, nausea, hematemesis, gross hematuria, and dysuria. Mucosal erosion and hemorrhage is seen in the upper gastrointestinal (GI) tract. Renal dysfunction is common and related to acute tubular necrosis and glomerular destruction.
  15. ^ a b Moed, L.; Shwayder, T. A.; Chang, M. W. (2001). "Cantharidin revisited: A blistering defense of an ancient medicine" (PDF). Archives of Dermatology. 137 (10): 1357–1360. doi:10.1001/archderm.137.10.1357. PMID 11594862.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ John L. Capinera, Encyclopedia of Entomology, Volume 4, Springer Science & Business Media, 2008. p.2010
  17. ^ Peter V. Taberner, Aphrodisiacs: The Science and the Myth, Springer Science & Business Media, 2012, pp.100ff
  18. ^ Neil Schaeffer, The Marquis de Sade: A Life, Harvard University Press, 2000, p.58.
  19. ^ Shamloul, R. (2010). "Natural aphrodisiacs". The Journal of Sexual Medicine. 7 (1 Pt 1): 39–49. doi:10.1111/j.1743-6109.2009.01521.x. PMID 19796015.
  20. ^ Sandroni, P. (2001). "Aphrodisiacs past and present: A historical review". Clinical Autonomic Research. 11 (5): 303–307. doi:10.1007/BF02332975. PMID 11758796. Cantharidin ("Spanish fly") is a chemical with vesicant properties derived from blister beetles, which has been used for millennia as a sexual stimulant by both sexes. Its mode of action is by inhibition of phosphodiesterase and protein phosphatase activity and stimulation of β-receptors, inducing vascular congestion and inflammation. Morbidity from its abuse is significant. The gastrointestinal tract sustains the brunt of toxicity, resulting in fatal hemorrhages. Renal toxicity is a result of its renal excretion, which may lead to acute tubular necrosis. Cardiac effects are most likely due to hemorrhagic shock, but they also can be due to myofibril degeneration, mitochondrial swelling, and pericardial and subendocardial hemorrhages.
  21. ^ "Blister Beetle Poisoning / Cantharidin toxicosis". Retrieved 2010-12-31.
  22. ^ Bravo, C.; Bautista, L.M.; García-París, M.; Blanco, G.; Alonso, J.C. (2014). "Males of a Strongly Polygynous Species Consume More Poisonous Food than Females". PLoS ONE. 9 (10): e111057. doi:10.1371/journal.pone.0111057. PMID 25337911.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  23. ^ Sánchez-Barbudo, I. S.; Camarero, P.; García-Montijano, M.; Mateo, R. (2012). "Possible cantharidin poisoning of a great bustard (Otis tarda)". Toxicon. 59 (1): 100–103. doi:10.1016/j.toxicon.2011.10.002. PMID 22001622.
  24. ^ Bertaux, B.; Prost, C.; Heslan, M.; Dubertret, L. (1988). "Cantharide acantholysis: endogenous protease activation leading to desmosomal plaque dissolution". British Journal of Dermatology. 118 (2): 157–165. doi:10.1111/j.1365-2133.1988.tb01769.x. PMID 3279999.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  25. ^ Ghaffarifar, F. (2010). "Leishmania major: In vitro and in vivo anti-leishmanial effect of cantharidin". Experimental Parasitology. 126 (2): 126–129. doi:10.1016/j.exppara.2010.04.004. PMID 20435039.
  26. ^ Ratcliffe, N. A.; Mello, C. B.; Garcia, E. S.; Butt, T. M.; Azambuja, P. (2011). "Insect natural products and processes: New treatments for human disease". Insect Biochemistry and Molecular Biology. 41 (10): 747–769. doi:10.1016/j.ibmb.2011.05.007. PMID 21658450.
  27. ^ Chen, Y. N.; Cheng, C. C.; Chen, J. C.; Tsauer, W.; Hsu, S. L. (2003). "Norcantharidin-induced apoptosis is via the extracellular signal-regulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells". British Journal of Pharmacology. 140 (3): 461–470. doi:10.1038/sj.bjp.0705461. PMC 1574052. PMID 12970086.
  28. ^ Zhang, C.; Peng, Y.; Wang, F.; Tan, X.; Liu, N.; Fan, S.; Wang, D.; Zhang, L.; Liu, D.; Wang, T.; Wang, S.; Zhou, Y.; Su, Y.; Cheng, T.; Zhuang, Z.; Shi, C. (2010). "A synthetic cantharidin analog for the enhancement of doxorubicin suppression of stem cell-derived aggressive sarcoma". Biomaterials. 31 (36): 9535–9543. doi:10.1016/j.biomaterials.2010.08.059. PMID 20875681.
  29. ^ Dorn, D. C.; Kou, C. A.; Png, K. J.; Moore, M. A. S. (2009). "The effect of cantharidins on leukemic stem cells". International Journal of Cancer. 124 (9): 2186–2199. doi:10.1002/ijc.24157. PMID 19123473.
  30. ^ Li, W.; Xie, L.; Chen, Z.; Zhu, Y.; Sun, Y.; Miao, Y.; Xu, Z.; Han, X. (2010). "Cantharidin, a potent and selective PP2A inhibitor, induces an oxidative stress-independent growth inhibition of pancreatic cancer cells through G2/M cell-cycle arrest and apoptosis". Cancer Science. 101 (5): 1226–1233. doi:10.1111/j.1349-7006.2010.01523.x. PMID 20331621.
  31. ^ "Bill Cosby 'date rape' routine surfaces". Sydney Morning-Herald. 18 November 2014. Retrieved 18 November 2014. From a 2-minute 55-second routine on the 1969 Cosby comedy album It's True! It's True!.
  32. ^ Planer, Lindsay. "Bill Cosby: It's True! It's True!" All Music Guide. Retrieved November 24, 2014.

External links

Retrieved from "https://en.wikipedia.org/w/index.php?title=Cantharidin&oldid=695171284"