Cantharidin

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
56-25-7 N
ChEMBL ChEMBL48449 N
ChemSpider 2297293 YesY
Jmol 3D model Interactive image
KEGG C16778 N
UNII IGL471WQ8P YesY
Properties
C10H12O4
Molar mass 196.20 g/mol
Density 1.41 g/cm3
Melting point 212 °C (414 °F; 485 K)
Hazards
Main hazards Highly toxic
GHS pictograms
T+
R-phrases R28-R36/37/38
S-phrases S53-S45
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g., canola oil Health code 4: Very short exposure could cause death or major residual injury. E.g., VX gas Reactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g., calcium Special hazards (white): no codeNFPA 704 four-colored diamond
1
4
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 YesYN ?)
Infobox references

Cantharidin is an odorless, colorless terpene secreted by many species of blister beetles, including broadly in genus Epicauta, and in species Lytta vesicatoria (Spanish fly). False blister beetles, cardinal beetles, and soldier beetles also produce cantharidin. Poisoning from the substance is a significant veterinary concern, especially in horses by Epicauta species, and in humans it also can also be poisonous if taken internally (where the origin is most often experimental self-exposure). Externally, cantharidin is a potent vesicant (blistering agent), exposure to which can cause severe chemical burns. Properly dosed and applied, the same properties have been used for effective topical medications for some conditions.

Chemistry

Structure and nomenclature

Cantharidin, from the Greek kantharis, for beetle,[1] is an odorless, colorless natural product with solubility in various organic solvents, but only slightly solubility in water.[2] It is a monoterpene, and so contains in its framework two isoprene units derived by biosynthesis from two equivalents of isopentenyl pyrophosphate. (The complete mechanism of the biosynthesis of cantharidin is currently unknown.) Its skeleton is tricyclic, formally, a tricyclo-[5.2.1.02,6]decane skeleton. Its functionalities include an carboxylic acid anhydride (-CO-O-CO-) substructure in one of its rings, as well as a cyclic ether in its bicyclic ring system.

Distribution and availability

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.[3]

History

Hycleus lugens, an aposematically colored beetle, secretes cantharidin.

Cantharidin was first isolated in 1810 by Pierre Robiquet,[4] 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.[5] 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.

There are many examples in historical sources that reference preparations of this natural product:

Veterinary issues

Poisoning from catharidin is a significant veterinary concern, especially in horses by Epicauta species; species infesting feedstocks depend on region—e.g., Epicauta pennsylvanica (black blisterbeetle) in the U.S. midwest and E. occidentalis, temexia, and vittata species (striped blister beetles) in the U.S. southwest—where the concentrations of the agent in each can vary substantially.[2] Beetles feed on weeds and occasionally move into crop fields used to produce livestock feeds (e.g., alfalfa), where they are found to cluster and find their way into baled hay, e.g., a single flake (4-5 in. section[13]) may have several hundred insects, or none at all.[2] Horses are very sensitive to the cantharidin produced by beetle infestations: 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.[14]

Great bustards, a strongly polygynous bird species,[15] are not immune to the toxicity of cantharidin; they become intoxicated after ingesting blister beetles; however, cantharidin has activity also against parasites that infect them.[16][17]

Human medical issues

General risks

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[18] and emergency personnel.[19] 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.[20]

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.[18]

Risks of aphrodisiac use

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,[21] and because it can cause priapism.[22] The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.[23][24] As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.[19]

Other uses

Diluted solutions of cantharidin can be used as a topical medication to remove warts[25][26] and tattoos and to treat the small papules of Molluscum contagiosum.[27]

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.[20][28]

Bioactivities

Cantharidin appears to have some effect in the topical treatment of cutaneous leishmaniasis in animal models.[29] In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells.[30][31][32] Laboratory studies with cultured tumor cells suggest that this activity may be the result of PP2A inhibition.[33][34]

Popular culture

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

Further reading

References

  1. ↑ Medical Dictionary, 2009, 2012, Farlex and Partners.
  2. 1 2 3 Schmitz, David G. (2013). "Overview of Cantharidin Poisoning (Blister Beetle Poisoning)". In Aiello, Susan E. & Moses, Michael A. The Merck Veterinary Manual. Kenilworth, NJ, USA: Merck Sharp & Dohme. ISBN 0911910611. Retrieved 14 December 2015.
  3. ↑ 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.
  4. ↑ Wolter, H. (1995). Kompendium der Tierärztlichen Homöopathie. Enke. ISBN 978-3432978925.
  5. ↑ Robiquet, P. J. (1810). "Expériences sur les cantharides". Annales de Chimie 76: 302–322.
  6. ↑ James, Peter (1995). Ancient Inventions. Ballantine Books. p. 177. ISBN 0-345-40102-6.
  7. ↑ Eplett, Layla (13 March 2012). "When Sparks Fly: Aphrodisiacs and the Fruit Fly". Scientific American. Retrieved 18 November 2014.
  8. ↑ (Milsten 2000, p. 170)
  9. ↑ Covarrubias-Horozco, S. (2006). Tesoros de la lengua castellana o española. Universidad de Navarra - Iberoamericana - Vervuert.
  10. ↑ (Cavendish 1968, p. 333)
  11. ↑ Ford, Peter; Howell, Michael (1985). The beetle of Aphrodite and other medical mysteries. New York: Random House. ISBN 0-394-54797-7.
  12. ↑ Schaeffer, Neil (2000). The Marquis de Sade: A Life, Cambridge, MA, USA: Harvard University Press, p. 58.
  13. ↑ Rockett, Jody & Bosted, Susanna (2015). Veterinary Clinical Procedures in Large Animal Practices. Boston, MA, USA: Cengage Learning. p. 65. ISBN 1305537653. Retrieved 14 December 2015.
  14. ↑ "Blister Beetle Poisoning / Cantharidin toxicosis". Retrieved 2010-12-31.
  15. ↑ Alonso, J.C.; Magaña, M.; Palacín, C.; Martín, C.A. (2010). "Correlates of male mating success in great bustard leks: the effects of age, weight, and display effort". Behavioral Ecology and Sociobiology 64 (10): 1589–1600. doi:10.1007/s00265-010-0972-6.
  16. ↑ 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.
  17. ↑ 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.
  18. 1 2 Binder, R. (1979). "Malpractice--in dermatology". Cutis; Cutaneous Medicine for the Practitioner 23 (5): 663–666. PMID 456036.
  19. 1 2 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.
  20. 1 2 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.
  21. ↑ John L. Capinera, Encyclopedia of Entomology, Volume 4, Springer Science & Business Media, 2008. p.2010
  22. ↑ Peter V. Taberner, Aphrodisiacs: The Science and the Myth, Springer Science & Business Media, 2012, pp.100ff
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ Bacelieri, R.; Johnson, S. M. (2005). "Cutaneous warts: An evidence-based approach to therapy". American Family Physician 72 (4): 647–652. PMID 16127954.
  27. ↑ "Molluscum contagiosum". Merck Manuals. November 2005. Retrieved 2007-10-21.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
  34. ↑ 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.
  35. ↑ "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!.
  36. ↑ Planer, Lindsay. "Bill Cosby: It's True! It's True!" All Music Guide. Retrieved November 24, 2014.

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