Cantharidin

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Cantharidin
Cantharidin structure.png
Identifiers
CAS number 56-25-7 N
ChemSpider 2297293 YesY
UNII IGL471WQ8P YesY
KEGG C16778 N
ChEMBL CHEMBL48449 N
Jmol-3D images Image 1
Properties
Molecular formula C10H12O4
Molar mass 196.20 g/mol
Density 1.41 g/cm³
Melting point 212 °C
Hazards
GHS pictograms The skull-and-crossbones pictogram in the Globally Harmonized System of Classification and Labelling of Chemicals (GHS)
EU classification Very Toxic T+
R-phrases R28-R36/37/38
S-phrases S53-S45
Main hazards Highly toxic
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
LD50 0.03–0.5 mg/kg (human)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 N (verify) (what is: YesY/N?)
Infobox references

Cantharidin, a type of terpenoid, is a chemical compound secreted by many species of blister beetle, and most notably by the Spanish fly, Lytta vesicatoria. The false blister beetles, cardinal beetles and soldier beetles also produce cantharidin. It is a poisonous substance, acting as a blister agent, and can cause severe chemical burns, but these same properties make it effective as a topical medication.

History[edit]

Hycleus lugens, an aposematically colored beetle secretes cantharidin

Cantharidin was first isolated in 1810 by Pierre Robiquet,[1] 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.[2] 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 will cover its 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 contain approximately 0.2 mg, E. maculata contain 0.7 mg, and E. immaculata contain 4.8 mg per beetle; males also contain higher levels than females.[3]

Medical uses[edit]

Diluted solutions of cantharidin can be used as a topical medication to remove warts[4][5] and tattoos and to treat the small papules of Molluscum contagiosum.[6]

Medical risks for humans[edit]

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[7] and emergency personnel.[8] 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.[9]

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 tract, and may also cause permanent renal damage. Symptoms of cantharidin poisoning include hematuria, abdominal pains, and rarely priapism.[7]

The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous.[10][11] As a result, it is illegal to sell (or use) cantharidin or preparations of spanish fly for this purpose in many countries.[8]

Medical risks for animals[edit]

Horses are highly sensitive to cantharidin: the LD50 for horses is approximately 1 mg/kg of the horse's body weight. Horses may be accidentally poisoned when fed bales of fodder with blister beetles in them.[12]

Mechanism of action[edit]

Cantharidin is absorbed by the lipid membranes of epidermal cells, causing the activation or release of serine proteases, enzymes that cleave (break) peptide bonds in proteins. This causes the disintegration of desmosmal plaques, cellular structures involved in cell-to-cell adhesion, leading to detachment of 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.[9][13]

Research[edit]

Topical treatment with cantharidin appears to have some effect in an animal model of cutaneous leishmaniasis.[14] In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells.[15][16][17] Laboratory studies with cultured tumor cell lines suggest that this activity may relate to inhibition of protein phosphatase 2A.[18][19]

References[edit]

  1. ^ Wolter, H. (1995). Kompendium der Tierärztlichen Homöopathie. Enke. ISBN 978-3432978925. 
  2. ^ Robiquet, P. J. (1810). "Expériences sur les cantharides". Annales de Chimie 76: 302–322. 
  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. ^ Epstein, W. L.; Kligman, A. M. (1958). "Treatment of warts with cantharidin". AMA Archives of Dermatology 77 (5): 508–511. PMID 13519856. 
  5. ^ Bacelieri, R.; Johnson, S. M. (2005). "Cutaneous warts: An evidence-based approach to therapy". American Family Physician 72 (4): 647–652. PMID 16127954. 
  6. ^ "Molluscum contagiosum". Merck Manuals. November 2005. Retrieved 2007-10-21. 
  7. ^ a b Binder, R. (1979). "Malpractice--in dermatology". Cutis; Cutaneous Medicine for the Practitioner 23 (5): 663–666. PMID 456036. 
  8. ^ 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." 
  9. ^ 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. PMID 11594862. 
  10. ^ 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. 
  11. ^ 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 have been used for millennia as a sexual stimulant by both sexes [22]. 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." 
  12. ^ "Blister Beetle Poisoning / Cantharidin toxicosis". Retrieved 2010-12-31. 
  13. ^ 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. 
  14. ^ 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.  edit
  15. ^ 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.  edit
  16. ^ 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.  edit
  17. ^ 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.  edit
  18. ^ 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.  edit
  19. ^ 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.  edit

External links[edit]