Cantharidin, Spanish Fly
|Jmol interactive 3D||Image|
|Molar mass||196.20 g/mol|
|Melting point||212 °C (414 °F; 485 K)|
|Main hazards||Highly toxic|
EU classification (DSD)
|Lethal dose or concentration (LD, LC):|
LD50 (Median dose)
|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).
|what is ?)(|
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 is a poisonous blistering agent and can cause severe chemical burns. However, these same properties make it effective as a topical medication.
Cantharidin was first isolated in 1810 by Pierre Robiquet, 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. 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.
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 and emergency personnel. 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.
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.
Cantharidin has been used since ancient times as an aphrodisiac, possibly because its physical effects were perceived to mimic those of sexual arousal, and because it can cause priapism. 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.
The extreme toxicity of cantharidin makes any use as an aphrodisiac highly dangerous. As a result, it is illegal to sell (or use) cantharidin or preparations containing it without a prescription in many countries.
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. Cantharidin has activity against parasites of great bustards, a strongly polygynous bird species. These birds are not immune to the toxicity of cantharidin; they become intoxicated after ingesting some blister beetles.
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.
Topical treatment with cantharidin appears to have some effect in an animal model of cutaneous leishmaniasis. In addition to topical medical applications, cantharidin and its analogues may have activity against cancer cells. Laboratory studies with cultured tumor cells suggest that this activity may be the result of PP2A inhibition.
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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.
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- John L. Capinera, Encyclopedia of Entomology, Volume 4, Springer Science & Business Media, 2008. p.2010
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- Neil Schaeffer, The Marquis de Sade: A Life, Harvard University Press, 2000, p.58.
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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.
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- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.