29 January 2018

Cylindrospermopsins - alkaloid hepatotoxins beyond the Palm Island mystery disease in the late 1970s

Natural toxin

Cylindrospermopsins are cyanobacterial secondary metabolites capable of causing severe damage to the liver, kidney and other organs.

Fig. 1: Cylindrospermopsis raciborskii (microscopic picture, upper left corner) can form toxic cyanobacterial blooms (big picture).

Cylindrospermopsins (CYNs) are a class of five chemical analogues: CYN (Fig. 2), 7-epi-CYN, 7-deoxy-CYN, 7-deoxydesulfo-CYN and 7-deoxydesulfo-12-acetyl-CYN. Cylindrospermopsin was first isolated from the cyanobacterium Cylindrospermopsis raciborskii which was found in a drinking water supply after an outbreak of hepatoenteritis in Palm Island in Northern Queensland, Australia in 1979. Since then, CYNs have been found across the globe in North, Central and South America, Asia, Australia, Africa and Europe and are produced by different cyanobacteria such as Aphanizomenon, Anabaena, Cylindrospermopsis, Lyngbya, Oscillatoria and Umezkia. CYN mainly occurs as an extracellular cyanotoxin excreted by producing cyanobacteria.

Fig. 2: Structure of cylindrospermopsin. Click image for 3D model

Cylindrospermopsin consist of a tricyclic guanidine group, a sulfate group and an uracil side chain, which provides the alkaloid with its biological active moiety. It is a potent protein synthesis inhibitor and can cause cell death, with its main target being the liver. However, it can also affect other organs and metabolic pathways, which makes it difficult to fully understand CYN’s toxicity.

Animals like mice exposed to CYN were suffering from progressive organ necrosis within few hours to days (i.p. 10.5 to 168 mg of freeze-dried C. raciborskii culture per kg body weight) and death after up to five days (i.p. 64 mg of freeze-dried C. raciborskii culture per kg body weight) due to renal and hepatic failure. CYN was also found to be a potential endocrine disrupting, carcinogenic and teratogenic agent which can accumulate in plants. Symptoms of human intoxication include anorexia, vomiting, headache, initial constipation and bloody diarrhea, dehydration, skin and eye irritation and others. A major human poisoning with CYN was first reported in 1979 in Palm Island, Australia, where more than 100 people had to be hospitalized due to hepatoenteritis after consuming CYN containing drinking water. Investigations of this dramatic incident found a toxic Cylindrospermopsis raciborskii bloom in the drinking water reservoir to be the cause.

Cylindrospermopsin is highly water soluble and relatively stable to a wide range of heat, light and pH conditions, contributing to its slow degradation in water. Additionally, it can permeate through membranes which makes it a cyanotoxin of concern in regard to water treatment.

SMILES: O=C1C=C(NC(=O)N1)[C@H](O)[C@H]2C[C@H]3C[C@H](OS([O-])(=O)=O)[C@H](C)[C@H]4C[NH+]=C(N2)N34

References:

  • Hawkins PR, Runnegar MT, Jackson AR, Falconer IR. 1985. Severe hepatotoxicity caused by the tropical cyanobacterium (blue green algae) Cylindrospermopsis raciborskii (Woloszynska) Seenaya and Subba Raju isolated from a domestic water supply reservoir. Appl. Environ. Microbiol. 50:1292-1295.
  • Banker R, Carmeli S, Werman M, Teltsch B, Porat R, Sukenik A. 2001. Uracil moiety is required for toxicity of the cyanobacterial hepatotoxin cylindrospermopsin. J. Toxicol. Environ. Health. A. 62:281-288. doi:10.1080/009841001459432.
  • Kokociński M, Cameán AM, Carmeli S, Guzmán-Guillén R, Jos Á, Mankiewicz-Boczek J, Metcalf JS, Moreno IM, Prieto AI, Sukenik A. 2016.Cylindrospermopsin and Congeners. In: Handbook of Cyanobacterial Monitoring and Cyanotoxin Analysis. John Wiley & Sons, Ltd, pp 127–137. doi:10.1002/9781119068761.ch12.
  • Buratti FM, Manganelli M, Vichi S, Stefanelli M, Scardala S, Testai E, Funari E. 2017. Cyanotoxins: producing organisms, occurrence, toxicity, mechanism of action and human health toxicological risk evaluation. Arch Toxicol 91:1049-1130. doi:10.1007/s00204-016-1913-6.

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