Cylindrospermopsins toxicity

Cylindrospermopsin s existence was first realized after 149 people were poisoned on Palm Island off the north-east Australian coastline when their freshwater dam became contaminated by C. raciborskii. The molecular mechanism by which this toxin exerts its toxicity is yet to be elucidated. Liver toxicity, however, is the main toxic manifestation but lesions in the kidney, heart, and thymus occur when tested on mice and rats. Orally, cylindrospermopsin has a median lethal dose to mice of 6 mg kg whereas intraperitoneal injection of mice yields an LD50 of 0.2 mg kg Other whole organism assays used to measure cylindrospermopsin toxicity include the brine shrimp Artemia saUna (LD5o = 0.7pgml after 72 h) and the crustacean Thamnocephalus platyurus. 

Froscio SM, Humpage AR, Burcham PC, Falconer IR (2003) Cylindrospermopsin-induced protein synthesis inhibition and its dissociation from acute toxicity in mouse hepatocytes. Environ Toxicol 18 243-251... 

Cyanobacteria toxins are toxins produced by certain species of blue-green algae that have become a major environmental and public health concern. The behavior of cyanotoxins during chlorination treatment has been recently reviewed by Merel et al. [129]. Chlorination DBFs have been reported only for the hepatotoxins microcystin-LR and cylindrospermopsin. Other cyanotoxins, such as nodularins, saxitoxins, and anatoxins, have yet to be investigated. Different isomers of six chlorination products of microcystin-LR have been characterized dihydroxy-microcystin, monochloro-microcystin, monochloro-hydroxy-microcystin, monochloro-dihydroxy-microcystin, dichloro-dihydroxy-microcystin, and trichloro-hydroxy-microcystin. Only two chlorination DBFs have been reported so far for cylindrospermopsin 5-chloro-cylindros-permopsin and cylindrospermopsic acid [129]. Chlorination of microcystin, cylindrospermopsin, and nodularins seems to reduce the mixture toxicity however, this aspect has not been extensively studied [129]. 

The novel structure of cylindrospermopsin, with a guanidine embedded in a tricyclic system, six chiral centers, and polar sulfate, uracil and guanidine functional groups, makes its synthesis challenging. Its potent toxicity makes the synthesis of cylindrospermopsin an important problem that has been the subject of intense interest.1,7 8... 

An extensive work has been developed for the control of microcystins but not much effort has been made for the development of methods for the detection of other cyanobacterial toxins sneh as anatoxins or cylindrospermopsins despite their important acute toxicity as occurs in the case of the... 

The same toxin has been subsequently isolated from the cyanobacterium Umezakia natans in Japan (Harada 1994) and Aphanizomenon ovalisporum in both Australia (Shaw 1999) and Israel (Banker 1997). An analogue of cylindrospermopsin such as 7-epicylindrospermopsin has been recently characterized as a toxic minor component of a strain of Aph. ovalisporum from Israel (Banker 2000). See Fig. 14.3. 

Fastner, I, Heinze,R., Humpage, A.R., Mischke, U, Eaglesham, G.K., and Chorus,L. 2003. Cylindrospermopsin occurrence in two German lakes and preliminary assessment of toxicity and toxin production of Cylindrospermopsis raciborskii (Cyanobacteria) isolates. Toxicon 42 313-321. 

Not surprisingly, the toxin s liver toxicity is reflected by the ability of micromolar concentrations of cylindrospermopsin to kill in vitro liver cells such as rat hepatocytes and the human hepatoblastoma cell line HEP-G2. Cylindrospermopsin is known to potently inhibit cellular protein synthesis that can be measured in vitro using rabbit reticulocyte lysate. 

Cylindrospermopsin is an alkaloid consisting of a tricyclic guanidine coupled with hydrox3unethyluracil (Figure 31.2). It is a zwitterionic, highly water-soluble molecule (Ohtani et al., 1992). There are two known structural variants deoxycylindrospermopsin (Norris et al., 1999), which is relatively less toxic, and 7-epicyl-indrospermopsin (Banker et al., 2001), which is relatively... 

Cylindrospermopsin was isolated from water used in dialysis in Brazil that caused liver failure in dialysis patients. However, the role of cylindrospermopsin in the disease process was not clear because the water was also contaminated with toxic concentrations of microcystin (Azevedo et al., 2002). 

Studies using crude extracts report higher potency and a wider range of effects compared with studies using pimfied cylindrospermopsin, indicating the components other than cylindrospermopsin contribute to the toxic effects (Shaw et al., 2000 Seifert et al., 2007). 

The mechanisms of toxicity of cylindrospermopsin are not yet fully imderstood, but ample evidence of its potential impact on human health exists, based on clinical cases, in vitro studies, and animal model studies (Poniedziatek et al., 2012). Its relatively infrequent natural occurrence, compared with more common cyanotox-ins such as microcystis, make it generally less accessible. The primary threats include contamination of drinking water supplies and food supplies. 

Banker, R., Carmeli, S., Werman, M., et al, 2001. Uracil moiety is required for toxicity of the cyanobacterial hepatotoxin cylindrospermopsin. J. Toxicol. Environ. Health-Part A 62 (4), 281-288. 

Incorporation experiments have shown that cylindrospermopsin is a polyketide formed starting from guani-dinoacetic acid, which condenses later with five acetic units (Moore et al, 1993 Burgoyne et al, 2000). This biosynthesis is summarized in Figure 8.6. For recent reviews on the toxicity of cylindrospermopsin, see Griffiths and Saker (2003), Rogers et al (2007) and Kinnear (2010). 

Rogers, E.H., Zehr, R.D., Gage, M.I., Humpage, A.R., Falconer, I.R., Marr, M., and Chernoff, N. (2007) The cyanobacterial toxin, cylindrospermopsin, induces fetal toxicity in the mouse after exposure late in gestation. Toxicon, 49, 855-864. 

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