Cucurbitacins toxicity

Cucumis melo L. Gua Di (Cantaloupe) (pedicel) Melotoxin, cucurbitacin B, cucurbitacin E, sterol33351 Produce vomiting for drug intoxication, treat toxic and chronic hepatitis and cirrhosis of the liver. 

Cucurbitacin A Cucumis hookeri, C. leptodermis, Bitter [toxic]... 

Bryonia alba (white bryony) contains toxic triterpenoids called cucurbitacins. 

The dried pulp of the fruit of Citrullus colocynthis (colocynth) is a drastic laxative, which contains toxic cucurbitacins. 

Ecballium elaterium (squirting cucumber) contains toxic cucurbitacins, which are violent purgatives. It is used in the Mediterranean as a purgative and in treating sinusitis. 

The main kind of anti-inflammatory triterpenes isolated have oleanane, ursane, taraxastane, lupane and lanostane skeletons (Table 1). Some minor compounds such as hopane are included in other structural groups. Other anti-inflammatory triterpenes like the different cucurbitacins are not included in this review because of their high toxicity. 

Some species containing cucurbitacins are used in traditional medicine as anti-inflammatories in different pathologies. In general, they are used in topical applications as they have a certain level of toxicity when applied per os (p.o.). In one paper, Miro [2] compiled the data on this subject that had been published up to 1995. The review cited only the antiinflammatory activity of cucurbitacin B isolated from the juice of Ecballium elaterium, as well as its possible mechanism of action by means of a modification in leukotriene B4 (LTB4) production. 

Dihydrocucurbitacin B exhibited a similar pattern of activity to that of cucurbitacin R except in the case of the carrageenan-test. In this assay, the former was clearly more active, but the toxicity against rat leukocytes was higher [43],... 

One of the highest priorities in cucurbitacin research has been the exploration of both the cytotoxic and anticancer effects of these compounds. This is due to the fact that they are generally considered to have a high level of toxicity, presumably also against cancer cells. 

Picracin (cucurbitacin Q) and deacetylpicracin (cucurbitacin O) from Picrorhiza scrophulariaeflora, Fig. (13), inhibited phytohemagglutinin-induced T-lymphocyte proliferation in a dose-dependent manner with an IC50 of 1 (iM. This effect cannot be due to the cytotoxicity of the compounds since in specific experiments the authors demonstrated that neither cucurbitacin exhibits toxic effects for IC50 values up to 50 pM. The mechanism of action seems to be an interference with the cytoskeleton and subsequent abrogation of proliferative signal transduction, which in turn inhibits T-lymphocyte proliferation [70]. 

As can be seen above, minor structural modifications not only change the cell cytotoxicity, but also affect the toxicity in animals (Table 6). Thus, while unsaturated C-l cucurbitacins clearly increased both the cytotoxic potency as well as the toxicity in animals (cucurbitacin E vs cucurbitacin B), the saturation of C-23 decreases the toxicity in both cells and animals (cucurbitacin I vs cucurbitacin L). 

Finally, blocking C-2, C-3, and C-l6 hydroxyls has been found to reduce the toxicity in all the known cases (Table 7). Comparative data of the cytotoxicity of cucurbitacin Q vs that of its triacetyl-derivative showed a spectacular difference in cytotoxicity, with the former being much more potent than the latter. 

In general, cucurbitacins and the extracts containing them are considered to be toxic, with the degree of toxicity depending on the plant material, type of extract, and the substitution partner of the compound. For example, exposure to the juice of the anti-inflammatory medicinal plant Ecbalium elaterium, especially in its undiluted form, often leads to a supposedly inflammatory irritation of mucous membranes [87]. These toxic effects seem to correspond to the juice s major active compound, cucurbitacin B. 

Some studies with chemical analogues seem to indicate that while side chain substitution is essential for toxicity, substitutions in the A-ring are not. For example, the dihydro-derivatives of cucurbitacin I (cucurbitacin L) and cucurbitacin D (cucurbitacin R) are clearly less toxic than their corresponding dehydro analogues [51]. Moreover, the presence of an acetoxyl group in the side chain (C-25) increases the toxicity of cucurbitacins [43,51], This data was corroborated by Oh et al. [88], who obtained LD5o values of 0.9 and 11.1 pM for cucurbitacin D and its dihydro-derivative, cucurbitacin R, against B16/F10 melanoma cells. 

The name of about 50 naturally abundant cucurbitanes stems from Cucurbitaceae, the Latin term of cucurbitaceous plants such as cucumbers and pumpkins, known since antiquity for their beneficial and toxic properties. One of the most frequently isolated representatives is the bitter substance (+)-cucurbitacin B from Phormium tenax and Ecballium elaterium (Cucurbitaceae), also found in Iberis species (Cru-ciferae), Euphorbiaceae and Scrophulariaceae. (+)-Cucurbitacin F from Cucumis angolensis and C. dinteri is reported to inhibit the growth of human tumor cells. Toxic cucurbitacines shape the unpleasant bitter taste of salads prepared from spoiled cucumbers Cucumis sativus some representatives are reported to be antihypertonic, antirheumatic, and also active against HIV. 

Cueurbitacins tetracyclic triterpenes found as their glycosides in the Cucurbitaceae and Cruciferae. These toxic, bitter compounds are structurally related to the parent hydrocarbon, cucurbitane [19(10-9P)-abeo-5p-lanostane], which differs from lanostane (see Lanosterol) in the formal shift of the 10-methyl group to the 9p-position. Cucurbitacin E was formerly known as elaterin. C. have a laxative action some serve as insect attractants, and a few have antineo-plastic and antigibberellin activity. 

It remains to be seen, however, whether these latter compounds or structural modifications of them will find application chnically. Certainly any earher hopes for useful therapeutic application of the triterpenoid cucurbitacins as founded on the high order of their cytotoxicity in vitro [479-484] have been dashed on account of the very low margins between the active and the toxic doses as revealed in in vivo experiments. Since the earlier review was written the structures of the cucurbitacins have been elucidated in full and they have been found to represent an unusual structural type in which backbone rearrangement in the formal carbonium ion initially formed from the cychsation of squalene epoxide in chair-boat-chair-boat conformational sequence proceeds beyond the stages giving rise to lanosterol and cycloartenol. Thus they can be regarded as overshoots of the biosynthetic pathway giving rise to the steroids in the same way as fusidic acid (LX), cephalosporin and helvolic acid represent undershoots of the same pathway. The structure of cucurbitacin A is as depicted in LXIV [485, 486]. 

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