Pyrrolizidine alkaloids toxicity

Herbs rich in toxic pyrrolizidine alkaloids Cape aloesf... 

PAs are found widely in the families Asteraceae, Boraginaceae, Fabaceae, and Apocynaceae. About 360 diverse structures have been characterized,23 and these widespread alkaloids are produced by at least 3% of all flowering plants. It is remarkable that one group of animals-the insects-have broken through the formidable alkaloidal defenses represented by the highly toxic pyrrolizidine alkaloids. This evolutionary adaptation has provided a large resource for these insects that is not available to PA-intolerant species, which constitute most of the herbivores. 

PASTEELS, J.M., THEURING, C WITTE, L HARTMANN, T, Sequestration and metabolism of pro-toxic pyrrolizidine alkaloids by larvae of the leaf beetle Platyphora boucardi and their transfer via pupae into the defensive secretions of adults. J. Chem. Ecol., 2002, in press. 

ZUCKERMAN, M STEENKAMP, V., STEWART, M.J., Hepatic veno-occlusive disease as a result of a traditional remedy confirmation of toxic pyrrolizidine alkaloids as the cause, using an in vitro technique., J. Clin. Pathol., 2002, 55, 676-679. 

The presence of toxic pyrrolizidine alkaloids in honey has been known for several decades [42]. The potential health concerns associated with pyrrolizidine alkaloids in food [27] and honey [28] in particular demand a rapid, sensitive method of detection in various matrices. The application of LC-MS methods to honey samples extracted using sex SPE cartridges has facilitated the analysis of honey for the presence of pyrrolizidine alkaloids and their N-oxides [34,41]. The SPE and LC-MS analysis has shown that honey attributed to known pyrrolizidine alkaloid-producing sources can have levels in excess of 5000 jrg/kg honey. Further to this, honey attributed to non-pyrrolizidine alkaloid-producing floral sources and unspecified blended honeys can also have significant amounts of alkaloids present. 

Pyrrolizidine alkaloids (PAs) constitute a class of plant toxin associated with disease in humans and animals. They are found in a wide variety of plant species in the world and it is estimated that 3% of the world s flowering plants contain toxic pyrrolizidine alkaloids. 

The toxic pyrrolizidine alkaloids are a large group of related compounds which occur in plants, mainly in species of Crotalaria, Senecio, Heliotropium, Trichodesma, Symphytum and Echium and are poisonous (Brown, 2003 Orech et al., 2005). 

Comfrey is a perennial herb used for the prevention of kidney stones nourishing and repairing bone and muscle and for the treatment of injuries such as burns and bruises. In Australia, comfrey is classified as a poison and its sales have been restricted in several regions. Many different commercial forms of comfrey are marketed, including oral and external products. Commercial comfrey is usually derived from the leaves or roots of Symphytum officinale (common comfrey). However, some products are also derived from Russian comfrey. Russian comfrey contains a very toxic pyrrolizidine alkaloid, echimidine, which is not found in common comfrey. However, common comfrey contains other hepatotoxic alkaloids, namely 7-acetylintermedine, 7-acetyllycopsamine and symphytine. The metabolites of these alkaloids are very toxic to the liver. Ridker et al. documented hepatic venocclusive disease associated with consumption of comfrey root. Long-term smdies in animals have also confirmed the carcinogenicity of comfrey in animal models. ... 

Commercial comfrey is usually derived from the leaves or roots of Symphytum officinale (common comfrey) (USP, 1998). However, some products are derived from Symphytum x uplandicum Nyman (Russian comfrey) or Symphytum asperum Lepech (prickly comfrey), which appear to be more toxic than common comfrey (Anonymous, 1998). Russian comfrey and prickly comfrey contain a very toxic pyrrolizidine alkaloid (PA) called echimidine that common comfrey does not contain (Tyler, 1994). Although common comfrey does not contain echimidine, it does contain other hepatotoxic PAs. These alkaloids include 7-acetylintermedine, 7-acetyllycopsamine, their unacetylated precursors, and symphytine (Tyler, 1993). 

Mattocks A. Toxic pyrrolizidine alkaloids in comfrey. Lancet 1980 2 1136-7. 

Nevertheless, Foster and Johnson emphasize that comfrey also contains toxic pyrrolizidine alkaloids (PAs), as documented in Chapter 6. Although PAs will help stop bleeding, the negative effects outweigh the beneficial, for comfrey has been found to cause liver damage and produce cancerous liver mmors. Despite its long history in herbal medicine, no clinical smdies have documented any positive effects attributable to comfrey. Many studies, however, have demonstrated its liver toxicity. 

Several of the synthanecine derivatives, and in particular the carbamates of synthanecine A (11), were shown to be metabolically dehydrogenated to pyrrole derivatives by rat liver in vivo and to cause toxic effects in animals very similar to, if not identical with, those produced by the toxic pyrrolizidine alkaloids. The synthetic pyrrole relatives of the synthanecines, like the pyrrolic analogues of the toxic alkaloids, were also capable of cross-linking DNA in vitro, and of causing cytotoxic effects in rats. ... 

Intramolecular Claisen condensation of triester (119) gave the ketopyrrolizine (120), which, following saponification and decarboxylation was reduced to (121) or (122). Dihydropyrrolizines such as (121) are metabolites of highly toxic pyrrolizidine alkaloids <71HCA449>. 

The American Herbal Products Association has established a trade requirement (AHPA 2011) that all products with botanical ingredients that contain toxic pyrrolizidine alkaloids, including borage herb, are not offered for sale for internal use and display the following cautionary label ... 

Smith, L.W., and C.C.J. Culvenor. 1981. Plant sources of hepato-toxic pyrrolizidine alkaloids. /. Nat. Prod. 44 129-152. 

Yu, L., Y. Xu, H. Feng, and S.F. Li. 2005. Separation and determination of toxic pyrrolizidine alkaloids in traditional Chinese herbal medicines by micellar electrokinetic chromatography with organic modifier. Electrophoresis 26(17) 3397-3404. 

Figure 5.25 Pyrrolizidine alkaloids structure of necine base 25, trachelanthic acid 26, a necic acid supinine 27 and indicine 28, monoester pyrrolizidine alkaloids heliosupme 29, a diester pyrrolizidine alkaloid retrorsine 30, a macrocyclic diester pyrrolizidine alkaloid senecionine N-oxide 31, a non-toxic pyrrolizidine alkaloid.

Mattocks, A. R. and R. Jukes, Improved field tests for toxic pyrrolizidine alkaloids, J. Nat. Prod., 50, 161-166 (1987). 

Mattocks AR, White INH (1971) Pyrrolic metabolites from non-toxic pyrrolizidine alkaloids. Nat New Biol 231 114-115... 

Crews C, Berthiller F, Krska R (2010) Update on analytical methods for toxic pyrrolizidine alkaloids. Anal Bioanal Chem 396 327-338... 

Zhou Y, Li N, Choi FF-K, Qiao C-F, Song J-Z, Li S-L, Liu X, Cai Z-W, Fu PP, Lin G, Xu H-X (2010) A new approach for simultaneous screening and quantification of toxic pyrrolizidine alkaloids in some potential pyrrolizidine alkaloid-containing plants by using ultra performance liquid chromatography-tandem quadrupole mass spectrometry. Anal Chim Acta 681 33 0... 

Roeder E, Pflueger T (1995) Analysis of pyrrolizidine alkaloids a competitive enzyme-linked immunoassay (ELISA) for the quantitative determination of some toxic pyrrolizidine alkaloids. Nat Tox 3 305-309... 

Yu LJ, Li SPY (2005) Dynamic pH junction-sweeping capillary electrophoresis for online preconcentration of toxic pyrrolizidine alkaloids in Chinese herbal medicine. Electrophoresis 26 4360 367... 

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