Pyrrolizidine alkaloids PAs

This group of alkaloids is found in a wide range of families, centred around the Asteraceae, Boraginaceae and Fabaceae (Hartmann and Witte, 1995 Hartmann, 2007). PAs are metabolically activated in the liver of herbivores and can then alkylate DNA and proteins, leading to mutations and even cancer. The occurrence of PAs in many Senecio species accounts for the high toxicity of these plants. PAs function as defence compounds against many herbivores however, a number of specialized insects are known which store and utilize the dietary defence chemicals (for a review, see Wink, 1993 Hartmann and Witte, 1995). 

The biosynthesis of the necic acid moiefy has, in contrast received relafively little attention. Label from C-isoleucine is effectively 

However, it has been shown that more than half the aminobutyl moiety of homospermidine comes directly from spermine, and the aminobutyl moiety of spermine is also incorporated directly into the necine base of pyrrolizidine alkaloids (Graser and Hartmann, 1997). 

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Pyrrolizidine alkaloids (PAs) such as senecionine (159) (Fig. 29) are also taken up from plants by various butterflies and moths belonging to the Danainae, Ithomiinae, and Arctiidae. The chemical ecology of PAs and their role in the interaction between plants and adapted Lepidoptera were reviewed several times in details during the last decade [155-159]. These insects use them for defense and for the production of male pheromones. 

At overwintering sites of the monarch butterfly [Danaus plexippus) in Mexico, only one of the three local mouse species, Peromyscus melanotis, actually feeds on the butterflies. The monarchs contain cardiac glycosides (CG) and pyrrolizidine alkaloids (PA). All three species of mice have similarly low avoidance thresholds to PA (specifically, monocrotaline). But P. melanotis is less sensitive to CG (specifically, digitoxin) than the other two, Reithrodontomys sumichrasti and Peromyscus aztecus. Laboratory tests indicate that PA is toxic to young mice. 

Table 7.1. Arctiids with a known association with pyrrolizidine alkaloids (PAs)a... 

Fig. 7.4. Phytogeny of the Arctiidae (after Jacobson and Weller, 2001) showing the evolutionary interrelationship of larval pyrrolizidine alkaloid (PA) sequestration and adult pharmacophagous behavior. Node 1, larval PA detoxifica-tion/sequestration abilities evolve node 2, adult pharmacophagy originates.

Figure 9.2. Metabolism of pyrrolizidine alkaloids (PAs) in Senecio vernalis. The substrates for alkaloid biosynthesis, putrescine and spermidine, are derived from primary metabolism. Homospermidine, synthesized by homospermidine synthase (HSS), is the first pathway specific intermediate. It is exclusively incorporated into the necine base moiety of senecionine A-oxide, the backbone structure of all PAs found in this Senecio species. During allocation from the roots as site of synthesis to the shoots, it is chemically modified to provide the species specific PA-pattem.

Figure 9.3. The two faces of pyrrolizidine alkaloids (PAs). The non-toxic PA JV-oxide is easily converted into the protoxic free base in the gut of herbivores or predators.

Pyrrolizidine alkaloids (PAs) are a typical class of plant secondary metabolites, which certain butterflies and moths in particular groups, that is, Danainae, Ithomiinae (Nymphalidae), and Arctiidae, sequester as larvae or adults and utilize as chemical defensive substances against predatory enemies, probably due to their bitter taste and hepatotoxicity.13 PAs also serve as precursors of male pheromones of PA-storing lepidopterans. 

Host plants play a key role in the production and use of sex pheromones by herbivorous insects through larval or adult sequestration of chemically active compounds and pheromone precursors [210]. One of the best examples of sequestration of plant chemicals by larvae and their subsequent use by adult males in sex attraction or courtship interactions is shown in Utetheisa ornatrix (Arctiidae), whose courtship pheromone derives from pyrrolizidine alkaloids (PAs) ingested at the larval stage from the host plant Crotalaria spectabilis [211]. U. omatrix larvae sequester PAs (e.g. monocrotaline) and retain the alkaloids through metamorphosis into the adult stage to provide egg protection for the next generation. 

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. 

Another important group of plant toxins are pyrrolizidine alkaloids (PAs) (71) of which even a single administration can be fatal (72). Poisonings by PAs are prevalent in Southern Africa (73), with a number of cases recorded for chil en (74). 

The hepatotoxic pyrrolizidine alkaloids (PAs) present in coltsfoot pose the greatest concern regarding use of coltsfoot, (see also Chapter 18 for additional discussion of the pyrrolizidine alkaloids). Hepatic venoocclusive disease is characteristic of PA intoxication. The specific histologic findings are described in Section 17.5, but generally include endothelial edema, sclerosis and occlusion of the small vessels, necrosis, progressive fibrosis, and eventually cirrhosis (Roulet et al., 1988). PAs are not hepatotoxic themselves, but are converted... 

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). 

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. 

There are numerous plants containing pyrrolizidine alkaloids (PAs) and they mainly belong to the Boraginaceae, Compositae and Leguminosae families [31,47, 48],... 

Borage seed oil is commonly traded as a source of gamma-linolenic acid (GLA). Processing methods eliminate pyrrolizidine alkaloids (PA) from the finished material (WretensjS and Karlberg 2003). A study of the effects of the borage seed oil refinement process on the content of pyrrolizidine alkaloids in the oil indicated that processing reduces the PA content by a factor of about 30,000. In finished samples. 

The presence or absence of pyrrolizidine alkaloids (PAs), some of which may cause liver toxicity, in boneset has not been fully investigated. Although many species of the genus Eupatorium contain PAs, these compounds have not been confirmed in boneset, and several references indicate a lack of these compounds in boneset (Arzneimittelkommission... 

Pyrrolizidine alkaloids (PAs) are compounds found in a number of plant species that have been associated with liver toxicity. Based on their chemistry, different PAs may be saturated or unsaturated (the difference between the two... 

Bolechova, Caslavsky, Pospichalova, and Kosubova report a protocol for the extraction of selected pyrrolizidine alkaloids (PAs) in feed. They determined PAs using an ultraperformance liquid chromatography (UPLC) system coupled to a tandem mass spectrometry equipped with an electrospray interface (ESI). Their steps to extract alkaloids for this determination are as follows ... 

Pyrrolizidine alkaloids (PAs) belong to a class of naturally occurring compounds characterized by a bridged dipyrrole structure. They encompass more than 400 different structures, which consist of a necine base of type 25 that may also be saturated between carbons 1 and 2 and esterified with one or more necic acids which exist as 5-11 carbon membered types (Figure 5.25). Thus, there are monosters such as supi-nine 27, indicine 28 obtained from retronecine 25a, and (-)-trachelanthic acid 26. Heliosupine 29 is an example of an open-chain diester, and retrorsine 30 is, instead, a macrocyclic diester. PAs are constitutively produced by the plant and are believed... 

Pyrrolizidine alkaloids (PAs) contain two fused five-membered rings in which a nitrogen atom is coirunon to both rings. The precursor is ornithine. A hydrogen atom nsnally occurs opposite the nitrogen atom in the a position, with a hydroxymethyl substitute at the adjacent C-1 position. Most pyrrolizidines have diester groups at C-1 and C-7—these may be non-cyclic, for example echimidine, or macrocyclic, for example senedonine. Toxicity (see below) appears to be mainly linked to the macrocyclic diester type (Denham 1996). The alkaloids also occur as water-soluble nitrogen oxides. 

Pyrrolizidine alkaloids (PAs) are typical constitutively produced plant secondary compounds. PAs exist in a great diversity of some 370 chemical structures [1-3]. They are assiuned to have evolved as chemical defenses under the selection pressure of competing herbivores. This is evidenced by a number of insect herbivores from imrelated taxa which have developed adaptations not only to overcome PA-mediated plant defense, but also to sequester and utilize these alkaloids for their own defense against predators. PAs are an excellent choice to exemplify mechanistic and functional aspects of plant secondary metabolism [4,5]. 

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