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Pyrrolizidine Alkaloids in Comfrey

Table 2: Pyrrolizidine Alkaloids in Comfrey
Pyrrolizidine AlkaloidsReferences
Acetyl lycopsamine [50, 61-69]
Acetyl intermedine [50, 61-63, 65, 66, 68, 69]
Lycopsamine [50, 61, 63-69]
Intermedine [50, 61, 63, 65, 66, 68, 69]
Symphytine [50, 63-71]
Symlandine [50, 63-66, 68, 69, 71]
Symviridine [63, 68, 72]
Echimidine [64, 65, 67, 69-71]
Lasiocarpine [73]
Uplandicine [65]
7-and 9-angeloylretronecine [66]

Comfrey is reported to contain a variety of PAs (table 2). However, the presence of some PAs, such as lasiocarpine, have not been confirmed. In fact, the variability of PA content from plant to plant presents a tremendous challenge to assessing risk to humans. Table 3 lists the analysis results from various laboratories using a wide selection of samples. PAs in root samples ranged from 100 to 8320 g/g and the content of leaf samples was from 4.5 - 2200 g/g dry weight. This variability is not due to lab to lab variation, as Muertterlein et al analyzed over 300 samples from 150 locations and reported a comparable diversity in concentrations (450 to 6000 g/g) [60].

While there is extreme variability from one individual comfrey plant to the next[60], there is also variability dependent on the growth state of the plant. Small young leaves show higher concentrations of PAs than larger leaves in later stages of the growing season[74]. Within the underground parts of comfrey, PAs are concentrated in small young roots, the extreme exodermis and the center of the rhizome[60].

Table 3: Total Pyrrolizidine Alkaloids in Comfrey
Total PA (includes N-oxides) g/g Ref Species of Symphytum
Root 100-900 [63] S. x uplandicum
Root 2270 [70] S. x uplandicum
Root 1280-8320 [64] S. officinale
Root 450 - 6000 [60] S. officinale (300 samples)
Root >700 [50] S. officinale
Root210 & 730 [69] Unknown
Root >700 [62] S. officinale
Root1400-3700 [75] Unknown
Leaf 100 [75]S. asperum
Leaf <50[75] S. officinale
Leaf 100-1500 [65] S. x uplandicum
Leaf 30 - 2200 [74] S. x uplandicum
Leaf 15-55 [64] S. officinale
Leaf 4.5 - 60 [60] S. officinale (based on leaf being 100x less than root.)
Whole plant 670 [76] S. x uplandicum
Tablets 841-5200 [64] Unknown
Tablets (Root) 2900 [66] Unknown
Tablet (Leaf) 270 [66] Unknown
Comfrey-Pepsin Pill 283 [77] Unknown

Symphytum spp. Pyrrolizidine Alkaloids Considered Individually

All of the major PA components of comfrey (table 2) are retronecine mono- and diesters and therefore expected to have low hepatic toxicity. The two major components lycopsamine and intermedine (retronecine monoesters), do not demonstrate hepatic toxicity when given as a single injection to 2 week old rats at doses up to 60 and 120 mg/kg respectively [23]. In addition, lycopsamine displayed no mutagenicity in the Ames Test [78] and had no observed toxicity to the potato beetle and noctuid moth larvae[79].

It is expected that acetyl lycopsamine and acetyl intermedine should have comparable hepatotoxicity to lycopsamine and intermedine, as results comparing heliotrine with acetyl heliotrine suggest the acetyl group is readily hydrolyzed leaving the monoester alkaloid to exert its toxic effect [23]. Symphytine, echimidine, and uplandicine (retronecine diesters) should have a stronger toxic effect than the previously mentioned four compounds [23, 26, 80], but not as strong an effect as the macrocyclic diesters or heliotridine diesters that have been implicated in poisonings from infusions made with Senecio or grains contaminated with Heliotropium, Crotalaria, or Senecio. Symphytine, found in Symphytum spp. samples at levels from trace to 25% of the total PAs, has an LD50 in rats about 300mg/kg i.p.[70]or 130mg/kg i.p.[81] and has been investigated for carcinogenic and mutagenic effects.

There is one claim in the literature that symphytine is mutagenic upon activation with S-9 microsome in the Ames test as well as in the lung fibroblast of Chinese hamster (V79 cell line) but does not induce transformation in cyropreserved hamster embryonic cells. The reference, cited frequently, contains no data or other details of the experiment, nor does it cite another reference [82]. Further, subsequent studies using extracts of comfrey leaf in the Ames test have shown no mutagenic effect suggesting that symphytine is not mutagenic[83]. Symphytine/symlandine in human Chang liver cells did not cause a mutation to the p53 tumor suppressor gene, although whole comfrey root extracts did [64]. Although single PA components of comfrey such as symphytine dont appear to induce mutagenesis there is some evidence that combined comfrey PAs or comfrey root extracts may induce mutagenesis (table 4). Two additional studies using total comfrey PAs or fractions of comfrey PAs and an aqueous infusion of S. officinale root have been performed. The first study, using human lymphocytes, demonstrated sister chromatid exchanges and chromosome aberrations at high doses only[84]. The second study demonstrated that an alkaloid fraction and dilutions of tea resulted in antimitotic and mutagenic activity in meristematic cells of the lateral roots of Vicia faba[73]. Further studies are warranted to confirm these findings and identify what, if any, component of comfrey is mutagenic.

One in vivo study using pure symphytine has been done. In an experiment that ran for 21 weeks males rats were given 13 mg/kg i.p. twice weekly for 4 weeks and then once a week for 52 weeks. One rat out of twenty developed liver cell adenoma and three rats out of twenty developed hemanagioendothelial sarcomas of the liver. All of the animals displayed megalocytosis in the liver. In order to relate this to human risk an equivalent dose for a 60 kg human has been estimated (table 5). In order to receive an equivalent dose of symphytine one would need to consume between 7 and 1040kg of dry leaf, assuming 5% of comfrey PA is symphytine [65] and the variability of PA concentrations in leaf as given in Table 2. An alternate way of estimating the equivalent dose would be to consider all the alkaloids in comfrey to be of equal carcinogenic potential (not probable). The dose administered then would be equivalent to 350g to 52 kg dry leaf. Given a typical therapeutic dose to be about 5g/day it is easy to conclude that the results of this study can not be used it to determine human risk, as levels are 100 to 10,000 times greater in the rat study.

Echimidine, once thought to be absent in S. officinale and used as a chemotaxonomic marker to separate S. asperum and S. x uplandicum from S. officinale, is actually present in about a quarter of S. officinale herbarium and botanical samples[67]. As with symphytine, the levels of echimidine vary considerably. It has been suggested that the values for echimidine are a third to a half those of symphytine[82], although some researchers have found it at concentrations five times symphytine levels[65] and one researcher found it at 85% of the total PAs or 600g/g root [69]. Echimidine has an LD50 in rats of 200mg/kg i.p.[85]. It has been shown to be mutagenic in Drosophila (primary reference not reviewed)[20]. Administration to three male rats at 20mg/kg thrice weekly for 136 days resulted in limited megalocytosis of the midzone and periphery of the lobule[85].

The minor PA lasiocarpine, a heliotridine diester, has been shown to be present in Symphytum spp. material analyzed by thin layer chromatography, but this has not been confirmed in analyses using more definitive methods. Lasiocarpine is a hepatotoxin, carcinogen, and mutagen. The PAs, 7- and 9-angeloylretronecine have also been shown in comfrey in one report[66]. These PAs have no hepatotoxicity at levels up to 190mg/kg i.p. in two week old rats[23]. In addition, one unconfirmed review reports the presence of heliosupine, viridiflorine, echinatine, and acetyl echimidine [86].

2004 Dorena Rode       Acknowledgment