Pyrrolizidine alkaloid

Short description: Class of chemical compounds

Skeletal formula of retronecine, a pyrrolizidine alkaloid found in the common groundsel (Senecio vulgaris) and comfrey (Symphytum spp.)

Pyrrolizidine alkaloids (PAs), sometimes referred to as necine bases, are a group of naturally occurring alkaloids based on the structure of pyrrolizidine. Pyrrolizidine alkaloids are produced by plants as a defense mechanism against insect herbivores. More than 660 PAs and PA N-oxides have been identified in over 6,000 plants, and about half of them exhibit hepatotoxicity.^[1] They are found frequently in plants in the Boraginaceae, Asteraceae, Orchidaceae and Fabaceae families; less frequently in the Convolvulaceae and Poaceae, and in at least one species in the Lamiaceae. It has been estimated that 3% of the world’s flowering plants contain pyrrolizidine alkaloids.^[2] Honey can contain pyrrolizidine alkaloids,^[3]^[4] as can grains, milk, offal and eggs.^[5] To date (2011), there is no international regulation of PAs in food, unlike those for herbs and medicines.^[6]^[7]

Unsaturated pyrrolizidine alkaloids are hepatotoxic, that is, damaging to the liver.^[8]^[9] PAs also cause hepatic veno-occlusive disease and liver cancer.^[10] PAs are tumorigenic.^[11] Disease associated with consumption of PAs is known as pyrrolizidine alkaloidosis.

In humans, the use of medicinal herbs containing PAs, notably borage leaf, comfrey and coltsfoot in the West, and some Chinese medicinal herbs, has been shown to pose health risks.^[11] The degree of toxicity can vary based on age and gender, with fetuses and neonates showing high sensitivity, including instances of death. ^[12]

Some ruminant animals, for example cattle, show no change in liver enzyme activities or any clinical signs of poisoning when fed low concentrations of plants containing pyrrolizidine alkaloids.^[13] Yet, Australian studies have demonstrated toxicity.^[14] Sheep and goats especially, and to a lesser degree cattle, are much more resistant and tolerate much higher PA dosages, thought to be due to thorough detoxification via PA-destroying rumen microbes. ^[12]

PA is also used as a defense mechanism by some organisms such as Utetheisa ornatrix. Utetheisa ornatrix caterpillars obtain these toxins from their food plants and use them as a deterrent for predators. PAs protect them from most of their natural enemies. The toxins stay in these organisms even when they metamorphose into adult moths, continuing to protect them throughout their adult stage.^[15]

Ecology

Main page: Biology:Pyrrolizidine alkaloid sequestration

Many plants contain pyrrolizidine alkaloids, and in turn there are many insects which consume the plants and build up the alkaloids in their bodies.^[16] For example, male queen butterflies utilize pyrrolizidine alkaloids to produce pheromones useful for mating.^[17] The butterfly Danaus chrysippus is known to obtain pyrrolizidine alkaloids in their diet and store these chemicals, making them toxic and unpalatable to predators.^[18] Greta oto, the glasswing butterfly, uses pyrrolizidine alkaloids for both toxicity in the adult moth and pheromone production in the male butterfly. The garden tiger moth also stores these compounds as a caterpillar, using them for larval (through the use of spines) and adult defense (in the form of a spray and bad taste).^[19]

Plants species containing pyrrolizidine alkaloids

Adenostyles alliariae
Adenostyles glabra
Ageratum conyzoides
Ageratum houstonianum^[20]
Anchusa officinalis^[21]
Arnebia euchroma
Borago officinalis (< 10 ppm, non-toxic)^{[citation needed]}
Cacalia hastata
Cacalia hupehensis
Chromolaena odorata
Cordia myxa
Crassocephalum crepidioides
Crotalaria albida
Crotalaria assamica
Crotalaria crispat
Crotalaria dura
Crotalaria globifera
Crotalaria mucronata
Crotalaria sesseliflora
Crotalaria spectabilis
Crotalaria tetragona
Crotalaria retusa
Cynoglossum amabile
Cynoglossum lanceolatum
Cynoglossum officinale
Cynoglossum zeylanicum
Echium plantagineum^[22]
Echium vulgare
Emilia sonchifolia
Eupatorium cannabinum
Eupatorium chinense
Eupatorium fortunei
Eupatorium japonicum
Eupatorium perfoliatum ^[23]
Eupatorium purpureum^[24]
Farfugium japonicum
Gynura bicolor
Gynura divaricata
Gynura segetum
Heliotropium amplexicaule^[22]
Heliotropium europaeum^[22]
Heliotropium indicum
Heliotropium popovii^[25]
Lappula intermedia
Ligularia cymbulifera
Ligularia dentata
Ligularia duiformis
Ligularia heterophylla
Ligularia hodgsonii
Ligularia intermedia
Ligularia lapathifolia
Ligularia lidjiangensis
Ligularia platyglossa
Ligularia tongolensis
Ligularia tsanchanensis
Ligularia vellerea
Liparis nervosa
Lithospermum erythrorhizon
Neurolaena lobata
Petasites japonicus
Senecio alpinus
Senecio argunensis
Senecio brasiliensis^[26]
Senecio chrysanthemoides
Senecio cineraria
Senecio glabellus
Senecio integrifolius var. fauriri
Senecio interggerrimus
Senecio jacobaea^[22]
Senecio lautus^[22]
Senecio linearifolius^[22]
Senecio madagascariensis^[22]
Senecio nemorensis
Senecio quadridentatus^[22]
Senecio riddelli
Senecio scandens
Senecio vulgaris
Syneilesis aconitifolia
Symphytum officinale^[27]
Tussilago farfara

The effect of PAs in humans, that is PAILDs (Pyrrolizidine Alkaloid Induced Liver Diseases),^[28] of epidemic proportions was recorded after a long field-level epidemiological investigation in the northern region of Ethiopia-Tigray.^[29]

Classification

One classification is based on the substitution pattern of the pyrrolizidine ring. This part of the structure is normally referred to as necine bases. The three largest groups are based on the three necine bases platynecine, heliotridine and retronecine.

Platynecine
Heliotridine
Retronecine

References

↑ Radominska-Pandya, A (2010). "Invited Speakers". Drug Metabolism Reviews 42 (S1): 1–2. doi:10.3109/03602532.2010.506057. PMID 20842800.
↑ Smith, L. W.; Culvenor, C. C. J. (1981). "Plant sources of hepatotoxic pyrrolizidine alkaloids". J. Nat. Prod. 44 (2): 129–15. doi:10.1021/np50014a001. PMID 7017073.
↑ Kempf, M; Reinhard, A; Beuerle, T (Jan 2010). "Pyrrolizidine alkaloids (PAs) in honey and pollen-legal regulation of PA levels in food and animal feed required". Mol Nutr Food Res 54 (1): 158–68. doi:10.1002/mnfr.200900529. PMID 20013889.
↑ Edgar, John A.; Roeder, Erhard; Molyneux, Russell J. (2002). "Honey from Plants Containing Pyrrolizidine Alkaloids: A Potential Threat to Health". J. Agric. Food Chem. 50 (10): 2719–2730. doi:10.1021/jf0114482. PMID 11982390.
↑ "Pyrrolizidine alkaloids in Food". http://www.foodstandards.gov.au/_srcfiles/tr2.pdf.
↑ Coulombe, Roger A. Jr (2003). "Pyrrolizidine alkaloids in foods". Advances in Food and Nutrition Research Volume 45. 45. 61–99. doi:10.1016/S1043-4526(03)45003-1. ISBN 9780120164455.
↑ German Commission E monographs
↑ "Foodborne Pathogenic Microorganisms and Natural Toxins Handbook: Pyrrolizidine Alkaloids". Bad Bug Book. United States Food and Drug Administration. https://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodbornePathogensNaturalToxins/BadBugBook/ucm071047.htm.
↑ Schoental, R.; Kelly, JS (April 1959). "Liver lesions in young rats suckled by mothers treated with the pyrrolizidine (Senecio) alkaloids, lasiocarpine and retrorsine". The Journal of Pathology and Bacteriology 77 (2): 485–495. doi:10.1002/path.1700770220. PMID 13642195.
↑ Schoental, R (1968). "Toxicology and Carcinogenic Action of Pyrrolizidine Alkaloids". Cancer Research 28 (11): 2237–2246. PMID 4302035. http://cancerres.aacrjournals.org/cgi/reprint/28/11/2237.pdf.
↑ ^11.0 ^11.1 Fu, P.P.; Yang, Y.C.; Xia, Q. et al. (2002). Pyrrolizidine alkaloids-tumorigenic components in Chinese herbal medicines and dietary supplements. https://www.researchgate.net/publication/265873732.
↑ ^12.0 ^12.1 Wiedenfeld, H.; Edgar, J. (2011). "Toxicity of pyrrolizidine alkaloids to humans and ruminants". Phytochemistry Reviews 2010 (1): 1–15. doi:10.1007/s11101-010-9174-0. Bibcode: 2011PChRv..10..137W.
↑ Skaanild, M.T.; Friis, C.; Brimer, L. (2001). "Interplant alkaloid variation and Senecio vernalis toxicity in cattle". Veterinary and Human Toxicology 43 (3): 147–151. PMID 11383654.
↑ Noble, J.W.; Crossley, J.; Hill, B.D. et al. (1994). "Pyrrolizidine alkaloidosis of cattle associated with Senecio lautus". Australian Veterinary Journal 71 (7): 196–200. doi:10.1111/j.1751-0813.1994.tb03400.x. PMID 7945096.
↑ Conner, W.E. (2009). Tiger Moths and Woolly Bears: Behaviour, Ecology, and Evolution of the Arctiidae. New York: Oxford University Press. pp. 1–10. ISBN 9780195327373.
↑ Nishida, R; Schulz, S; Kim, C. S et al. (1996). "Male sex pheromone of a giant danaine butterfly,Idea leuconoe". Journal of Chemical Ecology 22 (5): 949–72. doi:10.1007/BF02029947. PMID 24227617.
↑ Scott, James A. (1997). "Family Nymphalidae: Brush-Footed Butterflies". The Butterflies of North America: A Natural History and Field Guide. Stanford, California: Stanford University Press. pp. 228–232. ISBN 9780804720137.
↑ Edgar, J. A.; Cockrum, P. A.; Frahn, J. L. (1976-12-01). "Pyrrolizidine alkaloids inDanaus plexippus L. and Danaus chrysippus L." (in en). Experientia 32 (12): 1535–1537. doi:10.1007/bf01924437. ISSN 0014-4754.
↑ Macel, Mirka (2011-03-01). "Attract and deter: a dual role for pyrrolizidine alkaloids in plant–insect interactions" (in en). Phytochemistry Reviews 10 (1): 75–82. doi:10.1007/s11101-010-9181-1. ISSN 1568-7767. PMID 21475391. Bibcode: 2011PChRv..10...75M.
↑ Wiedenfeld, H; Andrade-Cetto, A (2001). "Pyrrolizidine alkaloids from Ageratum houstonianum Mill.". Phytochemistry 57 (8): 1269–71. doi:10.1016/S0031-9422(01)00192-3. PMID 11454357. Bibcode: 2001PChem..57.1269W.
↑ Broch-Due, Å. I.; Aasen, A. J. (1980). "Alkaloids of Anchusa officinalis L. Identification of the Pyrrolizidine Alkaloid Lycopsamine". Acta Chem. Scand. B34: 75–77. doi:10.3891/acta.chem.scand.34b-0075.
↑ ^22.0 ^22.1 ^22.2 ^22.3 ^22.4 ^22.5 ^22.6 ^22.7 "TABLE 05: Important Poisonous Vascular Plants of Australia". The Merck Veterinary Manual. http://www.merckvetmanual.com/mvm/htm/bc/ttox05.htm.
↑ Connor Yearsley. "American Herbal Pharmacopoeia Publishes Boneset Monograph and Therapeutic Compendium". HerbalGram (American Botanical Council) 125: 26–28. https://www.herbalgram.org/resources/herbalgram/issues/125/table-of-contents/hg125-orgnews-ahpboneset.
↑ Wood, Matthew. "The Book of Herbal Wisdom: Using Plants As Medicines." Berkeley CA. North Atlantic Books. 1997.
↑ "An outbreak of hepatic veno-occlusive disease in Western afghanistan associated with exposure to wheat flour contaminated with pyrrolizidine alkaloids". J Toxicol 2010: 313280. 28 Jun 2010. doi:10.1155/2010/313280. PMID 20652038.
↑ Rizk A. M. (1990). "The Pyrrolizidine Alkaloids: Plant Sources and Properties". Naturally Occurring Pyrrolizidine Alkaloids. CRC Press. p. 12. ISBN 0849346509.
↑ Yeong M. L. (1990). "Hepatic veno-occlusive disease associated with comfrey ingestion". Journal of Gastroenterology and Hepatology 5 (2): 211–214. doi:10.1111/j.1440-1746.1990.tb01827.x. PMID 2103401.
↑ "Pyrrolizidine Alkaloid Induced Liver Diseases", cited in Chiu, C; Buttke, D; Welde, G et al. (2013). "Evaluation of the Pyrrolizidine Alkaloid Induced Liver Disease (PAILD) Active Surveillance System in Tigray, Ethiopia". Online Journal of Public Health Informatics 5 (1): e167. doi:10.5210/ojphi.v5i1.4560.
↑ "Investigating Liver disease in Ethiopia". CDC. 30 Oct 2012. https://www.cdc.gov/nceh/stories/Ethiopia.html.

External links

Subhuti Dharmananda. "Safety issues affecting herbs: pyrrolizidine alkaloids". Institute for Traditional Medicine, Portland, Oregon. http://www.itmonline.org/arts/pas.htm.
E. Röder (1995). "Medicinal plants in Europe containing pyrrolizidine alkaloids". Die Pharmazie 50 (2): 83–98. PMID 7700976. http://www.henriettes-herb.com/PAs/PAs.html.
Retronecine at KEGG
msn.com/de News Report: Well-known brands affected: This is how much poison there is in these herbal and chamomile teas. 6 out of 13 brands of herbal tea available in Germany contain the poison.

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Original source: https://en.wikipedia.org/wiki/Pyrrolizidine alkaloid. Read more

[1] Radominska-Pandya, A (2010). "Invited Speakers". Drug Metabolism Reviews 42 (S1): 1–2. doi:10.3109/03602532.2010.506057. PMID 20842800.

[2] Smith, L. W.; Culvenor, C. C. J. (1981). "Plant sources of hepatotoxic pyrrolizidine alkaloids". J. Nat. Prod. 44 (2): 129–15. doi:10.1021/np50014a001. PMID 7017073.

[3] Kempf, M; Reinhard, A; Beuerle, T (Jan 2010). "Pyrrolizidine alkaloids (PAs) in honey and pollen-legal regulation of PA levels in food and animal feed required". Mol Nutr Food Res 54 (1): 158–68. doi:10.1002/mnfr.200900529. PMID 20013889.

[4] Edgar, John A.; Roeder, Erhard; Molyneux, Russell J. (2002). "Honey from Plants Containing Pyrrolizidine Alkaloids: A Potential Threat to Health". J. Agric. Food Chem. 50 (10): 2719–2730. doi:10.1021/jf0114482. PMID 11982390.

[5] "Pyrrolizidine alkaloids in Food". http://www.foodstandards.gov.au/_srcfiles/tr2.pdf.

[6] Coulombe, Roger A. Jr (2003). "Pyrrolizidine alkaloids in foods". Advances in Food and Nutrition Research Volume 45. 45. 61–99. doi:10.1016/S1043-4526(03)45003-1. ISBN 9780120164455.

[7] German Commission E monographs

[FDA-8] "Foodborne Pathogenic Microorganisms and Natural Toxins Handbook: Pyrrolizidine Alkaloids". Bad Bug Book. United States Food and Drug Administration. https://www.fda.gov/Food/FoodSafety/FoodborneIllness/FoodborneIllnessFoodbornePathogensNaturalToxins/BadBugBook/ucm071047.htm.

[9] Schoental, R.; Kelly, JS (April 1959). "Liver lesions in young rats suckled by mothers treated with the pyrrolizidine (Senecio) alkaloids, lasiocarpine and retrorsine". The Journal of Pathology and Bacteriology 77 (2): 485–495. doi:10.1002/path.1700770220. PMID 13642195.

[10] Schoental, R (1968). "Toxicology and Carcinogenic Action of Pyrrolizidine Alkaloids". Cancer Research 28 (11): 2237–2246. PMID 4302035. http://cancerres.aacrjournals.org/cgi/reprint/28/11/2237.pdf.

[Fu1-11] 11.0 ^11.1 Fu, P.P.; Yang, Y.C.; Xia, Q. et al. (2002). Pyrrolizidine alkaloids-tumorigenic components in Chinese herbal medicines and dietary supplements. https://www.researchgate.net/publication/265873732.

[wiedenfeld-12] 12.0 ^12.1 Wiedenfeld, H.; Edgar, J. (2011). "Toxicity of pyrrolizidine alkaloids to humans and ruminants". Phytochemistry Reviews 2010 (1): 1–15. doi:10.1007/s11101-010-9174-0. Bibcode: 2011PChRv..10..137W.

[13] Skaanild, M.T.; Friis, C.; Brimer, L. (2001). "Interplant alkaloid variation and Senecio vernalis toxicity in cattle". Veterinary and Human Toxicology 43 (3): 147–151. PMID 11383654.

[14] Noble, J.W.; Crossley, J.; Hill, B.D. et al. (1994). "Pyrrolizidine alkaloidosis of cattle associated with Senecio lautus". Australian Veterinary Journal 71 (7): 196–200. doi:10.1111/j.1751-0813.1994.tb03400.x. PMID 7945096.

[15] Conner, W.E. (2009). Tiger Moths and Woolly Bears: Behaviour, Ecology, and Evolution of the Arctiidae. New York: Oxford University Press. pp. 1–10. ISBN 9780195327373.

[16] Nishida, R; Schulz, S; Kim, C. S et al. (1996). "Male sex pheromone of a giant danaine butterfly,Idea leuconoe". Journal of Chemical Ecology 22 (5): 949–72. doi:10.1007/BF02029947. PMID 24227617.

[17] Scott, James A. (1997). "Family Nymphalidae: Brush-Footed Butterflies". The Butterflies of North America: A Natural History and Field Guide. Stanford, California: Stanford University Press. pp. 228–232. ISBN 9780804720137.

[18] Edgar, J. A.; Cockrum, P. A.; Frahn, J. L. (1976-12-01). "Pyrrolizidine alkaloids inDanaus plexippus L. and Danaus chrysippus L." (in en). Experientia 32 (12): 1535–1537. doi:10.1007/bf01924437. ISSN 0014-4754.

[19] Macel, Mirka (2011-03-01). "Attract and deter: a dual role for pyrrolizidine alkaloids in plant–insect interactions" (in en). Phytochemistry Reviews 10 (1): 75–82. doi:10.1007/s11101-010-9181-1. ISSN 1568-7767. PMID 21475391. Bibcode: 2011PChRv..10...75M.

[20] Wiedenfeld, H; Andrade-Cetto, A (2001). "Pyrrolizidine alkaloids from Ageratum houstonianum Mill.". Phytochemistry 57 (8): 1269–71. doi:10.1016/S0031-9422(01)00192-3. PMID 11454357. Bibcode: 2001PChem..57.1269W.

[21] Broch-Due, Å. I.; Aasen, A. J. (1980). "Alkaloids of Anchusa officinalis L. Identification of the Pyrrolizidine Alkaloid Lycopsamine". Acta Chem. Scand. B34: 75–77. doi:10.3891/acta.chem.scand.34b-0075.

[MERCK-22] 22.0 ^22.1 ^22.2 ^22.3 ^22.4 ^22.5 ^22.6 ^22.7 "TABLE 05: Important Poisonous Vascular Plants of Australia". The Merck Veterinary Manual. http://www.merckvetmanual.com/mvm/htm/bc/ttox05.htm.

[23] Connor Yearsley. "American Herbal Pharmacopoeia Publishes Boneset Monograph and Therapeutic Compendium". HerbalGram (American Botanical Council) 125: 26–28. https://www.herbalgram.org/resources/herbalgram/issues/125/table-of-contents/hg125-orgnews-ahpboneset.

[24] Wood, Matthew. "The Book of Herbal Wisdom: Using Plants As Medicines." Berkeley CA. North Atlantic Books. 1997.

[25] "An outbreak of hepatic veno-occlusive disease in Western afghanistan associated with exposure to wheat flour contaminated with pyrrolizidine alkaloids". J Toxicol 2010: 313280. 28 Jun 2010. doi:10.1155/2010/313280. PMID 20652038.

[26] Rizk A. M. (1990). "The Pyrrolizidine Alkaloids: Plant Sources and Properties". Naturally Occurring Pyrrolizidine Alkaloids. CRC Press. p. 12. ISBN 0849346509.

[27] Yeong M. L. (1990). "Hepatic veno-occlusive disease associated with comfrey ingestion". Journal of Gastroenterology and Hepatology 5 (2): 211–214. doi:10.1111/j.1440-1746.1990.tb01827.x. PMID 2103401.

[28] "Pyrrolizidine Alkaloid Induced Liver Diseases", cited in Chiu, C; Buttke, D; Welde, G et al. (2013). "Evaluation of the Pyrrolizidine Alkaloid Induced Liver Disease (PAILD) Active Surveillance System in Tigray, Ethiopia". Online Journal of Public Health Informatics 5 (1): e167. doi:10.5210/ojphi.v5i1.4560.

[29] "Investigating Liver disease in Ethiopia". CDC. 30 Oct 2012. https://www.cdc.gov/nceh/stories/Ethiopia.html.

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