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Jmbennett/sandbox/chm275
Names
Other names
Aureine, Senecionin
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
KEGG
  • InChI=1S/C18H25NO5/c1-4-12-9-11(2)18(3,22)17(21)23-10-13-5-7-19-8-6-14(15(13)19)24-16(12)20/h4-5,11,14-15,22H,6-10H2,1-3H3/b12-4-/t11-,14-,15-,18-/m1/s1 checkY
    Key: HKODIGSRFALUTA-JTLQZVBZSA-N checkY
  • O=C1O[C@@H]3CCN2C\C=C(\COC(=O)[C@](C)(O)[C@H](C)CC1=[C@H]C)[C@@H]23
Properties
C18H25NO5
Molar mass 335.400 g·mol−1
Density 1.25 g/cm3
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Senecionine is a toxic pyrrolizidine alkaloid isolated from various botanical sources. It takes its name from the Senecio species and is produced by many different plants in the genus, including Jacobaea vulgaris. It has also been isolated from several other different plants including Brachyglottis repanda, Emilia, Erechtites hieraciifolius, Petacites, Syneilesis, Crotalaria, Caltha leptosepala, and Caslilleja.[1]

The compound is toxic and consumption can lead to liver damage, cancer, and pyrrolizidine alkaloidosis. Because of this, consumption of plants that produce it has resulted in poisonings, both in humans and in animals.[2]


Bioactivity

Like other pyrrolizidine alkaloids, senecionine is hepatotoxic when ingested.[3] The ingested molecule is a prodrug that is metabolized to its active form.

In larger quantities, ingestion can lead to convulsions and death. Studies in rodents have shown an LD50 of 65 mg/kg.[4]


Biosynthesis

In Senecio species, biosynthesis of senecionine starts from L-arginine or L-ornithine.[5] Since plants don't have decarboxylase enzyme for L-ornithine, it must be first converted into L-arginine. Arginine can then be readily converted to putrescine and spermidine. Spermidine then transfers an aminopropyl group to spermidine to form homospermidine in an NAD+-dependent reaction catalyzed by homospermidine synthase (HSS), releasing 1,3-diaminopropane.[6] HSS is the only enzyme that has been definitively implicated in this biosynthesis.[7]

Homospermidine is then oxidized and subsequently cyclized to form the stereospecific pyrrolizidine backbone. The aldehyde is then reduced and then the pyrrolizidine core is desaturated and hydroxylated through yet undetermined mechanisms to form retronecine. Retronecine is acylated by senecic acid, formed from two equivalents of L-isoleucine. This step forms the N-oxide of senecionine, which is subsequently reduced to yield senecionine.[8]

Biosynthesis of senecionine[9]

Chemistry

Senecionine has a core structure of retronecine, an unsaturated pyrrolizide, with a 12-membered lactone ring attached to the core.[10] It has six hydrogen bond acceptors and one hydrogen bond donor. It has minimal solubility in water, low solubility in ethanol and diethyl ether, and is freely soluble in chloroform. The nitrogen atom in the pyrrolizidine core is weakly basic with an estimated pKa of 5.9.[11]

Metabolism and Mechanism of Action

After oral ingestion, senecionine is absorbed from the gastrointestinal tract. When it reaches the liver, it is metabolized via three pathways: N-oxidation, oxidation, and ester hydrolysis. N-oxidation and hydrolysis are detoxification pathways, and the products of these reactions are conjugated and excreted by the kidneys. However, the N-oxide may be converted back into senecionine by cytochrome P-450 (CYP450) monooxygenases. Oxidation of senecionine to its respective dehydropyrrolizidine is responsible for its toxicity.[12]

In the toxic pathway, the 2-pyrroline in the core is desaturated via an oxidation reaction to form a pyrrolic ester. This metabolite can still subsequently be eliminated if it is conjugated to glutathione. However, this metabolite is toxic because it can act as an electrophile. It may be attacked by either DNA base pairs or by liver proteins, resulting in the formation of toxic adducts, including cross-linked adducts.[13] These adducts can damage DNA, leading to genotoxicity and carcinogenesis, and liver enzymes, leading to hepatotoxicity.[14]

Metabolism and mechanism of action of senecionine. Nuc=nucleophilic protein or DNA base[15]

History and Biology

Danaus chrysippus butterflies consume senecionine as both a defense mechanism and to increase sexual fitness[16][17]

The Senecio plants groundsel and ragwort are both common and are found in many regions, most commonly as weeds on cultivated ground. Common ragwort is especially prevalent in Europe and has been responsible for livestock poisoning and deaths when it is consumed. In Africa, Australia, and the United States, Crotalaria species, shrub-like herbs, have been found to be responsible for similar livestock deaths. Horses seem to be particularly vulnerable to senecionine poisoning through ingestion of ragwort. Symptoms of poisoning in horses (known as "horse staggers") include nervousness, yawning, fatigue, and unsteady gait.[18]

Some species have evolved to leverage senecionine for their own benefit. Danaus chrysippus butterflies can safely consume senecionine-containing plants, making them taste very bitter and thus unpalatable to predators.[19] This adaptation is also present in the caterpillars of the Cinnabar moth.[20] Additionally, D. chrysippus are able to convert senecionine to pheromones necessary for successful mating. Consequently, experiments have shown that males deprived of pyrrolizidine alkaloids, including senecionine, in their diets are less successful at mating.[21]

Senecionine-containing herbs have been used in folk medicine for the treatment of diabetes mellitus, hemorrhage, hypertension, and as a uterine stimulant, despite no documented evidence that it is effective for any of those conditions and overwhelming evidence of its toxicity.[22]

In humans, bread contaminated with ragwort has caused senecionine poisonings (a condition colloquially known as "bread poisoning" in South Africa). In the West Indies, poisonings have been reported from the consumption of herbal teas made with Crotalaria.[23]

See also

Riddelliine, a closely related pyrrolizidine alkaloid

References

  1. ^ Smith, L. W.; Culvenor, C. C. J. (March 1981). "Plant Sources of Hepatotoxic Pyrrolizidine Alkaloids". Journal of Natural Products. 44 (2): 129–152. doi:10.1021/np50014a001.
  2. ^ Fu, Peter P.; Xia, Qingsu; Lin, Ge; Chou, Ming W. (2004). "Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms". Drug Metabolism Reviews. 36 (1): 1–55. doi:10.1081/DMR-120028426. PMID 15072438.
  3. ^ MATTOCKS, A. R. (February 1968). "Toxicity of Pyrrolizidine Alkaloids". Nature. 217 (5130): 723–728. doi:10.1038/217723a0.
  4. ^ Stegelmeier, BL; Colegate, SM; Brown, AW (29 November 2016). "Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity". Toxins. 8 (12). doi:10.3390/toxins8120356. PMID 27916846.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Dewick, M,Paul (Feb 4, 2009). Medicinal Natural Products. wiley online. pp. 324–325. doi:10.1002/9780470742761. ISBN 9780470742761.{{cite book}}: CS1 maint: multiple names: authors list (link)
  6. ^ . PMID 10611289. {{cite journal}}: Cite journal requires |journal= (help); Missing or empty |title= (help)
  7. ^ Schramm, S; Köhler, N; Rozhon, W (30 January 2019). "Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants". Molecules (Basel, Switzerland). 24 (3). doi:10.3390/molecules24030498. PMID 30704105.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Schramm, S; Köhler, N; Rozhon, W (30 January 2019). "Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants". Molecules (Basel, Switzerland). 24 (3). doi:10.3390/molecules24030498. PMID 30704105.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  9. ^ Schramm, S; Köhler, N; Rozhon, W (30 January 2019). "Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants". Molecules (Basel, Switzerland). 24 (3). doi:10.3390/molecules24030498. PMID 30704105.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  10. ^ Were, Obuya; Benn, Michael; Munavu, Raphael M. (March 1991). "Pyrrolizidine Alkaloids from Senecio hadiensis". Journal of Natural Products. 54 (2): 491–499. doi:10.1021/np50074a022.
  11. ^ "Senecionine". pubchem.ncbi.nlm.nih.gov. Retrieved 23 April 2020.
  12. ^ Moreira, Rute; Pereira, David M.; Valentão, Patrícia; Andrade, Paula B. (2018-06-05). "Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety". International Journal of Molecular Sciences. 19 (6). doi:10.3390/ijms19061668. ISSN 1422-0067. PMC 6032134. PMID 29874826.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  13. ^ Zhu, L; Xue, J; Xia, Q; Fu, PP; Lin, G (February 2017). "The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice". Archives of toxicology. 91 (2): 949–965. doi:10.1007/s00204-016-1713-z. PMID 27125825.
  14. ^ Moreira, Rute; Pereira, David M.; Valentão, Patrícia; Andrade, Paula B. (2018-06-05). "Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety". International Journal of Molecular Sciences. 19 (6). doi:10.3390/ijms19061668. ISSN 1422-0067. PMC 6032134. PMID 29874826.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  15. ^ Moreira, R; Pereira, DM; Valentão, P; Andrade, PB (5 June 2018). "Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety". International journal of molecular sciences. 19 (6). doi:10.3390/ijms19061668. PMID 29874826.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  16. ^ Edgar, J. A.; Cockrum, P. A.; Frahn, J. L. (December 1976). "Pyrrolizidine alkaloids inDanaus plexippus L. andDanaus chrysippus L.". Experientia. 32 (12): 1535–1537. doi:10.1007/BF01924437.
  17. ^ Biology of Australian Butterflies. CSIRO Publishing. ISBN 9780643105140.
  18. ^ Vickery, Margaret (2010). "Plant poisons: their occurrence, biochemistry and physiological properties". Science Progress. 93 (Pt 2): 181–221. doi:10.3184/003685010X12729948220326. ISSN 0036-8504. PMID 20681322.
  19. ^ Edgar, J. A.; Cockrum, P. A.; Frahn, J. L. (December 1976). "Pyrrolizidine alkaloids inDanaus plexippus L. andDanaus chrysippus L.". Experientia. 32 (12): 1535–1537. doi:10.1007/BF01924437.
  20. ^ "Cinnabar moth". A Nature Observer's Scrapbook. June 2007. Retrieved 2020-04-22.
  21. ^ Biology of Australian Butterflies. CSIRO Publishing. ISBN 9780643105140.
  22. ^ Blumenthal, ed., M. The complete German Commission E monographs, Therapeutic guide to herbal medicines. American Botanical Council. p. 376. ISBN 096555550X. {{cite book}}: |last1= has generic name (help)
  23. ^ Vickery, Margaret (2010). "Plant poisons: their occurrence, biochemistry and physiological properties". Science Progress. 93 (Pt 2): 181–221. doi:10.3184/003685010X12729948220326. ISSN 0036-8504. PMID 20681322.
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