Senecionine

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'''Senecionine''' is a toxic pyrrolizidine alkaloid isolated from various botanical sources. It takes its name from the ''Senecio'' genus and is produced by many different plants in that genus, including ''Jacobaea vulgaris'' (''Senecio jacobaea''). It has also been isolated from several other plants, including ''Brachyglottis repanda'', ''Emilia'', ''Erechtites hieraciifolius'', ''Petasites'', ''Syneilesis'', ''Crotalaria'', ''Caltha leptosepala'', and ''Castilleja''.<ref>{{cite journal |last1=Smith |first1=L. W. |last2=Culvenor |first2=C. C. J. |title=Plant Sources of Hepatotoxic Pyrrolizidine Alkaloids |journal=Journal of Natural Products |date=March 1981 |volume=44 |issue=2 |pages=129–152 |doi=10.1021/np50014a001|pmid=7017073 |bibcode=1981JNAtP..44..129S }}</ref>

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.<ref>{{cite journal| doi = 10.1081/DMR-120028426 |pmid=15072438|title=Pyrrolizidine Alkaloids—Genotoxicity, Metabolism Enzymes, Metabolic Activation, and Mechanisms|journal=Drug Metabolism Reviews|volume=36|issue=1|pages=1–55|year=2004|last1=Fu|first1=Peter P.|last2=Xia|first2=Qingsu|last3=Lin|first3=Ge|last4=Chou|first4=Ming W.|s2cid=13746999}}</ref>

==Toxicity== Like other pyrrolizidine alkaloids, senecionine is toxic when ingested. The ingested molecule is a protoxin that is metabolized to its active form.<ref>{{cite journal |last1=MATTOCKS |first1=A. R. |title=Toxicity of Pyrrolizidine Alkaloids |journal=Nature |date=February 1968 |volume=217 |issue=5130 |pages=723–728 |doi=10.1038/217723a0|pmid=5641123 |bibcode=1968Natur.217..723M |s2cid=4157573 }}</ref>

In large quantities, ingestion can lead to critical illness, including convulsions and death. Studies in rodents have shown an LD₅₀ of 65&nbsp;mg/kg.<ref>{{cite journal |last1=Stegelmeier |first1=BL |last2=Colegate |first2=SM |last3=Brown |first3=AW |title=Dehydropyrrolizidine Alkaloid Toxicity, Cytotoxicity, and Carcinogenicity. |journal=Toxins |date=29 November 2016 |volume=8 |issue=12 |pages=356 |doi=10.3390/toxins8120356 |pmid=27916846|pmc=5198550 |doi-access=free }}</ref> In smaller, non-lethal quantities, ingestion can lead to intoxication, although clinical signs and symptoms may not present until months after exposure depending on the level of exposure.<ref name=":1"/>

Ingestion can lead to both liver and DNA damage.

===Liver toxicity=== {{See also|Hepatotoxicity}} The liver damage in both acute and chronic intoxication can cause hepatic veno-occlusive disease (VOS), signs and symptoms of which include nausea, vomiting, hepatomegaly, and bloody diarrhea.<ref name=":1">{{Cite book|title=Comprehensive toxicology.|date=2010|publisher=Elsevier|others=McQueen, Charlene A., 1947-|isbn=978-0-08-046884-6|edition=2nd|location=Oxford|oclc=697121354}}</ref> Additionally, acute intoxication can cause hemorrhagic necrosis and liver failure, with signs and symptoms including weight loss, jaundice, depression, behavior changes, and ascites. Photosensitive dermatitis may also be seen.<ref name=":1"/> Other symptoms and manifestations of chronic exposure include weakness, portal hypertension, and cirrhosis.<ref name=":1"/><ref name="ReferenceA">{{Cite journal|last1=Moreira|first1=Rute|last2=Pereira|first2=David M.|last3=Valentão|first3=Patrícia|last4=Andrade|first4=Paula B.|date=2018-06-05|title=Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety|journal=International Journal of Molecular Sciences|volume=19|issue=6|pages=1668|doi=10.3390/ijms19061668|issn=1422-0067|pmc=6032134|pmid=29874826|doi-access=free}}</ref>

===DNA damage=== Senecionine ingestion can also induce DNA damage. Although there are few if any cases of human cancers directly linked to senecionine intoxication, rodent studies have shown that it is capable of inducing tumor formation in the liver, lung, skin, brain, spinal cord, pancreas, and gastrointestinal tract.<ref name="ReferenceA"/>

===Diagnosis=== Diagnosis of senecionine toxicity is made based on history, physical examination, and liver biopsy.<ref name=":1"/> Lab findings may include increased bile acid concentrations, hyperbilirubinemia, hypoproteinemia, and abnormal liver function tests (LFTs). However, it has been observed that chronically exposed animals may have normal lab values for months to years despite ongoing liver damage.<ref>{{Cite journal|last1=Stegelmeier|first1=B. L.|last2=Edgar|first2=J. A.|last3=Colegate|first3=S. M.|last4=Gardner|first4=D. R.|last5=Schoch|first5=T. K.|last6=Coulombe|first6=R. A.|last7=Molyneux|first7=R. J.|date=1999|title=Pyrrolizidine alkaloid plants, metabolism and toxicity|journal=Journal of Natural Toxins|volume=8|issue=1|pages=95–116|issn=1058-8108|pmid=10091131}}</ref> Histological abnormalities on biopsy include megalocytosis, necrosis, fibrosis, and biliary hyperplasia, similar to other hepatotoxic ingestions and immune system disorders.<ref name=":1"/>

===Other bioactivity=== Senecionine has also been evaluated as an anti-microbial. A cocktail of pyrrolizidine alkaloids with senecionine in it has been shown to be toxic to ''Fusarium'' fungi at millimolar concentrations.<ref name="ReferenceA"/>

==Treatment== There are currently no known available drugs or antidotes to treat senecionine poisoning. Treatment is supportive to permit liver regeneration, which may include administration of intravenous (IV) fluids to correct dehydration and electrolyte imbalances, IV glucose, and wound care with antibiotics if dermatitis is a presenting symptom.<ref name=":1" /> Additionally, albumin infusions may be used to reduce ascites. Prevention remains the best method to reduce senecionine poisonings, including avoiding consumption of senecionine-containing plants and pesticide use to kill infestations of those plants.<ref name=":1"/>

==Biosynthesis and chemistry== thumb|right|500px|Biosynthesis of senecionine<ref name="Pyrrolizidine Alkaloids: Biosynthes"/> In ''Senecio'' species, biosynthesis of senecionine starts from <small>L</small>-arginine or <small>L</small>-ornithine.<ref>{{cite book |last=Dewick |first= M,Paul |date= Feb 4, 2009| title = Medicinal Natural Products|publisher= wiley online|pages=324–325 |isbn=9780470742761|doi=10.1002/9780470742761}}</ref> Because plants don't have decarboxylase enzyme for <small>L</small>-ornithine, it must be first converted into <small>L</small>-arginine. Arginine can then be readily converted to putrescine and spermidine. Next, in an NAD+-dependent reaction catalyzed by homospermidine synthase (HSS), an aminopropyl group from putrescine is transferred to spermidine to form homospermidine, releasing 1,3-diaminopropane (see biosynthesis scheme).<ref>{{cite journal |pmid=10611289|year=1999|last1=Ober|first1=D.|last2=Hartmann|first2=T.|title=Homospermidine synthase, the first pathway-specific enzyme of pyrrolizidine alkaloid biosynthesis, evolved from deoxyhypusine synthase|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=96|issue=26|pages=14777–82|doi=10.1073/pnas.96.26.14777|pmc=24724|bibcode=1999PNAS...9614777O|doi-access=free}}</ref> HSS is the only enzyme that has been definitively implicated in this biosynthesis.<ref name="Pyrrolizidine Alkaloids: Biosynthes">{{cite journal |last1=Schramm |first1=S |last2=Köhler |first2=N |last3=Rozhon |first3=W |title=Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants. |journal=Molecules (Basel, Switzerland) |date=30 January 2019 |volume=24 |issue=3 |pages=498 |doi=10.3390/molecules24030498 |pmid=30704105|pmc=6385001 |doi-access=free }}</ref>

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 <small>L</small>-isoleucine. This step forms the ''N''-oxide of senecionine, which is subsequently reduced to yield senecionine.<ref name="Pyrrolizidine Alkaloids: Biosynthes"/>

Senecionine has a core structure of retronecine, an unsaturated pyrrolizide, with a 12-membered lactone ring attached to the core.<ref>{{cite journal |last1=Were |first1=Obuya |last2=Benn |first2=Michael |last3=Munavu |first3=Raphael M. |title=Pyrrolizidine Alkaloids from Senecio hadiensis |journal=Journal of Natural Products |date=March 1991 |volume=54 |issue=2 |pages=491–499 |doi=10.1021/np50074a022|bibcode=1991JNAtP..54..491W }}</ref> The nitrogen atom in the pyrrolizidine core is weakly basic with an estimated pKa of 5.9.<ref>{{cite web |title=Senecionine |url=https://pubchem.ncbi.nlm.nih.gov/compound/Senecionine#section=Computed-Properties |website=pubchem.ncbi.nlm.nih.gov |access-date=23 April 2020 |language=en}}</ref>

==Metabolism and mechanism of action== [[File:Senecionine_metabolism1.png|thumb|right|400px|Metabolism and mechanism of action of pyrrolizidine alkaloid toxicity. Nuc=nucleophilic protein residue or DNA base<ref>{{cite journal |last1=Moreira |first1=R |last2=Pereira |first2=DM |last3=Valentão |first3=P |last4=Andrade |first4=PB |title=Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety. |journal=International Journal of Molecular Sciences |date=5 June 2018 |volume=19 |issue=6 |pages=1668 |doi=10.3390/ijms19061668 |pmid=29874826|pmc=6032134 |doi-access=free }}</ref>]] 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 toxic effects.<ref name="ReferenceA"/>

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 amino acid residues in liver proteins, resulting in the formation of toxic adducts, including cross-linked adducts between DNA base pairs, liver proteins, or both.<ref>{{cite journal |last1=Zhu |first1=L |last2=Xue |first2=J |last3=Xia |first3=Q |last4=Fu |first4=PP |last5=Lin |first5=G |title=The long persistence of pyrrolizidine alkaloid-derived DNA adducts in vivo: kinetic study following single and multiple exposures in male ICR mice. |journal=Archives of Toxicology |date=February 2017 |volume=91 |issue=2 |pages=949–965 |doi=10.1007/s00204-016-1713-z |pmid=27125825|bibcode=2017ArTox..91..949Z |s2cid=7962889 }}</ref> These adducts can damage DNA, leading to genotoxicity and carcinogenesis, and liver enzymes and hepatocytes, leading to hepatotoxicity.<ref name="ReferenceA"/>

==Biology and society== [[File:African monarch (Danaus chrysippus orientis).jpg|thumb|''Danaus chrysippus'' butterflies consume senecionine to repel predators through a defense mechanism and to make pheromones<ref name="Pyrrolizidine alkaloids inDanaus pl">{{cite journal |last1=Edgar |first1=J. A. |last2=Cockrum |first2=P. A. |last3=Frahn |first3=J. L. |title=Pyrrolizidine alkaloids inDanaus plexippus L. and Danaus chrysippus L. |journal=Experientia |date=December 1976 |volume=32 |issue=12 |pages=1535–1537 |doi=10.1007/BF01924437|s2cid=27664625 }}</ref><ref name="Biology of Australian Butterflies">{{cite book |title=Biology of Australian Butterflies. |publisher=CSIRO Publishing |isbn=9780643105140}}</ref>]]

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.<ref name="Vickery 2010 181–221">{{Cite journal|last=Vickery|first=Margaret|date=2010|title=Plant poisons: their occurrence, biochemistry and physiological properties|journal=Science Progress|volume=93|issue=Pt 2|pages=181–221|doi=10.3184/003685010X12729948220326|issn=0036-8504|pmid=20681322|s2cid=29455831|doi-access=free|pmc=10365355}}</ref>

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.<ref name="Pyrrolizidine alkaloids inDanaus pl"/> This adaptation is also present in grasshoppers of the genus ''Zonocerus''<ref>{{Cite journal|last=Housecroft|first=Catherine E.|date=2018-03-30|title=Tolerating Toxins: Grasshoppers that Feast on Pyrrolizidine Alkaloids §|journal=CHIMIA|volume=72|issue=3|pages=156–157|doi=10.2533/chimia.2018.156|issn=0009-4293|pmid=29631671|url=https://edoc.unibas.ch/63518/3/s11%282%29.pdf}}</ref> and the caterpillars of the Cinnabar moth.<ref name="Bugs&Weeds">{{cite web |url=http://www.bugsandweeds.co.uk/moths%20p2.html#cinnab |title=Cinnabar moth |work=A Nature Observer's Scrapbook |date=June 2007 |access-date=2020-04-22 |archive-date=2008-01-06 |archive-url=https://web.archive.org/web/20080106103931/http://www.bugsandweeds.co.uk/moths%20p2.html#cinnab |url-status=dead }}</ref> 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.<ref name="Biology of Australian Butterflies"/>

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.<ref>{{cite book |editor-last1=Blumenthal |editor-first1=M |title=The complete German Commission E monographs, Therapeutic guide to herbal medicines |year=1998 |publisher=American Botanical Council |isbn=096555550X |page=376}}</ref>

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''.<ref name="Vickery 2010 181–221"/>

==See also== * Riddelliine, a closely related pyrrolizidine alkaloid

==References== <references />

Category:Tertiary alcohols Category:Pyrrolizidine alkaloids Category:Lactones Category:Alkene derivatives Category:Plant toxins Category:Heterocyclic compounds with 3 rings