Senecionine

Last updated
Senecionine
Senecionine chemicalstructure1.png
Names
Preferred IUPAC name
(3Z,5R,6R,9a1R,14aR)-3-Ethylidene-3,4,5,6,9,9a1,11,13,14,14a-decahydro[1,6]dioxacyclododecino[2,3,4-gh]pyrrolizine-2,7-dione
Other names
Aureine
Identifiers
3D model (JSmol)
94450
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.125.118 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 603-379-6
KEGG
PubChem CID
UNII
  • 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 Yes check.svgY
    Key: HKODIGSRFALUTA-JTLQZVBZSA-N Yes check.svgY
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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 . [1]

Contents

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]

Toxicity

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

In large quantities, ingestion can lead to critical illness, including convulsions and death. Studies in rodents have shown an LD50 of 65 mg/kg. [4] 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. [5]

Ingestion can lead to both liver and DNA damage.

Liver toxicity

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. [5] 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. [5] Other symptoms and manifestations of chronic exposure include weakness, portal hypertension, and cirrhosis. [5] [6]

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. [6]

Diagnosis

Diagnosis of senecionine toxicity is made based on history, physical examination, and liver biopsy. [5] 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. [7] Histological abnormalities on biopsy include megalocytosis, necrosis, fibrosis, and biliary hyperplasia, similar to other hepatotoxic ingestions and immune system disorders. [5]

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. [6]

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. [5] 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. [5]

Biosynthesis and Chemistry

In Senecio species, biosynthesis of senecionine starts from L-arginine or L-ornithine. [8] Because 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. 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). [9] HSS is the only enzyme that has been definitively implicated in this biosynthesis. [10]

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. [10]

Senecionine has a core structure of retronecine, an unsaturated pyrrolizide, with a 12-membered lactone ring attached to the core. [11] The nitrogen atom in the pyrrolizidine core is weakly basic with an estimated pKa of 5.9. [12]

Biosynthesis of senecionine Senecionine biosynthesis5.png
Biosynthesis of senecionine

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 toxic effects. [6]

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. [13] These adducts can damage DNA, leading to genotoxicity and carcinogenesis, and liver enzymes and hepatocytes, leading to hepatotoxicity. [6]

Metabolism and mechanism of action of pyrrolizidine alkaloid toxicity. Nuc=nucleophilic protein residue or DNA base Senecionine metabolism1.png
Metabolism and mechanism of action of pyrrolizidine alkaloid toxicity. Nuc=nucleophilic protein residue or DNA base

Biology and Society

Danaus chrysippus butterflies consume senecionine to repel predators through a defense mechanism and to make pheromones African monarch (Danaus chrysippus orientis).jpg
Danaus chrysippus butterflies consume senecionine to repel predators through a defense mechanism and to make pheromones

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. [17]

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. [15] This adaptation is also present in grasshoppers of the genus Zonocerus [18] and the caterpillars of the Cinnabar moth. [19] 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. [16]

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. [20]

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. [17]

See also

Related Research Articles

<i>Jacobaea vulgaris</i> Flowering plant, daisy family Asteraceae

Jacobaea vulgaris, syn. Senecio jacobaea, is a very common wild flower in the family Asteraceae that is native to northern Eurasia, usually in dry, open places, and has also been widely distributed as a weed elsewhere.

<span class="mw-page-title-main">Strychnine</span> Poisonous substance used as pesticide

Strychnine is a highly toxic, colorless, bitter, crystalline alkaloid used as a pesticide, particularly for killing small vertebrates such as birds and rodents. Strychnine, when inhaled, swallowed, or absorbed through the eyes or mouth, causes poisoning which results in muscular convulsions and eventually death through asphyxia. While it is no longer used medicinally, it was used historically in small doses to strengthen muscle contractions, such as a heart and bowel stimulant and performance-enhancing drug. The most common source is from the seeds of the Strychnos nux-vomica tree.

<i>Senecio vulgaris</i> Species of flowering plant in the daisy family Asteraceae

Senecio vulgaris, often known by the common names groundsel and old-man-in-the-spring, is a flowering plant in the family Asteraceae. It is an annual herb, native to the Palaearctic and widely naturalised as a ruderal species in suitable disturbed habitats worldwide.

<span class="mw-page-title-main">Aristolochic acid</span> Chemical compound

Aristolochic acids are a family of carcinogenic, mutagenic, and nephrotoxic phytochemicals commonly found in the flowering plant family Aristolochiaceae (birthworts). Aristolochic acid (AA) I is the most abundant one. The family Aristolochiaceae includes the genera Aristolochia and Asarum, which are commonly used in Chinese herbal medicine. Although these compounds are widely associated with kidney problems, liver and urothelial cancers, the use of AA-containing plants for medicinal purposes has a long history. The FDA has issued warnings regarding consumption of AA-containing supplements.

<span class="mw-page-title-main">Hepatotoxicity</span> Liver damage caused by a drug or chemical

Hepatotoxicity implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn from the market after approval.

<i>Crotalaria</i> Genus of legumes

Crotalaria is a genus of flowering plants in the family Fabaceae commonly known as rattlepods. The genus includes over 700 species of herbaceous plants and shrubs. Africa is the continent with the majority of Crotalaria species, which are mainly found in damp grassland, especially in floodplains, depressions and along edges of swamps and rivers, but also in deciduous bush land, roadsides and fields. Some species of Crotalaria are grown as ornamentals. The common name rattlepod or rattlebox is derived from the fact that the seeds become loose in the pod as they mature, and rattle when the pod is shaken. The name derives from the Ancient Greek κρόταλον, meaning "castanet", and is the same root as the name for the rattlesnakes (Crotalus).

<i>Petasites hybridus</i> Species of flowering plant in the daisy family Asteraceae

Petasites hybridus, also known as the butterbur, is a herbaceous perennial flowering plant in the family Asteraceae that is native to Europe and northern Asia.

<i>Danaus chrysippus</i> Species of butterfly

Danaus chrysippus, also known as the plain tiger, African queen, or African monarch, is a medium-sized butterfly widespread in Asia, Australia and Africa. It belongs to the Danainae subfamily of the brush-footed butterfly family Nymphalidae. Danainae primarily consume plants in the genus Asclepias, more commonly called milkweed. Milkweed contains toxic compounds, cardenolides, which are often consumed and stored by many butterflies. Because of their emetic properties, the plain tiger is unpalatable to most predators. As a result, its colouration is widely mimicked by other species of butterflies. The plain tiger inhabits a wide variety of habitats, although it is less likely to thrive in jungle-like conditions and is most often found in drier, wide-open areas.

<span class="mw-page-title-main">Pyrrolizidine alkaloid</span> Class of chemical compounds

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. 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. Honey can contain pyrrolizidine alkaloids, as can grains, milk, offal and eggs. To date (2011), there is no international regulation of PAs in food, unlike those for herbs and medicines.

In enzymology, a senecionine N-oxygenase (EC 1.14.13.101) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Nodularin</span> Chemical compound

Nodularins are potent toxins produced by the cyanobacterium Nodularia spumigena, among others. This aquatic, photosynthetic cyanobacterium forms visible colonies that present as algal blooms in brackish water bodies throughout the world. The late summer blooms of Nodularia spumigena are among the largest cyanobacterial mass occurrences in the world. Cyanobacteria are composed of many toxic substances, most notably of microcystins and nodularins: the two are not easily differentiated. A significant homology of structure and function exists between the two, and microcystins have been studied in greater detail. Because of this, facts from microcystins are often extended to nodularins.

Hepatic veno-occlusive disease (VOD) or veno-occlusive disease with immunodeficiency is a potentially life-threatening condition in which some of the small veins in the liver are obstructed. It is a complication of high-dose chemotherapy given before a bone marrow transplant and/or excessive exposure to hepatotoxic pyrrolizidine alkaloids. It is classically marked by weight gain due to fluid retention, increased liver size, and raised levels of bilirubin in the blood. The name sinusoidal obstruction syndrome (SOS) is preferred if hepatic veno-occlusive disease happens as a result of chemotherapy or bone marrow transplantation.

<span class="mw-page-title-main">Paracetamol poisoning</span> Toxicity due to paracetamol overdose

Paracetamol poisoning, also known as acetaminophen poisoning, is caused by excessive use of the medication paracetamol (acetaminophen). Most people have few or non-specific symptoms in the first 24 hours following overdose. These symptoms include feeling tired, abdominal pain, or nausea. This is typically followed by absence of symptoms for a couple of days, after which yellowish skin, blood clotting problems, and confusion occurs as a result of liver failure. Additional complications may include kidney failure, pancreatitis, low blood sugar, and lactic acidosis. If death does not occur, people tend to recover fully over a couple of weeks. Without treatment, death from toxicity occurs 4 to 18 days later.

<span class="mw-page-title-main">Loline alkaloid</span> Class of chemical compounds

A loline alkaloid is a member of the 1-aminopyrrolizidines, which are bioactive natural products with several distinct biological and chemical features. The lolines are insecticidal and insect-deterrent compounds that are produced in grasses infected by endophytic fungal symbionts of the genus Epichloë. Lolines increase resistance of endophyte-infected grasses to insect herbivores, and may also protect the infected plants from environmental stresses such as drought and spatial competition. They are alkaloids, organic compounds containing basic nitrogen atoms. The basic chemical structure of the lolines comprises a saturated pyrrolizidine ring, a primary amine at the C-1 carbon, and an internal ether bridge—a hallmark feature of the lolines, which is uncommon in organic compounds—joining two distant ring carbons. Different substituents at the C-1 amine, such as methyl, formyl, and acetyl groups, yield loline species that have variable bioactivity against insects. Besides endophyte–grass symbionts, loline alkaloids have also been identified in some other plant species; namely, Adenocarpus species and Argyreia mollis.

Pyrrolizidine alkaloidosis is a disease caused by chronic poisoning found in humans and other animals caused by ingesting poisonous plants which contain the natural chemical compounds known as pyrrolizidine alkaloids. Pyrrolizidine alkaloidosis can result in damage to the liver, kidneys, heart, brain, smooth muscles, lungs, DNA, lesions all over the body, and could be a potential cause of cancer. Pyrrolizidine alkaloidosis is known by many other names such as "Pictou Disease" in Canada and "Winton Disease" in New Zealand. Cereal crops and forage crops can sometimes become polluted with pyrrolizidine-containing seeds, resulting in the alkaloids contaminating flour and other foods, including milk from cows feeding on these plants.

<span class="mw-page-title-main">Riddelliine</span> Chemical compound

Riddelliine is a chemical compound classified as a pyrrolizidine alkaloid. It was first isolated from Senecio riddellii and is also found in a variety of plants including Jacobaea vulgaris, Senecio vulgaris, and others plants in the genus Senecio.

<span class="mw-page-title-main">Hydroxydanaidal</span> Chemical compound

Hydroxydanaidal is an insect pheromone synthesized by some species of moth from pyrrolizidine alkaloids found in their diet.

<i>Echites umbellatus</i> Species of flowering plant

Echites umbellatus is a flowering climber, belonging to subfamily Apocynoideae of the family Apocynaceae and has the English common name devil's potato. It was first described in 1760 by Dutch botanist, Nikolaus Joseph von Jacquin. The species grows in parts of Florida, Tabasco, Yucatán Peninsula, Belize, Honduras, Cayman Islands, Cuba, Hispaniola, Jamaica, Leeward Islands, Bahamas, Turks and Caicos Islands, and the Colombian islands in the Western Caribbean.

<span class="mw-page-title-main">Thomas Hartmann (biologist)</span> German pharmaceutical biologist (1937–2017)

Thomas Hartmann,, was a German pharmaceutical biologist and ecologist who was professor in the Department of Pharmaceutical Biology at the Technische Universität Braunschweig. His research focused on the biosynthesis, intracellular transport, and action of quinolizidine and pyrrolizidine alkaloids in fungi and plants and the sequestration of these secondary natural products by insects.

<span class="mw-page-title-main">Monocrotaline</span> Chemical compound

Monocrotaline (MCT) is a pyrrolizidine alkaloid that is present in plants of the Crotalaria genus. These species can synthesise MCT out of amino acids and can cause liver, lung and kidney damage in various organisms. Initial stress factors are released intracellular upon binding of MCT to BMPR2 receptors and elevated MAPK phosphorylation levels are induced, which can cause cancer in Homo sapiens. MCT can be detoxified in rats via oxidation, followed by glutathione-conjugation and hydrolysis.

References

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