Pyrrolizidine alkaloidosis

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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. [1] 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. [1] [2] Pyrrolizidine alkaloidosis is known by many other names such as "Pictou Disease" in Canada [3] and "Winton Disease" in New Zealand. [4] 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. [5] [6]

Contents

Plant types and causes

Yellow tarweed (Amsinckia intermedia); a plant which causes pyrrolizidine alkaloidosis when eaten by animals. Amsinckia intermedia 2003-03-04.jpg
Yellow tarweed ( Amsinckia intermedia ); a plant which causes pyrrolizidine alkaloidosis when eaten by animals.

Pyrrolizidine alkaloidosis is caused by the consumption of one or more of the 200 known plant species containing the toxic pyrrolizine alkaloids found all over the world today. [4] Established as the most common source of this illness are plants such as ragwort ( Senecio jacobaea ), woolly groundsels (Senecio redellii, Senecio longilobus ), rattleweed ( Crotalaria retusa ), and seeds of yellow tarweed ( Amsinckia intermedia ). [1] There are 30 known pyrrolizidine alkaloids that are hepatotoxic, meaning they cause injury to the liver. [2] Although animals innately know to give these toxic plants a wide berth while grazing, in extreme drought conditions animals have been known to ingest them as a source of minimal protein. Animals can also be poisoned if the toxic plant material is in pellets, or harvested with grain. [1] [7]

Echites umbellatus , belonging to the dogbane family Apocynaceae and having the English common name Devil's potato, has recently been found to contain lycopsamine-type pyrrolizidine alkaloids. [8]

Frequency and exposure

Humans

Pyrrolizidine alkaloidosis poisoning in the United States has remained moderately rare among humans. The most common reports are the outcome of the misuse of medicinal home remedies, or the alkaloids are present in food and drink substances such as milk and honey when the animal carriers were exposed to the toxins. In other countries, mass human poisonings have occurred when cereal crops used were infected with seeds containing pyrrolizidine alkaloids. [5] [9] [10] [11]

Infants and young children are most likely to acquire pyrrolizidine alkaloidosis because of their intrinsic nature to put everything they find into their mouths. However, anyone who consumes one of the mentioned toxic plants is susceptible to the disease. [9]

The typical case of pyrrolizidine alkaloidosis toxicity ends in liver damage in the form of hepatic veno-occlusive disease that ranges from moderate to severe, as well as damage to other organs. Monocrotaline specifically causes pulmonary arterial hypertension. The longevity of the disease is wide ranging from 2 weeks to 2 years subsequent to when the poison was ingested. HVOC and PAH, however, are both irreversible once developed. The patient's recovery results may be as diverse as the permanence. Some have recovered as if they were never affected by pyrrolizidine alkaloidosis poisoning if the damage to the liver was not too severe, and others have died from it. [5]

The severity of pyrrolizidine alkaloidosis depends on how much of the poisonous plant was consumed in a height, age, and weight to the amount of substance ingested ratio. The only difference in the symptoms will be how prominent they are depending on the above ratio. Symptoms include: [2] [5] [9] [12]

To stop the spread and severity of pyrrolizidine alkaloidosis the first step is to remove the poisonous plant from the source. Once the plant has been removed, the alkaloids can be extracted with chloroform. However, ethyl acetate is a handy and less toxic substitute. [2] Depending on the severity of the toxicity and how long the person has been exposed to the disease, there may be no means of treatment and fatality may occur.

Mechanism of action

After oral ingestion, pyrrolizidine alkaloids are absorbed from the gastrointestinal tract. When they reach the liver, they are 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 the pyrrolizidine by cytochrome P-450 (CYP450) monooxygenases. Oxidation of the pyrrolizidine to its respective dehydropyrrolizidine is responsible for the toxic effects.

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

Metabolism and mechanism of action of pyrrolizidine toxicity. Nuc=nucleophilic protein residue or DNA base PA metabolism2.png
Metabolism and mechanism of action of pyrrolizidine toxicity. Nuc=nucleophilic protein residue or DNA base


Prevention

The only known technique of prevention is to avoid ingesting the poisonous alkaloids. Some methods of control have been defoliation in areas in both Oregon and California. Also mass relocation efforts of moths, flea beetles and seed flies have been made in hopes that they will eat the toxic plants and help control the population of the plants. This manner of alkaloid control has been met with variable success. Because sheep and goats have such a high immunity to the toxicity of the alkaloids they are commonly used to graze on the plants to control them. However, this method has its risks unless sheep meant for early slaughter are used. Before hay cutting in the spring is the optimal time frame for annual herbicide applications which have also enhanced the destruction of the alkaloids. [1] [9] [14]

Related Research Articles

<i>Jacobaea vulgaris</i> Species of flowering plant in the 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.

<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">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>Tussilago</i> Species of flowering plant in the daisy family Asteraceae

Tussilago farfara, commonly known as coltsfoot, is a plant in the tribe Senecioneae in the family Asteraceae, native to Europe and parts of western and central Asia. The name "tussilago" is derived from the Latin tussis, meaning cough, and ago, meaning to cast or to act on. It has had uses in traditional medicine, but the discovery of toxic pyrrolizidine alkaloids in the plant has resulted in liver health concerns.

<i>Heliotropium arborescens</i> Species of flowering plant in the family Boraginaceae

Heliotropium arborescens, the garden heliotrope or just heliotrope, is a species of flowering plant in the borage family Boraginaceae, native to Bolivia, Colombia, and Peru. Growing to 1.2 m (3.9 ft) tall and broad, it is a bushy, evergreen, short-lived shrub with dense clusters of bright purple flowers, notable for their intense, rather vanilla-like fragrance. Common names also include cherry pie and common heliotrope. Note that the common name "garden heliotrope" may also refer to valerian, which is not closely related.

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<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.

<i>Packera aurea</i> Species of flowering plant

Packera aurea, commonly known as golden ragwort or simply ragwort, is a perennial flower in the family Asteraceae. It is also known as golden groundsel, squaw weed, life root, golden Senecio, uncum, uncum root, waw weed, false valerian, cough weed, female regulator, cocash weed, ragweed, staggerwort, and St. James wort.

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.

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

Senecio flaccidus, formerly recorded as Senecio douglasii, member of the daisy family and genus Senecio also known as threadleaf ragwort, is a native of the southwestern Great Plains of North America.

<i>Conium maculatum</i> Poisonous herbaceous plant in the carrot family

Conium maculatum, colloquially known as hemlock, poison hemlock or wild hemlock, is a highly poisonous biennial herbaceous flowering plant in the carrot family Apiaceae, native to Europe and North Africa. A hardy plant capable of living in a variety of environments, hemlock is widely naturalized in locations outside its native range, such as parts of Australia, West Asia, and North and South America, to which it has been introduced. It is capable of spreading and thereby becoming an invasive weed.

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

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

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<i>Crotalaria novae-hollandiae</i> Species of plant

Crotalaria novae-hollandiae, known commonly as the New Holland rattlepod, is a species of flowering plant that is native to Australia.

<i>Senecio ilicifolius</i> Species of flowering plant

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<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.

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Some substances are poisonous to dogs through ingestion, contact or inhalation. The poisonous substances most commonly consumed by pet dogs include human foods, medication not suitable for animals, household products, and plants.

<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.

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

The Lantadenes are naturally occurring pentacyclic triterpenoids found in the Lantana camara plant. They are known to be poisonous to livestock that graze on the leaves of the plant, causing photosensitivity and hepatotoxicity as major symptoms. Lantadenes A and B are the most abundant and bioactive triterpenoids found in the Lantana camara leaves.

References

  1. 1 2 3 4 5 The Merck Veterinary Manual. Pyrrolizidine Alkaloidosis: Introduction (Seneciosis, Senecio poisoning, Ragwort toxicity). Merck & Co., Inc., 2008. Web. 15 November
  2. 1 2 3 4 Rizk, Abdel-Fattah M., Naturally Occurring Pyrrolizidine Alkaloids. Doah: CRC Press, 1990
  3. ↑ "Pictou disease". TheFreeDictionary.com. Retrieved 2019-03-27.
  4. 1 2 Hirono, I. Naturally Occurring Carcinogens of Plant Origin. Toyoake: Elsevier, 1987
  5. 1 2 3 4 Bad Bug Book. Pyrrolizidine Alkaloids. U.S. Food & Drug Administration, 17 Sep, 1998. Web. 3 November
  6. ↑ Dharmananda, Ubhuti. Safety Issues Concerning Herbs: Pyrrolizidine Alkaloids. Institute for Traditional Medicine, 2007. Web. 5 November
  7. ↑ Talcott P: Pyrrolizidine Alkaloid Poisoning. In: Robinson NE (ed): Current Therapy in Equine Medicine, 5th Edition. Philadelphia, W.B. Saunders Co., 2003, pp. 788-790
  8. ↑ Burzynski, Elizabeth A., Minbiole, Kevin P.C. and Livshultz, Tatyana, "New sources of lycopsamine-type pyrrolizidine alkaloids and their distribution in Apocynaceae" March 2015 Biochemical Systematics and Ecology 59:331-339
  9. 1 2 3 4 World Health Organization, Environmental Health Criteria 80. Geneva: World Health Organization, 1988
  10. ↑ Culvenor, C.C., Edgar J.A. Smith L.W., "Pubmed." Pyrrolizidine Alkaloids in honey from Echium Plantagineum L. USA.gov, 2009. Web. 17 September
  11. ↑ Magnuson, Bernadene. "ExtoxNet FAQs" Pyrrolizidine Alkaloids. EXTOXNET FAQ Team, 1997. Web. 20 October
  12. ↑ Plant poisoning - Pyrrolizidine alkaloids, wrongdiagnosis.com
  13. ↑ 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): 1668. doi: 10.3390/ijms19061668 . PMC   6032134 . PMID   29874826.
  14. ↑ Cheeke, P.R. Symposium on Pyrrolizidine (Senecio) Alkaloids: Toxicity, Metabolism, and Poisonous Plant Control Measures
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