Pyrrolizidine alkaloid

PAs were first discovered in plants in the 19th century, but their toxic effects were not immediately recognized. Instead, many PA-containing plants were traditionally used for medicinal purposes in various cultures around the world. For example, herbs containing PAs were used in traditional Chinese medicine and by Native American tribes for their purported therapeutic properties. 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 the early to mid-20th century, researchers began to observe and document cases of livestock poisoning linked to the consumption of PA-containing plants. These observations led to the recognition of PAs as potent hepatotoxic and genotoxic compounds. In response to growing concerns about PA exposure, regulatory agencies around the world began to establish guidelines and regulations to limit PA levels in food, herbal products, and animal feed. These regulations aim to protect human and animal health by minimizing PA exposure and mitigating the risk of toxicity. Despite regulatory efforts, the issue of PA exposure remains relevant today. Ongoing research continues to explore various aspects of PA toxicity, including the identification of new PA-containing plants, the development of sensitive analytical methods, and the assessment of human health risks associated with PA exposure. Additionally, efforts to raise awareness among healthcare professionals, herbal product manufacturers, and the general public about the risks of PA exposure are ongoing. == Natural occurrence ==

PAs are a group of naturally occurring compounds found in a wide range of plant species. These alkaloids are secondary metabolites synthesized by plants primarily as a defense mechanism against herbivores, insects, and pathogens. The biosynthesis of PAs was discovered to occur through the first pathway-specific enzyme homospermidine synthase. The polyamines putrescine and spermidine are derived from the basic amino acid arginine. Subsequently, homospermidine synthase exchanges the 1,3-diaminopropane by putrescine and forms symmetric homospermidine. Oxidation of homospermidine by copper-dependent diamine oxidases initiates cyclization to pyrrolizidine-1-carbaldehyde, which is reduced, to 1-hydroxymethylpyrrolizidine. Desaturation and hydroxylation ultimately form retronecine, which is acylated with an activated necic acid, for instance with senecyl-CoA2 as in the example shown below. PAs are preferably found in the plant families Asteraceae (tribes Eupatorieae and Senecioneae), Boraginaceae (many genera), Fabaceae (mainly the genus Crotalaria), and Orchidaceae (nine genera). More than 95% of the PA-containing species investigated thus far belong to these four families. == Structure and reactivity ==

PAs are compounds made up of a necine base, a double five-membered ring with a nitrogen atom in the middle, and one or two carboxylic esters called necic acids. Four major necine bases are described, with retronecine and its enantiomer heliotridine being the largest group, and highly toxic. Another group is the platynecine, the difference between these groups is its saturated base, which makes it less toxic. Most bases have a 1,2-unsaturated base. Another difference in the groups is with otonecine, which cannot form N-oxides, due to the methylation of the nitrogen atom. The alcohol groups on the necine bases can make esters in a wide variety of forms. Among the possibilities are mono-esters, like Floridine and Heliotrine, and di-esters either with an open or closed ring structure, like Usaramine and Lasiocarpine. In total more than 660 PAs and PA N-oxides have been identified in over 6000 plants. == Synthesis ==

There are multiple ways to synthesize PAs and their derivatives. A flexible strategy would be to start with a Boc (tert-butoxycarbonyl) protected pyrrole molecule and use specific reaction for synthesis into the desired compound. == Mechanisms of actions and metabolism ==

PAs are commonly introduced into the body via oral ingestion through contaminated food or traditional medicine, notably borage leaf, comfrey and coltsfoot. It can readily form salts with nitrates, chlorides and sulphates, which facilitate the uptake in the gastrointestinal tract. After which they travel to the liver via the portal vein. Metabolites form mostly in the liver. Here esterases can hydrolyze the PAs to reduce the compound into its necine acids and bases, both forms are non-toxic for humans and do not damage the body. However, cytochrome P450 (CYP450) also metabolizes PAs, this enzyme can form pyrrolic esters (EPy), these are hepatotoxic due to their high reactivity. The EPy can also be hydrolyzed into alcoholic pyrroles, which are mutagenic and carcinogenic. A second detoxifying pathway is the formation of the N-oxide In the liver and lungs of certain mammal species enzymes called monooxygenase can prevent aromatization of the double 5-ring and in turn prevent the formation of the pyrrole-protein adduct. == Toxicological effects ==

The toxicity consequences resulting from the metabolism of PAs in humans primarily revolve around hepatotoxicity and genotoxicity. The pathogenesis of PAs-induces HSOS is shown by Xu. Genotoxicity is another consequence of PA metabolism. The reactive metabolites formed during PA metabolism can also bind to DNA, leading to the formation of DNA adducts. These adducts can induce mutations and DNA damage, increasing the risk of cancer development and other adverse health effects. Genotoxicity is particularly concerning as it can lead to long-term health consequences, including carcinogenesis. The toxicity of PA metabolites can vary depending on the specific PA compound and its chemical structure. Different PAs may undergo metabolic activation to varying degrees, resulting in differences in toxicity. For example, retronecine-type PAs like monocrotaline are known to be highly hepatotoxic, while other types may exhibit lower toxicity or different toxicological profiles. == Pharmacological effects ==

Next to its toxicological effects, PAs have long been researched for their potential beneficial effects. Among these traditional medicines is the root of Ligularia achyrotricha of Tibet. Several pharmacological effects have been found. Among these effects are antimicrobial activity, antiviral activity and antineoplastic activity, acetylcholinesterase inhibition, and gastric ulcers treatment. Antimicrobial activity of several PAs have been identified as having mild to strong effect against bacteria: E. coli and P. chrysogenum. Symptoms tend to start with a change in rough hair coat and depression. When pregnant livestock is exposed to PAs an effect can be seen on the foetus, mainly stillbirth and accumulation in the foetus. The main lethal responses in adult livestock exhibit necrosis, HSOS and megalocytosis. Additional to the short-term effect PAs have been found to lead to carcinogenic growths on the long term. The carcinogenic effect is caused by formation of DNA adducts, LOAEL and (oral) for 40 PAs have been experimentally found out. These values can be seen in the Table below. The found low LD50 values clearly show the relatively high toxicity of PAs, however no significant relation was found between the LD50 and LOAEL. PAs are 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. == Plant species containing pyrrolizidine alkaloids ==

This is a dynamic list and may never be able to satisfy particular standards for completeness. You can help by adding missing items with reliable sources • Adenostyles alliariae • Adenostyles glabra • Ageratum conyzoides • Ageratum houstonianum • Anchusa officinalis • Arnebia euchroma • Borago officinalis • 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 • Echium vulgare • Emilia sonchifolia • Eupatorium cannabinum • Eupatorium chinense • Eupatorium fortunei • Eupatorium japonicum • Eupatorium perfoliatum • Eupatorium purpureum • Farfugium japonicum • Gynura bicolor • Gynura divaricata • Gynura segetum • Heliotropium amplexicaule • Heliotropium europaeum • Heliotropium indicum • Heliotropium popovii • 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 • Senecio chrysanthemoides • Senecio cineraria • Senecio glabellus • Senecio integrifolius var. fauriri • Senecio interggerrimus • Senecio jacobaea • Senecio lautus • Senecio linearifolius • Senecio madagascariensis • Senecio nemorensis • Senecio quadridentatus • Senecio riddelli • Senecio scandens • Senecio vulgaris • Syneilesis aconitifolia • Symphytum officinale • Tussilago farfara == See also ==