Pyrrolizidine alkaloid

For example, herbs containing PAs were used in traditional Chinese medicine and by Native American tribes for their purported therapeutic properties.[8] 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.[11] These regulations aim to protect human and animal health by minimizing PA exposure and mitigating the risk of toxicity.[12] Additionally, efforts to raise awareness among healthcare professionals, herbal product manufacturers, and the general public about the risks of PA exposure are ongoing.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.[14] 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.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.[19] PAs are commonly introduced into the body via oral ingestion through contaminated food or traditional medicine, notably borage leaf, comfrey and coltsfoot.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.This metabolic process leads to the formation of reactive intermediates, such as pyrrolic metabolites, which can covalently bind to proteins in the liver, forming pyrrole-protein adducts.These adducts can induce mutations and DNA damage, increasing the risk of cancer development and other adverse health effects.For example, retronecine-type PAs like monocrotaline are known to be highly hepatotoxic, while other types may exhibit lower toxicity or different toxicological profiles.Several PAs have been found with significant inhibition of growth in the following viruses: coxsackie, poliomyelitis, measles, and vesicular stomatitis.PAs like senecionine, integerrimine, retrorsine, usaramine and seneciphylline have been shown to cause an increase in both the levels of gastrin and the expression of epidermal growth factor (EGF).
Skeletal formula of retronecine , a pyrrolizidine alkaloid found in the common groundsel ( Senecio vulgaris ) and comfrey ( Symphytum spp.)
Biosynthesis of PAs [ 15 ]
Chemical structures of the necine bases [ 16 ]
Chemical structures of various PAs
A general strategy for the production of pyrrolizidine alkaloids is described, starting from intermediate (+)−9. The key features are diastereoselective dihydroxylation, inversion at the ring junction by hydroboration of an enamine, and ring closure to form the bicyclo ring system. [ 19 ]
Proposed hepatic metabolic activation of retronecine-type and otonecine-type PAs to form pyrrolic esters, which further interact with glutathione or proteins to generate pyrrole–GSH conjugates or pyrrole–protein adducts, respectively. [ 23 ]
Pathogenesis of PA-induced HSOS [ 16 ]
Skeletal formularetronecinecommon groundselcomfreyalkaloidspyrrolizidinetoxicitytraditional Chinese medicinehepatotoxicgenotoxicAmine oxidase (copper-containing)homospermidine synthasepolyaminesputrescine1,3-diaminopropanediamine oxidasesAsteraceaeEupatorieaeSenecioneaeBoraginaceaeFabaceaeCrotalariaOrchidaceaeesters N-oxidesmethylationpyrroleboragecoltsfootgastrointestinal tractportal veinesterasescytochrome P450Disse spaceglutathionemonooxygenasemetabolismliver injuryinflammationnecrosismutationscancercarcinogenesismonocrotalineantineoplasticacetylcholinesterasegastric ulcersE. coliP. chrysogenumFusarium oxysporumcoxsackiepoliomyelitismeaslesvesicular stomatitisleukemiaAlzheimer's diseasegastrinepidermal growth factorstillbirthmegalacytosisUtetheisa ornatrixAdenostyles alliariaeAdenostyles glabraAgeratum conyzoidesAgeratum houstonianumAnchusa officinalisBorago officinalisCacalia hastataChromolaena odorataCordia myxaCrassocephalum crepidioidesCrotalaria spectabilisCrotalaria retusaCynoglossum amabileCynoglossum lanceolatumCynoglossum officinaleCynoglossum zeylanicumEchium plantagineumEchium vulgareEmilia sonchifoliaEupatorium cannabinumEupatorium chinenseEupatorium fortuneiEupatorium japonicumEupatorium perfoliatumEupatorium purpureumFarfugium japonicumGynura bicolorHeliotropium amplexicauleHeliotropium europaeumHeliotropium indicumLigularia dentataLiparis nervosaLithospermum erythrorhizonNeurolaena lobataPetasites japonicusSenecio brasiliensisSenecio cinerariaSenecio glabellusSenecio jacobaeaSenecio linearifoliusSenecio madagascariensisSenecio nemorensisSenecio quadridentatusSenecio scandensSenecio vulgarisSymphytum officinaleTussilago farfaraBibcode