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48-414: A member of the loline alkaloids was first isolated from the grass Lolium temulentum and its elemental composition determined in 1892. It was initially named temuline and later renamed norloline . (Reviewed by Schardl et al. (2007).) Studies in the 1950s and 1960s by Russian researchers established the name loline and identified the characteristic 2,7 ether bridge in its molecular structure. Since then

96-445: A Boc (tert-Butoxycarbonyl) protected pyrrole molecule and use specific reaction for synthesis into the desired compound. 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

144-451: A condensation reaction linking the γ-carbon in homoserine to the secondary amine in proline in a PLP–type enzyme–catalyzed reaction to form the loline intermediate, N -(3-amino-3-carboxy)propylproline (NACPP). Further steps in loline biosynthesis are thought to proceed with sequential PLP-enzyme-catalyzed and oxidative decarboxylations of the carboxy groups in the homoserine and proline moieties, respectively, cyclization to form

192-522: 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-diamonopropane by putrescine and forms symmetric homospermidine. Oxidation of homospermidine by copper-dependent diamine oxidases initiates cyclization to pyrrolizidine-1-carbaldehyde, which

240-779: A more widespread occurrence of these compounds in nature. Lolines are insecticidal and deterrent to a broad range of insects, including species in the Hemiptera , Coleoptera , Hymenoptera , Lepidoptera , and Blattodea , such as the bird cherry-oat aphid (genus Rhopalosiphum ), large milkweed bug ( Oncopeltus fasciatus ), and American cockroach ( Periplaneta americana ). LC 50 values of N -formylloline or N -acetylloline from grass seed extracts are 1-20 μg/ml for aphids and milkweed bugs and impair insect development and fecundity and cause avoidance of loline-containing grass tissues. However, results of feeding tests with grass extracts are occasionally difficult to interpret due to

288-762: A pyrrolizidine ring structure. Unlike the lolines, however, the senecio alkaloids exhibit strong hepatotoxicity , owing to a double bond between C-1 and C-2 in their ring structure. This double bond is absent in the lolines, explaining the lack of hepatotoxicity of this group of compounds. The lolines have been suggested to inhibit seed germination or growth of other plants ( allelopathy ), and to increase resistance of infected grasses against drought , but such effects have not been substantiated under more natural conditions of cultivation or in habitats. Lolines are produced by several grass–endophyte symbioses involving epichloae species, often along with other bioactive metabolites including ergot alkaloids and indole diterpenoids , and

336-659: A repellant at higher concentrations. However, ergot alkaloids also have repellent and immobilizing effects on P. scribneri , and an endophyte of perennial ryegrass lacking lolines, and genetically engineered to produce no ergot alkaloids, exhibits resistance to this nematode. Therefore, the relative importance of the loline and ergot alkaloids to nematode resistance remains unclear. Many epichloae endophytes—including N. coenophialum symbiotic with Lolium arundinaceum (syn. Festuca arundinacea , tall fescue)—also produce ergot alkaloids that are toxic to mammalian herbivores. The ergot alkaloids occur at relatively low concentrations in

384-419: 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 megalacytosis . 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, because of metabolic reactions. No minimum dosage for

432-425: 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

480-443: 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

528-462: Is regulated by the expression of loline genes. The lolines are structurally similar to pyrrolizidine alkaloids produced by many plants, notably the necine ring containing a tertiary amine . This led to the early hypothesis that the biosynthesis of the lolines is similar to that of the plant pyrrolizidines, which are synthesized from polyamines . However, feeding studies with carbon isotope –labeled amino acids or related molecules in pure cultures of

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576-493: 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

624-465: 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. The toxicity consequences resulting from the metabolism of PAs in humans primarily revolve around hepatotoxicity and genotoxicity. PAs are metabolized in the liver through CYP450-mediated pathways. This metabolic process leads to

672-565: 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. Since this mostly happens in

720-549: 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

768-448: The C-1 amine of N -methylloline, which gives the most abundant loline in many grass–endophyte symbionts, N -formylloline. Lolium temulentum Lolium temulentum , typically known as darnel , poison darnel , darnel ryegrass or cockle , is an annual plant of the genus Lolium within the family Poaceae . The plant stem can grow up to one meter tall, with inflorescence in

816-484: The LD 50 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. This

864-475: The PA-containing species investigated thus far belong to these four families. 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,

912-535: The analytical methods for purification and analysis of the lolines have been refined and several different loline species have been identified in many Lolium and related grasses infected by the Epichloë/Neotyphodium (epichloae) endophytes. Lolines are absent in grass plants that do not harbor the epichloae endophytes, and not all epichloae produce the lolines. Because of the very intimate association of plant and endophyte and difficulties to reproduce

960-454: The carcinogenic effect is currently known. However, there have been studies to determine the lowest dose for an adverse effect, also known as LOAEL . LOAEL and LD 50 (oral) for 40 PAs have been experimentally found out. These values can be seen in the Table below. The found low LD 50 values clearly show the relatively high toxicity of PAs, however no significant relation was found between

1008-472: The core loline ring structure, and oxidation of the C-2 and C-7 carbons to give the oxygen bridge spanning the two pyrrolizidine rings. Genetic studies agree with the biosynthetic routes established in the precursor-feeding experiments. AFLP -based studies using crosses between strains of the endophyte, Epichloë festucae , that differ in the capacity to produce lolines, show that loline production and protection of

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1056-457: 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. 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

1104-696: The developmental stage of specific grass tissues suggests regulation of in planta loline distributions, providing greater protection of newly grown or embryonic tissues against attacks by insects. Surprisingly, exogenous application of the plant signaling compound, methyl jasmonate —which commonly signals predation by insects—decreases expression of the genes for the lolines. The factors that control loline production vary also among endophyte-infected grass tissues: whereas plant-supplied amino acids that are loline precursors limit accumulation of lolines in many grass tissues, their production in tissues that bear external mycelial growth for fungal reproduction ( stromata )

1152-707: 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. There are multiple ways to synthesize PAs and their derivatives. A flexible strategy would be to start with

1200-404: The ear appears. The spikes of L. temulentum are more slender than those of wheat. The spikelets are oriented edgeways to the rachis and have only a single glume , while those of wheat are oriented with the flat side to the rachis and have two glumes. Wheat will appear brown when ripe, whereas darnel is black. Darnel can be infected by an endophytic fungus of the genus Neotyphodium and

1248-426: The ears and purple grain. It has a cosmopolitan distribution . Darnel usually grows in the same production zones as wheat and was a serious weed of cultivation until modern sorting machinery enabled darnel seeds to be separated efficiently from seed wheat. The similarity between these two plants is so great that in some regions, darnel is referred to as " false wheat ". It bears a close resemblance to wheat until

1296-418: The endophyte-produced, insecticidal loline alkaloids were first isolated from this plant. The French word for darnel is ivraie (from Latin ebriacus , intoxicated), which expresses the drunken nausea from eating the infected plant, which can be fatal. The French name echoes the scientific name, Latin temulentus "drunk." Let both grow together until the harvest: and in the time of harvest I will say to

1344-820: The exact effect of the PAs regarding beneficial effect of the plants is debated. 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 . In particular Lasiocarpine and 7-angeloyl heliotrine were found to have significant activity against these microbes. Derivatives of PAs have been found to induce cell death in these bacteria by attacking bacterial cell membranes. Retronecine derivatives have been found slow

1392-443: The following viruses: coxsackie , poliomyelitis , measles , and vesicular stomatitis . Antineoplastic activity, specifically against leukemia , has been found in retronecine derivatives such as indicine. A 1984 study by L. Letendre treated 22 leukaemia patients with indicine, this resulted in a significant observed antineoplastic response with four complete remissions and five partial remissions. An observed adverse side effect of

1440-556: The formation of reactive intermediates, such as pyrrolic metabolites, which can covalently bind to proteins in the liver, forming pyrrole-protein adducts. These adducts impair the function of essential liver proteins, leading to hepatotoxicity. The severity of liver damage correlates with the level of pyrrole-protein adduct formation. Hepatotoxicity induced by PAs can manifest as liver injury , inflammation , necrosis , HSOS (Hepatic Sinusoidal Obstruction Syndrome) and even liver failure in severe cases. The pathogenesis of PAs-induces HSOS

1488-408: The grass plant. Loline bioactivities show some unexpected variability with variation in their concentration in grass tissues. For example, the tall fescue endophyte, N. coenophialum , has been associated with enhanced resistance to the migratory root-endoparasitic nematode, Pratylenchus scribneri . At low concentrations, N -formylloline serves as a chemoattractant for P. scribneri , but acts as

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1536-557: The grass, Lolium giganteum , from feeding by the aphid , Rhopalosiphum padi , segregate in a Mendelian fashion. The presence of a single locus for loline production was later confirmed by the finding that loline-producing epichloae endophytes contain a gene cluster ( LOL cluster) of at least eleven genes. The LOL genes are greatly and coordinately upregulated during loline alkaloid production, and experimental genetic tests involving manipulation of selected LOL genes by RNA interference and gene knockout have directly confirmed

1584-431: The growth rate of several strains of the fungus Fusarium oxysporum . Antiviral activity has been found in haliotridine derivates. However, effects are not consistent across PA compounds, derivates significantly differ in activity between different viral pathogens. As a result, it is difficult to determine an exact PA with an effect on a specific virus. Several PAs have been found with significant inhibition of growth in

1632-518: The involvement of two of the LOL genes in loline biosynthesis. These tests and similarities in the peptide sequences of the proteins encoded by these genes to known enzymes indicate that one gene, termed lolC , is likely required for the first step in loline biosynthesis (condensation of L -proline and L -homoserine for NACPP formation), and another gene, LolP —likely encoding a cytochrome P450 monooxygenase —, for oxygenation of one methyl group on

1680-479: The liver, this is the most affected organ. Other affected organs are the lungs and kidneys. The EPy can escape the liver, and travel through the Disse space into the bloodstream. The electrophilic nature of pyrroles makes it an easy target for nucleophilic attack from nucleic acids and protein. If bound by glutathione it can become a non-toxic conjugate and be excreted via the kidneys. A second detoxifying pathway

1728-407: The loline-producing fungus N. uncinatum recently demonstrated that the loline alkaloid pathway is fundamentally different from that of the plant pyrrolizidines. The basic loline chemical structure is assembled in several biosynthetic steps from the amino acid precursors , L -proline and L -homoserine . In the proposed first step in loline biosynthesis, these two amino acids are coupled in

1776-432: The plant and are often difficult to detect analytically. By contrast, the lolines frequently accumulate to very high levels in grass tissues, and were, therefore, initially associated also with toxicity to mammalian herbivores. Specifically, the lolines were thought to be responsible for toxic symptoms called fescue toxicosis displayed by livestock grazing on grasses infected by N. coenophialum . However, subsequently it

1824-559: The presence of other endophyte alkaloids in these extracts, and the exact mechanisms of the insecticidal actions of the lolines are unknown. The lolines may be neurotoxic to the insects, and differences in the chemical groups at the C-1-amine result in different levels of insect toxicity; for example, N -formylloline (see Fig. 2), which occurs in higher concentrations in endophyte-infected grass plants, has greater insect toxicity than some other lolines, which occur at lower concentrations in

1872-517: The reapers, Gather ye together first the tares , and bind them in bundles to burn them: but gather the wheat into my barn. Pyrrolizidine alkaloid Pyrrolizidine alkaloids ( PAs ), sometimes referred to as necine bases, are a group of naturally occurring alkaloids based on the structure of pyrrolizidine . Their use dates back centuries and is intertwined with the discovery, understanding, and eventual recognition of their toxicity on humans and animals. PAs were first discovered in plants in

1920-439: The repair of the stomach after gastric ulcers. A high concentration of said compounds can reduce lesions in the stomach. This may aid in treatment after operation to the stomach. The toxicological effects of PAs have been studied on animals. Retronecine derivatives are known to cause a toxic response in the livers of livestock like cows. Symptoms tend to start with a change in rough hair coat and depression. When Pregnant livestock

1968-695: The seeds and in younger leaf tissues, and the lolines display seasonal changes in concentration levels throughout the plant. The periodical appearance of tissues with high loline concentrations, such as flowering stems and seeds, contributes to this seasonal variation. Loline concentrations often increase in grass tissues regrown after defoliation and clipping of plants, suggesting an inducible defense response mechanism, involving both symbiotic partners. However, this increase appears to be due to higher loline levels in younger leaves compared to older leaves, but loline increases resembling inducible plant defenses have also been reported. Variation of loline concentration with

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2016-505: 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. Next to its toxicological effects, PAs have long been researched for their potential beneficial effects. Traditional medicinal plants have long been known to contain PAs,

2064-496: The symbiotic conditions in vitro , it was long unknown if the fungus was the producer of the lolines, or if they were synthesized by the plant in response to endophyte infection. In 2001, it was demonstrated that the endophyte Neotyphodium uncinatum produces lolines in some chemically defined growth media , which suggests that the endophyte is also the producer of the lolines in the grass plant. The lolines have also been reported from some plants in several plant families , suggesting

2112-712: The treatment was observed in 5 patients who died of hepatic toxicity likely caused by the medication. Two different dose levels were tested on children: 2 g/m2/ day for 5 consecutive days (14 patients) and 2,5 g/m2/ day for 5 consecutive days (17 patients). Therapeutic effect was determined based on these doses and deemed to have a limited antileukemic effect below a dose of 3 g/m2/ day. However, this study also found severe hepatotoxic responses to be common at these doses. Four known PAs, 7- O -angeloyllycopsamine N -oxide, echimidine N -oxide, echimidine, and 7- O -angeloylretronecine have been clinically shown to inhibit acetylcholinesterase (AChE) . AChE inhibitors have been used as one of

2160-423: The treatments for Alzheimer's disease . The effect of these compounds was significant in the reduction of AChE production and thus a potential alternative in the fight against Alzheimer's. 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). These two compounds aid in

2208-619: The unusual pyrrolopyrazine alkaloid, peramine , which is not found in other biological communities or organisms. The lolines are produced at levels, however, that can exceed 10 mg/g grass tissue (ranging from 2–20,000 μg/g), exceeding the concentrations of the other endophyte alkaloids by >1000-fold. Lolines produced in the grasses Lolium pratense (syn. Festuca pratensis , meadow fescue) and tall fescue infected by N. uncinatum and N. coenophialum (see Fig. 3), respectively, exhibit variable concentrations in grass tissues. Higher loline concentrations (100–1000 μg/g) are present in

2256-445: 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,

2304-400: Was demonstrated that only the endophyte-produced ergot alkaloids are responsible for the symptoms of fescue toxicosis (or summer syndrome ), and not the lolines which, even at high doses, have only very small physiological effects on mammalians feeders. Another group of alkaloids, the senecio-type alkaloids, are produced by various plants and like the lolines, the senecio alkaloids possess

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