213:
475:, 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 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.
288:
182:
134:
347:
245:
31:
530:. 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 the carcinogenic effect is currently known. However, there have been studies to determine the lowest dose for an adverse effect, also known as
442:. 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 the growth rate of several strains of the fungus
408:
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, the exact effect of the PAs regarding beneficial effect of the plants is debated. Among these traditional medicines is the root of
356:
PAs are metabolized in the liver through CYP450-mediated pathways. 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 impair the function of essential
93:
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
521:
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 is exposed to PAs an effect can be seen on
197:
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
141:
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
451:
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
109:
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
113:
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
1038:
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.
220:
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
88:
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
249:
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
142:
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.
395:
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
122:
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.
306:(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.
292:
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,
97:
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
513:(EGF). These two compounds aid in 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.
114:
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.
1535:
357:
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
309:
Since this mostly happens in 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
1514:
1612:
1451:
1430:
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1542:
1423:
1402:
411:
1444:
1437:
1381:
1416:
1367:
1209:
1188:
1181:
3523:"Modulation of gastrin and epidermal growth factor by pyrrolizidine alkaloids obtained from Senecio brasiliensis in acute and chronic induced gastric ulcers"
2888:
Miranda, Cristobal L.; Chung, Woongye; Reed, Ralph E.; Zhao, Xine; Henderson, Marilyn C.; Wang, Jun-Lan; Williams, David E.; Buhler, Donald R. (1991-07-31).
1409:
1395:
1160:
1500:
1458:
1374:
1167:
1125:
2646:
1328:
1153:
1591:
1103:
502:. The effect of these compounds was significant in the reduction of AChE production and thus a potential alternative in the fight against Alzheimer's.
302:
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,
1493:
1174:
1556:
1335:
388:
development and other adverse health effects. Genotoxicity is particularly concerning as it can lead to long-term health consequences, including
3045:"Hepatotoxicity of Pyrrolizidine Alkaloid Compound Intermedine: Comparison with Other Pyrrolizidine Alkaloids and Its Toxicological Mechanism"
2592:"Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis"
505:
PAs like senecionine, integerrimine, retrorsine, usaramine and seneciphylline have been shown to cause an increase in both the levels of
3346:
2234:"Homospermidine synthase, the first pathway-specific enzyme of pyrrolizidine alkaloid biosynthesis, evolved from deoxyhypusine synthase"
373:(Hepatic Sinusoidal Obstruction Syndrome) and even liver failure in severe cases. The pathogenesis of PAs-induces HSOS is shown by Xu.
2045:"The chronic pathological effects on the liver of the rat of the pyrrolizidine alkaloids heliotrine, lasiocarpine, and their N -oxides"
189:
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
3429:
Benamar, Houari; Tomassini, Lamberto; Venditti, Alessandro; Marouf, Abderrazak; Bennaceur, Malika; Nicoletti, Marcello (2016-11-16).
415:
of Tibet. Several pharmacological effects have been found. Among these effects are antimicrobial activity, antiviral activity and
2802:"In vitro metabolism of pyrrolizidine alkaloids – Metabolic degradation and GSH conjugate formation of different structure types"
1052:
370:
316:
The electrophilic nature of pyrroles makes it an easy target for nucleophilic attack from nucleic acids and protein. If bound by
17:
3618:
Zheng, Pimiao; Xu, Yuliang; Ren, Zhenhui; Wang, Zile; Wang, Sihan; Xiong, Jincheng; Zhang, Huixia; Jiang, Haiyang (2021-01-04).
2937:"Sinusoidal obstruction syndrome: A systematic review of etiologies, clinical symptoms, and magnetic resonance imaging features"
2499:
Donohoe, Timothy J.; Thomas, Rhian E.; Cheeseman, Matthew D.; Rigby, Caroline L.; Bhalay, Gurdip; Linney, Ian D. (2008-08-21).
1930:
234:
2890:"Flavin-containing monooxygenase: A major detoxifying enzyme for the pyrrolizidine alkaloid senecionine in guinea pig tissues"
3688:
2418:
1988:
3381:"Phase II trial of indicine N-oxide in relapsed acute leukemia of childhood. A report from the Childrens Cancer Study Group"
376:
Genotoxicity is another consequence of PA metabolism. The reactive metabolites formed during PA metabolism can also bind to
212:
2131:
Mulder, Patrick P.J.; Sánchez, Patricia López; These, Anja; Preiss-Weigert, Angelika; Castellari, Massimo (August 2015).
76:. Their use dates back centuries and is intertwined with the discovery, understanding, and eventual recognition of their
260:
PAs are commonly introduced into the body via oral ingestion through contaminated food or traditional medicine, notably
1048:
400:
are known to be highly hepatotoxic, while other types may exhibit lower toxicity or different toxicological profiles.
3521:
Toma, Walber; Trigo, José Roberto; Bensuaski de Paula, Ana Cláudia; Monteiro Souza Brito, Alba Regina (2004-05-01).
3723:
541:(oral) for 40 PAs have been experimentally found out. These values can be seen in the Table below. The found low LD
3043:
Wang, Ziqi; Han, Haolei; Wang, Chen; Zheng, Qinqin; Chen, Hongping; Zhang, Xiangchun; Hou, Ruyan (December 2021).
1838:"Pyrrolizidine alkaloids (PAs) in honey and pollen-legal regulation of PA levels in food and animal feed required"
430:
Antimicrobial activity of several PAs have been identified as having mild to strong effect against bacteria:
3379:
Miser, J. S.; Smithson, W. A.; Krivit, W.; Hughes, C. H.; Davis, D.; Krailo, M. D.; Hammond, G. D. (April 1992).
545:
values clearly show the relatively high toxicity of PAs, however no significant relation was found between the LD
2800:
Geburek, Ina; Preiss-Weigert, Angelika; Lahrssen-Wiederholt, Monika; Schrenk, Dieter; These, Anja (2020-01-01).
331:
can prevent aromatization of the double 5-ring and in turn prevent the formation of the pyrrole-protein adduct.
173:(nine genera). More than 95% of the PA-containing species investigated thus far belong to these four families.
2439:"Current Knowledge and Perspectives of Pyrrolizidine Alkaloids in Pharmacological Applications: A Mini-Review"
233:
There are multiple ways to synthesize PAs and their derivatives. A flexible strategy would be to start with a
3620:"Toxic Prediction of Pyrrolizidine Alkaloids and Structure-Dependent Induction of Apoptosis in HepaRG Cells"
90:
2851:"The role of flavin-containing monooxygenase in the N-oxidation of the pyrrolizidine alkaloid senecionine"
1981:"Pyrrolizidine alkaloids in foods". Advances in Food and Nutrition Research Volume 45. Vol. 45. pp. 61–99
1146:
1965:
526:
and accumulation in the foetus. The main lethal responses in adult livestock exhibit necrosis, HSOS and
3574:
Food
Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
1472:
1056:
272:. It can readily form salts with nitrates, chlorides and sulphates, which facilitate the uptake in the
3162:
2746:
2591:
2553:"Pyrrolizidine alkaloids - Tumorigenic components in Chinese herbal medicines and dietary supplements"
2005:
3430:
1342:
3431:"Pyrrolizidine alkaloids from Solenanthus lanatus DC. with acetylcholinesterase inhibitory activity"
2697:"Metabolic Activation of Pyrrolizidine Alkaloids: Insights into the Structural and Enzymatic Basis"
2093:
1570:
3288:
287:
3331:"Hepatocellular toxicity during the treatment of refractory acute leukemia with indicine N-oxide"
3196:
1230:
510:
438:
127:
3289:"Antineoplastic and Antiviral Screening of Pyrrolizidine Alkaloids from Heliotropium subulatum"
1584:
1349:
1300:
1244:
1237:
1202:
499:
273:
3163:"A new pyrrolizidine alkaloid and other constituents from the roots of Ligularia achyrotricha"
2745:
Prakash, Arungundrum S; Pereira, Tamara N; Reilly, Paul E. B; Seawright, Alan A (1999-07-15).
2044:
3728:
3718:
2368:
Xu, Jie; Wang, Weiqian; Yang, Xiao; Xiong, Aizhen; Yang, Li; Wang, Zhengtao (December 2019).
1837:
1563:
1272:
1089:
1068:
2304:"Pyrrolizidine Alkaloids: Biosynthesis, Biological Activities and Occurrence in Crop Plants"
1931:
https://web.archive.org/web/20091014232504/http://www.foodstandards.gov.au/_srcfiles/TR2.pdf
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2177:
1755:
1619:
1507:
1360:
1307:
1293:
495:
465:
420:
310:
126:
The biosynthesis of PAs was discovered to occur through the first pathway-specific enzyme
8:
2166:"Attract and deter: a dual role for pyrrolizidine alkaloids in plant–insect interactions"
1486:
1314:
1286:
1279:
1251:
1223:
1132:
1096:
1082:
2762:
2607:
2249:
2181:
1759:
1051:
and may never be able to satisfy particular standards for completeness. You can help by
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2206:
1694:
1659:
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1110:
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535:
444:
3522:
3496:
3212:
2889:
2770:
2021:
3694:
3684:
3659:
3641:
3597:
3589:
3550:
3542:
3500:
3458:
3450:
3408:
3400:
3396:
3358:
3350:
3329:
Letendre, L.; Ludwig, J.; Perrault, J.; Smithson, W. A.; Kovach, J. S. (1984-10-01).
3308:
3266:
3258:
3216:
3143:
3125:
3084:
3066:
3025:
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2917:
2909:
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2831:
2823:
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2666:
2662:
2627:
2619:
2572:
2528:
2520:
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2460:
2414:
2391:
2370:"Pyrrolizidine alkaloids: An update on their metabolism and hepatotoxicity mechanism"
2343:
2325:
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2072:
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1984:
1952:
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1904:
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1818:
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1771:
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1699:
1681:
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Moreira, Rute; Pereira, David M.; Valentão, Patrícia; Andrade, Paula B. (June 2018).
1626:
1528:
1521:
1479:
1388:
1216:
453:
181:
2849:
Williams, D. E.; Reed, R. L.; Kedzierski, B.; Ziegler, D. M.; Buhler, D. R. (1989).
1934:
1885:"Honey from Plants Containing Pyrrolizidine Alkaloids: A Potential Threat to Health"
133:
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2017:
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432:
42:
34:
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3585:
3481:"Potent Acetylcholinesterase Inhibitors: Potential Drugs for Alzheimer's Disease"
3178:
2386:
2369:
2109:
1465:
1118:
303:
3304:
3104:"Extracting and Analyzing Pyrrolizidine Alkaloids in Medicinal Plants: A Review"
2149:
2132:
452:
have been found with significant inhibition of growth in the following viruses:
3680:
Tiger moths and woolly bears: behavior, ecology, and evolution of the
Arctiidae
3570:"Pyrrolizidine alkaloid toxicity in livestock: a paradigm for human poisoning?"
3520:
3347:
10.1002/1097-0142(19841001)54:7<1256::aid-cncr2820540704>3.0.co;2-s
3197:"Antimicrobial activity of pyrrolizidine alkaloids from Heliotropium subulatum"
2799:
2590:
Luckert, Claudia; Hessel, Stefanie; Lenze, Dido; Lampen, Alfonso (2015-10-01).
2551:
Fu, P.P.; Yang, Y.-C.; Xia, Q.; Chou, M. W.; Cui, Y. Y.; Lin, G. (2020-07-14).
1321:
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99:
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1660:"Pyrrolizidine Alkaloids: Chemistry, Pharmacology, Toxicology and Food Safety"
244:
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3593:
3568:
Molyneux, R. J.; Gardner, D. L.; Colegate, S. M.; Edgar, J. A. (March 2011).
3546:
3454:
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3262:
3129:
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3011:
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2866:
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2500:
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2029:
1908:
1884:
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1814:
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1728:
1685:
527:
397:
328:
73:
68:), sometimes referred to as necine bases, are a group of naturally occurring
3569:
2568:
2165:
2060:
1743:
241:
molecule and use specific reaction for synthesis into the desired compound.
3678:
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2347:
2285:
2215:
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1916:
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1853:
1703:
416:
362:
358:
343:
of PAs in humans primarily revolve around hepatotoxicity and genotoxicity.
158:
103:
3412:
3362:
3238:
2921:
2874:
1822:
1720:
Hepatic cirrhosis
Affecting Horses and Cattle (So-Called "Winton Disease")
1718:
2695:
Ruan, Jianqing; Yang, Mengbi; Fu, Peter; Ye, Yang; Lin, Ge (2014-06-16).
1676:
1139:
317:
281:
206:
199:
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154:
150:
38:
1806:
523:
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327:-oxide In the liver and lungs of certain mammal species enzymes called
166:
146:
2712:
2516:
2302:
Schramm, Sebastian; Köhler, Nikolai; Rozhon, Wilfried (January 2019).
1900:
3003:
498:(AChE) . AChE inhibitors have been used as one of the treatments for
320:
it can become a non-toxic conjugate and be excreted via the kidneys.
269:
3538:
3239:"Pyrrolizidine Alkaloids from Senecio jacobaea Affect Fungal Growth"
1042:
380:, leading to the formation of DNA adducts. These adducts can induce
1883:
Edgar, John A.; Roeder, Erhard; Molyneux, Russell J. (2002-05-08).
1028:
PAs are also used as a defense mechanism by some organisms such as
472:
381:
366:
299:
162:
77:
69:
2751:
Mutation
Research/Genetic Toxicology and Environmental Mutagenesis
2855:
Drug
Metabolism and Disposition: The Biological Fate of Chemicals
506:
461:
265:
238:
50:
2501:"Flexible Strategy for the Synthesis of Pyrrolizidine Alkaloids"
2130:
1836:
Kempf, Michael; Reinhard, Annika; Beuerle, Till (January 2010).
193:
called necic acids. Four major necine bases are described, with
2647:"Pyrrolizidine Poisoning: A Neglected Area in Human Toxicology"
385:
261:
170:
3428:
3328:
3102:
Kopp, Thomas; Abdel-Tawab, Mona; Mizaikoff, Boris (May 2020).
30:
3287:
Singh, B.; Sahu, P.M.; Jain, S.C.; Singh, S. (January 2002).
2848:
2744:
2006:"Hepatic Cirrhosis in Sheep Due to Ragwort (Senecio Jacobœa)"
1744:"Toxicity of pyrrolizidine alkaloids to humans and ruminants"
1657:
531:
457:
277:
190:
3567:
2437:
Wei, Xianqin; Ruan, Weibin; Vrieling, Klaas (January 2021).
2498:
494:-angeloylretronecine have been clinically shown to inhibit
3378:
2645:
Stewart, Michael J.; Steenkamp, Vanessa (December 2001).
377:
3101:
2589:
2411:
255:
1791:"Plant Sources of Hepatotoxic Pyrrolizidine Alkaloids"
94:
of PAs in food, unlike those for herbs and medicines.
323:
A second detoxifying pathway is the formation of the
2887:
1835:
3683:. Oxford ; New York: Oxford University Press.
2894:
Biochemical and Biophysical Research Communications
2301:
1882:
3286:
225:-oxides have been identified in over 6000 plants.
1043:Plants species containing pyrrolizidine alkaloids
3710:
3478:
3042:
2986:Chen, Tao; Mei, Nan; Fu, Peter P. (April 2010).
2644:
3527:Canadian Journal of Physiology and Pharmacology
3195:Singh, B.; Sahu, P.M.; Singh, S. (April 2002).
2494:
2492:
2436:
2367:
2238:Proceedings of the National Academy of Sciences
2232:Ober, Dietrich; Hartmann, Thomas (1999-12-21).
2133:"Occurrence of Pyrrolizidine Alkaloids in food"
1789:Smith, L. W.; Culvenor, C. C. J. (April 1981).
1741:
145:PAs are preferably found in the plant families
3617:
3194:
1742:Wiedenfeld, Helmut; Edgar, John (2011-03-01).
471:Antineoplastic activity, specifically against
3237:Hol, W. H. G.; Van Veen, J. A. (2002-09-01).
2550:
2297:
2295:
1788:
339:The toxicity consequences resulting from the
2694:
2489:
2231:
1653:
1651:
3236:
1664:International Journal of Molecular Sciences
298:Metabolites form mostly in the liver. Here
176:
3479:Akıncıoğlu, Hulya; Gülçin, İlhami (2020).
3160:
2408:
2292:
1889:Journal of Agricultural and Food Chemistry
403:
3653:
3635:
3624:Oxidative Medicine and Cellular Longevity
3137:
3119:
3078:
3060:
3019:
2988:"Genotoxicity of pyrrolizidine alkaloids"
2985:
2962:
2952:
2817:
2472:
2454:
2385:
2337:
2319:
2275:
2257:
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2148:
2049:The Journal of Pathology and Bacteriology
2043:Bull, L. B.; Dick, A. T. (October 1959).
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1675:
1648:
2042:
1978:
345:
334:
286:
243:
211:
180:
132:
41:, a pyrrolizidine alkaloid found in the
29:
2747:"Pyrrolizidine alkaloids in human diet"
2003:
1842:Molecular Nutrition & Food Research
1716:
384:and DNA damage, increasing the risk of
185:Chemical structures of the necine bases
14:
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3472:
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3324:
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577:
3385:American Journal of Clinical Oncology
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921:
516:
117:
1061:
256:Mechanisms of actions and metabolism
3608:
3511:
3485:Mini-Reviews in Medicinal Chemistry
3469:
3419:
3369:
3319:
3161:Hua, L.; Chen, J.; Gao, K. (2012).
24:
3277:
3227:
3185:
2735:
2685:
2539:
2427:
2354:
2222:
2083:
1536:Senecio integrifolius var. fauriri
216:Chemical structures of various PAs
25:
3740:
3497:10.2174/1389557520666200103100521
2557:Journal of Food and Drug Analysis
276:. After which they travel to the
3677:Conner, William E., ed. (2009).
3397:10.1097/00000421-199204000-00008
2663:10.1097/00007691-200112000-00018
237:(tert-Butoxycarbonyl) protected
3670:
3561:
3154:
3095:
3036:
2979:
2941:World Journal of Clinical Cases
2928:
2881:
2842:
2793:
2701:Chemical Research in Toxicology
2638:
2583:
2402:
2157:
2124:
2036:
351:Pathogenesis of PA-induced HSOS
1997:
1979:Coulombe, Roger A. Jr (2003).
1972:
1923:
1876:
1829:
1782:
1735:
1710:
13:
1:
3447:10.1080/14786419.2015.1131984
3213:10.1016/S0367-326X(02)00016-3
2992:Journal of Applied Toxicology
2771:10.1016/S1383-5742(99)00010-1
2022:10.1016/S0372-5545(17)70348-3
2004:Gilruth, J. A. (1905-07-01).
1641:
3586:10.1080/19440049.2010.547519
3179:10.1016/j.phytol.2012.05.009
2906:10.1016/0006-291X(91)90142-T
2806:Food and Chemical Toxicology
2387:10.1016/j.livres.2019.11.004
2137:EFSA Supporting Publications
2110:10.3109/03602532.2010.506057
2104:(sup1): 1–323. August 2010.
1114:(< 10 ppm, non-toxic)
228:
91:traditional Chinese medicine
7:
3305:10.1076/phbi.40.8.581.14659
3243:Journal of Chemical Ecology
2651:Therapeutic Drug Monitoring
2164:Macel, Mirka (2011-03-01).
2150:10.2903/sp.efsa.2015.EN-859
1795:Journal of Natural Products
1147:Crassocephalum crepidioides
27:Class of chemical compounds
10:
3745:
1473:Lithospermum erythrorhizon
490:-oxide, echimidine, and 7-
83:
72:based on the structure of
2954:10.12998/wjcc.v7.i18.2746
2819:10.1016/j.fct.2019.110868
2616:10.1016/j.tiv.2015.06.021
2456:10.3390/molecules26071970
2321:10.3390/molecules24030498
2190:10.1007/s11101-010-9181-1
1768:10.1007/s11101-010-9174-0
1343:Heliotropium amplexicaule
3435:Natural Product Research
2259:10.1073/pnas.96.26.14777
1571:Senecio madagascariensis
1515:Senecio chrysanthemoides
177:Structure and reactivity
3724:Pyrrolizidine alkaloids
3255:10.1023/A:1020557000707
2569:10.38212/2224-6614.2743
2409:Aniszewski, T. (2015).
2098:Drug Metabolism Reviews
2061:10.1002/path.1700780215
1613:Syneilesis aconitifolia
1452:Ligularia tsanchanensis
1431:Ligularia lidjiangensis
1231:Cynoglossum lanceolatum
1196:Crotalaria sesseliflora
511:epidermal growth factor
404:Pharmacological effects
128:homospermidine synthase
80:on humans and animals.
62:Pyrrolizidine alkaloids
18:Pyrrolizidine alkaloids
3293:Pharmaceutical Biology
3167:Phytochemistry Letters
3121:10.3390/toxins12050320
3062:10.3390/toxins13120849
2170:Phytochemistry Reviews
2010:The Veterinary Journal
1854:10.1002/mnfr.200900529
1748:Phytochemistry Reviews
1585:Senecio quadridentatus
1543:Senecio interggerrimus
1424:Ligularia lapathifolia
1403:Ligularia heterophylla
1350:Heliotropium europaeum
1301:Eupatorium perfoliatum
1245:Cynoglossum zeylanicum
1238:Cynoglossum officinale
1203:Crotalaria spectabilis
509:and the expression of
412:Ligularia achyrotricha
353:
313:into the bloodstream.
295:
274:gastrointestinal tract
252:
217:
209:of the nitrogen atom.
186:
138:
58:
1564:Senecio linearifolius
1445:Ligularia tongolensis
1438:Ligularia platyglossa
1382:Ligularia cymbulifera
1273:Eupatorium cannabinum
1090:Ageratum houstonianum
1069:Adenostyles alliariae
482:-angeloyllycopsamine
349:
335:Toxicological effects
290:
247:
215:
184:
136:
33:
3637:10.1155/2021/8822304
1983:. Elsevier Science.
1677:10.3390/ijms19061668
1620:Symphytum officinale
1508:Senecio brasiliensis
1417:Ligularia intermedia
1368:Heliotropium popovii
1361:Heliotropium indicum
1308:Eupatorium purpureum
1294:Eupatorium japonicum
1210:Crotalaria tetragona
1189:Crotalaria mucronata
1182:Crotalaria globifera
1053:adding missing items
757:7-Acetyllycopsamine
746:7-Acetylintermedine
496:acetylcholinesterase
466:vesicular stomatitis
421:acetylcholinesterase
2763:1999MRGTE.443...53P
2608:2015ToxVi..29.1669L
2596:Toxicology in Vitro
2250:1999PNAS...9614777O
2244:(26): 14777–14782.
2182:2011PChRv..10...75M
1807:10.1021/np50014a001
1760:2011PChRv..10..137W
1717:Gilruth, J (1903).
1487:Petasites japonicus
1410:Ligularia hodgsonii
1396:Ligularia duiformis
1315:Farfugium japonicum
1287:Eupatorium fortunei
1280:Eupatorium chinense
1252:Echium plantagineum
1224:Cynoglossum amabile
1161:Crotalaria assamica
1133:Chromolaena odorata
1097:Anchusa officinalis
1083:Ageratum conyzoides
958:Heliocurassavicine
947:Heliocoromandaline
560:
522:the foetus, mainly
500:Alzheimer's disease
486:-oxide, echimidine
137:Biosynthesis of PAs
2935:Zhang, Y. (2019).
2094:"Invited Speakers"
1578:Senecio nemorensis
1501:Senecio argunensis
1459:Ligularia vellerea
1375:Lappula intermedia
1266:Emilia sonchifolia
1168:Crotalaria crispat
1126:Cacalia hupehensis
1111:Borago officinalis
1076:Adenostyles glabra
1036:Utetheisa ornatrix
1031:Utetheisa ornatrix
922:Platynecine types
578:Retronecine types
552:
517:Effects on animals
478:Four known PAs, 7-
445:Fusarium oxysporum
354:
296:
253:
218:
187:
165:(mainly the genus
139:
118:Natural occurrence
110:risk of toxicity.
59:
3690:978-0-19-532737-3
3441:(22): 2567–2574.
2947:(18): 2746–2759.
2713:10.1021/tx500071q
2517:10.1021/ol801415d
2511:(16): 3615–3618.
2420:978-0-444-59462-4
1990:978-0-12-016445-5
1960:Missing or empty
1901:10.1021/jf0114482
1895:(10): 2719–2730.
1638:
1637:
1627:Tussilago farfara
1529:Senecio glabellus
1522:Senecio cineraria
1480:Neurolaena lobata
1389:Ligularia dentata
1329:Gynura divaricata
1217:Crotalaria retusa
1154:Crotalaria albida
1026:
1025:
936:Trachelanthamine
16:(Redirected from
3736:
3703:
3702:
3674:
3668:
3667:
3657:
3639:
3615:
3606:
3605:
3565:
3559:
3558:
3518:
3509:
3508:
3476:
3467:
3466:
3426:
3417:
3416:
3376:
3367:
3366:
3341:(7): 1256–1259.
3326:
3317:
3316:
3284:
3275:
3274:
3249:(9): 1763–1772.
3234:
3225:
3224:
3192:
3183:
3182:
3158:
3152:
3151:
3141:
3123:
3099:
3093:
3092:
3082:
3064:
3040:
3034:
3033:
3023:
3004:10.1002/jat.1504
2983:
2977:
2976:
2966:
2956:
2932:
2926:
2925:
2885:
2879:
2878:
2846:
2840:
2839:
2821:
2797:
2791:
2790:
2742:
2733:
2732:
2707:(6): 1030–1039.
2692:
2683:
2682:
2642:
2636:
2635:
2602:(7): 1669–1682.
2587:
2581:
2580:
2548:
2537:
2536:
2496:
2487:
2486:
2476:
2458:
2434:
2425:
2424:
2406:
2400:
2399:
2389:
2380:(3–4): 176–184.
2365:
2352:
2351:
2341:
2323:
2299:
2290:
2289:
2279:
2261:
2229:
2220:
2219:
2209:
2161:
2155:
2154:
2152:
2128:
2122:
2121:
2090:
2081:
2080:
2040:
2034:
2033:
2001:
1995:
1994:
1976:
1970:
1969:
1963:
1958:
1956:
1948:
1946:
1945:
1939:
1933:. Archived from
1927:
1921:
1920:
1880:
1874:
1873:
1833:
1827:
1826:
1786:
1780:
1779:
1739:
1733:
1732:
1714:
1708:
1707:
1697:
1679:
1655:
1606:Senecio vulgaris
1599:Senecio scandens
1592:Senecio riddelli
1550:Senecio jacobaea
1104:Arnebia euchroma
1062:
1057:reliable sources
972:Acetylanonamine
969:Otonicine types
561:
558:and LOAEL values
551:
423:inhibition, and
47:Senecio vulgaris
43:common groundsel
35:Skeletal formula
21:
3744:
3743:
3739:
3738:
3737:
3735:
3734:
3733:
3709:
3708:
3707:
3706:
3691:
3675:
3671:
3616:
3609:
3566:
3562:
3539:10.1139/y04-023
3519:
3512:
3477:
3470:
3427:
3420:
3377:
3370:
3327:
3320:
3285:
3278:
3235:
3228:
3193:
3186:
3159:
3155:
3100:
3096:
3041:
3037:
2984:
2980:
2933:
2929:
2886:
2882:
2847:
2843:
2798:
2794:
2743:
2736:
2693:
2686:
2643:
2639:
2588:
2584:
2549:
2540:
2505:Organic Letters
2497:
2490:
2435:
2428:
2421:
2407:
2403:
2366:
2355:
2300:
2293:
2230:
2223:
2162:
2158:
2129:
2125:
2092:
2091:
2084:
2041:
2037:
2002:
1998:
1991:
1977:
1973:
1961:
1959:
1950:
1949:
1943:
1941:
1937:
1929:
1928:
1924:
1881:
1877:
1834:
1830:
1787:
1783:
1740:
1736:
1715:
1711:
1656:
1649:
1644:
1639:
1494:Senecio alpinus
1466:Liparis nervosa
1175:Crotalaria dura
1119:Cacalia hastata
1045:
925:Platyphylline∗
658:Seneciphylline
647:Monocrotaline∗
557:
548:
544:
539:
519:
406:
337:
304:cytochrome P450
258:
231:
179:
161:(many genera),
120:
86:
28:
23:
22:
15:
12:
11:
5:
3742:
3732:
3731:
3726:
3721:
3705:
3704:
3689:
3669:
3607:
3580:(3): 293–307.
3560:
3533:(5): 319–325.
3510:
3491:(8): 703–715.
3468:
3418:
3391:(2): 135–140.
3368:
3318:
3299:(8): 581–586.
3276:
3226:
3207:(2): 153–155.
3184:
3173:(3): 541–544.
3153:
3094:
3035:
2998:(3): 183–196.
2978:
2927:
2900:(2): 546–552.
2880:
2861:(4): 380–386.
2841:
2792:
2734:
2684:
2657:(6): 698–708.
2637:
2582:
2538:
2488:
2426:
2419:
2401:
2374:Liver Research
2353:
2291:
2221:
2156:
2123:
2082:
2055:(2): 483–502.
2035:
1996:
1989:
1971:
1922:
1875:
1848:(1): 158–168.
1828:
1801:(2): 129–152.
1781:
1754:(1): 137–151.
1734:
1709:
1646:
1645:
1643:
1640:
1636:
1635:
1631:
1630:
1623:
1616:
1609:
1602:
1595:
1588:
1581:
1574:
1567:
1560:
1557:Senecio lautus
1553:
1546:
1539:
1532:
1525:
1518:
1511:
1504:
1497:
1490:
1483:
1476:
1469:
1462:
1455:
1448:
1441:
1434:
1427:
1420:
1413:
1406:
1399:
1392:
1385:
1378:
1371:
1364:
1355:
1354:
1353:
1346:
1339:
1336:Gynura segetum
1332:
1325:
1322:Gynura bicolor
1318:
1311:
1304:
1297:
1290:
1283:
1276:
1269:
1262:
1259:Echium vulgare
1255:
1248:
1241:
1234:
1227:
1220:
1213:
1206:
1199:
1192:
1185:
1178:
1171:
1164:
1157:
1150:
1143:
1136:
1129:
1122:
1115:
1107:
1100:
1093:
1086:
1079:
1072:
1060:
1044:
1041:
1024:
1023:
1020:
1017:
1013:
1012:
1009:
1006:
1002:
1001:
998:
995:
991:
990:
987:
984:
980:
979:
976:
973:
970:
966:
965:
962:
959:
955:
954:
951:
948:
944:
943:
940:
937:
933:
932:
929:
926:
923:
919:
918:
915:
912:
908:
907:
904:
901:
897:
896:
893:
890:
886:
885:
882:
879:
878:Callimorphine
875:
874:
871:
868:
864:
863:
860:
857:
853:
852:
849:
846:
842:
841:
838:
835:
831:
830:
827:
824:
820:
819:
816:
813:
809:
808:
805:
802:
798:
797:
794:
791:
787:
786:
783:
780:
776:
775:
772:
769:
765:
764:
761:
758:
754:
753:
750:
747:
743:
742:
739:
736:
732:
731:
728:
725:
721:
720:
717:
714:
710:
709:
706:
703:
702:Trichodesmine
699:
698:
695:
692:
688:
687:
684:
681:
680:Senecivernine
677:
676:
673:
670:
669:Integerrimine
666:
665:
662:
659:
655:
654:
651:
648:
644:
643:
640:
637:
633:
632:
629:
626:
622:
621:
618:
615:
611:
610:
607:
604:
600:
599:
596:
593:
589:
588:
585:
582:
579:
575:
574:
571:
568:
565:
555:
546:
542:
537:
518:
515:
439:P. chrysogenum
425:gastric ulcers
417:antineoplastic
405:
402:
390:carcinogenesis
336:
333:
257:
254:
230:
227:
178:
175:
119:
116:
85:
82:
26:
9:
6:
4:
3:
2:
3741:
3730:
3727:
3725:
3722:
3720:
3717:
3716:
3714:
3700:
3696:
3692:
3686:
3682:
3681:
3673:
3665:
3661:
3656:
3651:
3647:
3643:
3638:
3633:
3629:
3625:
3621:
3614:
3612:
3603:
3599:
3595:
3591:
3587:
3583:
3579:
3575:
3571:
3564:
3556:
3552:
3548:
3544:
3540:
3536:
3532:
3528:
3524:
3517:
3515:
3506:
3502:
3498:
3494:
3490:
3486:
3482:
3475:
3473:
3464:
3460:
3456:
3452:
3448:
3444:
3440:
3436:
3432:
3425:
3423:
3414:
3410:
3406:
3402:
3398:
3394:
3390:
3386:
3382:
3375:
3373:
3364:
3360:
3356:
3352:
3348:
3344:
3340:
3336:
3332:
3325:
3323:
3314:
3310:
3306:
3302:
3298:
3294:
3290:
3283:
3281:
3272:
3268:
3264:
3260:
3256:
3252:
3248:
3244:
3240:
3233:
3231:
3222:
3218:
3214:
3210:
3206:
3202:
3198:
3191:
3189:
3180:
3176:
3172:
3168:
3164:
3157:
3149:
3145:
3140:
3135:
3131:
3127:
3122:
3117:
3113:
3109:
3105:
3098:
3090:
3086:
3081:
3076:
3072:
3068:
3063:
3058:
3054:
3050:
3046:
3039:
3031:
3027:
3022:
3017:
3013:
3009:
3005:
3001:
2997:
2993:
2989:
2982:
2974:
2970:
2965:
2960:
2955:
2950:
2946:
2942:
2938:
2931:
2923:
2919:
2915:
2911:
2907:
2903:
2899:
2895:
2891:
2884:
2876:
2872:
2868:
2864:
2860:
2856:
2852:
2845:
2837:
2833:
2829:
2825:
2820:
2815:
2811:
2807:
2803:
2796:
2788:
2784:
2780:
2776:
2772:
2768:
2764:
2760:
2756:
2752:
2748:
2741:
2739:
2730:
2726:
2722:
2718:
2714:
2710:
2706:
2702:
2698:
2691:
2689:
2680:
2676:
2672:
2668:
2664:
2660:
2656:
2652:
2648:
2641:
2633:
2629:
2625:
2621:
2617:
2613:
2609:
2605:
2601:
2597:
2593:
2586:
2578:
2574:
2570:
2566:
2562:
2558:
2554:
2547:
2545:
2543:
2534:
2530:
2526:
2522:
2518:
2514:
2510:
2506:
2502:
2495:
2493:
2484:
2480:
2475:
2470:
2466:
2462:
2457:
2452:
2448:
2444:
2440:
2433:
2431:
2422:
2416:
2412:
2405:
2397:
2393:
2388:
2383:
2379:
2375:
2371:
2364:
2362:
2360:
2358:
2349:
2345:
2340:
2335:
2331:
2327:
2322:
2317:
2313:
2309:
2305:
2298:
2296:
2287:
2283:
2278:
2273:
2269:
2265:
2260:
2255:
2251:
2247:
2243:
2239:
2235:
2228:
2226:
2217:
2213:
2208:
2203:
2199:
2195:
2191:
2187:
2183:
2179:
2175:
2171:
2167:
2160:
2151:
2146:
2142:
2138:
2134:
2127:
2119:
2115:
2111:
2107:
2103:
2099:
2095:
2089:
2087:
2078:
2074:
2070:
2066:
2062:
2058:
2054:
2050:
2046:
2039:
2031:
2027:
2023:
2019:
2015:
2011:
2007:
2000:
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839:
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834:Lasiocarpine
833:
832:
828:
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823:Retronecine∗
822:
821:
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811:
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803:
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583:
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573:LOAEL (g/kg)
572:
569:
566:
563:
562:
559:
550:
540:
533:
529:
528:megalacytosis
525:
514:
512:
508:
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501:
497:
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485:
481:
476:
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469:
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458:poliomyelitis
455:
449:
447:
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440:
435:
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428:
426:
422:
418:
414:
413:
401:
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398:monocrotaline
393:
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368:
364:
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352:
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344:
342:
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329:monooxygenase
326:
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293:respectively.
289:
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135:
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115:
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92:
81:
79:
75:
74:pyrrolizidine
71:
67:
63:
56:
52:
48:
44:
40:
36:
32:
19:
3729:Hepatotoxins
3719:Plant toxins
3679:
3672:
3630:: e8822304.
3627:
3623:
3577:
3573:
3563:
3530:
3526:
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2940:
2930:
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2809:
2805:
2795:
2757:(1): 53–67.
2754:
2750:
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2640:
2599:
2595:
2585:
2560:
2556:
2508:
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2442:
2413:. Elsevier.
2410:
2404:
2377:
2373:
2311:
2307:
2241:
2237:
2176:(1): 75–82.
2173:
2169:
2159:
2140:
2136:
2126:
2101:
2097:
2052:
2048:
2038:
2016:(7): 30–33.
2013:
2009:
1999:
1980:
1974:
1962:|title=
1942:. Retrieved
1935:the original
1925:
1892:
1888:
1878:
1845:
1841:
1831:
1798:
1794:
1784:
1751:
1747:
1737:
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1138:
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1124:
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1109:
1102:
1095:
1088:
1081:
1074:
1067:
1049:dynamic list
1046:
1035:
1029:
1027:
845:Heliosupine
801:Intermedine
790:Lycopsamine
735:Crotananine
614:Senecionine
603:Riddelliine
581:Retrorsine∗
570:LD50 (g/kg)
553:
549:and LOAEL.
534:. LOAEL and
520:
504:
491:
487:
483:
479:
477:
470:
450:
443:
437:
431:
429:
410:
407:
394:
375:
363:inflammation
359:liver injury
355:
350:
338:
324:
322:
315:
308:
297:
291:
259:
248:
232:
222:
219:
200:
188:
159:Boraginaceae
144:
140:
125:
121:
112:
108:
96:
87:
65:
61:
60:
54:
46:
3201:Fitoterapia
3055:(12): 849.
2449:(7): 1970.
1670:(6): 1668.
1140:Cordia myxa
983:Senkirkine
900:Echinatine
889:Heliotrine
768:Echimidine
724:Angularine
554:Recorded LD
427:treatment.
318:glutathione
311:Disse space
282:portal vein
207:methylation
195:retronecine
171:Orchidaceae
155:Senecioneae
151:Eupatorieae
106:compounds.
100:hepatotoxic
39:retronecine
3713:Categories
3114:(5): 320.
2812:: 110868.
2314:(3): 498.
1944:2024-03-15
1642:References
1047:This is a
1016:Otonecine
994:Otosenine
911:Rinderine
856:Heleurine
779:Echiumine
625:Usaramine
592:Clivorine
524:stillbirth
419:activity,
341:metabolism
167:Crotalaria
147:Asteraceae
3699:212908684
3646:1942-0900
3594:1944-0057
3547:0008-4212
3455:1478-6419
3405:0277-3732
3355:0008-543X
3313:1388-0209
3263:1573-1561
3130:2072-6651
3071:2072-6651
3012:0260-437X
2914:0006-291X
2867:0090-9556
2828:0278-6915
2779:1383-5718
2721:0893-228X
2671:0163-4356
2624:0887-2333
2577:2224-6614
2525:1523-7060
2465:1420-3049
2443:Molecules
2396:2542-5684
2330:1420-3049
2308:Molecules
2268:0027-8424
2198:1572-980X
2118:0360-2532
2069:0368-3494
2030:0372-5545
1909:0021-8561
1862:1613-4125
1815:0163-3864
1776:1572-980X
1729:418874883
1686:1422-0067
867:Supinine
812:Indicine
691:Jacoline
636:Jacobine
567:Compound
454:coxsackie
382:mutations
300:esterases
270:coltsfoot
229:Synthesis
104:genotoxic
70:alkaloids
55:Symphytum
3664:33488944
3602:21360375
3555:15213731
3505:31902355
3463:26735939
3271:12449504
3221:11978430
3148:32413969
3089:34941687
3030:20112250
2973:31616690
2836:31586656
2787:10415431
2729:24836403
2679:11802107
2632:26100227
2533:18636741
2483:33807368
2348:30704105
2286:10611289
2216:21475391
2077:13805866
1953:cite web
1917:11982390
1870:20013889
1704:29874826
713:Fulvine
473:leukemia
367:necrosis
280:via the
163:Fabaceae
149:(tribes
78:toxicity
3655:7801077
3413:1553901
3363:6590115
3139:7290370
3080:8709407
3021:6376482
2964:6789402
2922:1907134
2875:2571476
2759:Bibcode
2604:Bibcode
2474:8037423
2339:6385001
2246:Bibcode
2207:3047672
2178:Bibcode
1823:7017073
1756:Bibcode
1695:6032134
507:gastrin
462:measles
433:E. coli
266:comfrey
250:system.
239:pyrrole
203:-oxides
169:), and
84:History
51:comfrey
3697:
3687:
3662:
3652:
3644:
3600:
3592:
3553:
3545:
3503:
3461:
3453:
3411:
3403:
3361:
3353:
3335:Cancer
3311:
3269:
3261:
3219:
3146:
3136:
3128:
3108:Toxins
3087:
3077:
3069:
3049:Toxins
3028:
3018:
3010:
2971:
2961:
2920:
2912:
2873:
2865:
2834:
2826:
2785:
2777:
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2346:
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1774:
1727:
1702:
1692:
1684:
1633:
1022:0.001
1019:0.467
1011:0.002
1008:0.264
1000:0.001
997:0.106
989:0.001
986:0.275
978:0.001
975:0.230
964:0.001
961:0.404
953:0.004
950:0.246
942:0.001
939:0.391
931:0.002
928:0.443
917:0.001
914:0.486
906:0.003
903:0.250
895:0.001
892:0.056
884:0.009
881:0.559
873:0.001
870:0.215
862:0.015
859:0.616
851:0.002
848:0.708
840:0.001
837:0.555
829:0.001
826:0.242
818:0.002
815:0.264
807:0.002
804:0.264
796:0.001
793:0.239
785:0.001
782:0.122
774:0.015
771:0.616
763:0.003
760:0.356
752:0.009
749:0.559
741:0.004
738:0.592
730:0.009
727:0.559
719:0.002
716:0.369
708:0.004
705:0.324
697:0.001
694:0.230
686:0.004
683:0.592
675:0.002
672:0.254
664:0.002
661:0.264
653:0.002
650:0.731
642:0.003
639:0.461
631:0.002
628:0.264
620:0.001
617:0.127
609:0.015
606:0.616
598:0.002
595:0.386
587:0.001
584:0.320
464:, and
386:cancer
264:leaf,
262:borage
191:esters
57:spp.)
49:) and
2563:(4).
2277:24724
2143:(8).
1938:(PDF)
1055:with
564:Type
532:LOAEL
278:liver
198:form
3695:OCLC
3685:ISBN
3660:PMID
3642:ISSN
3628:2021
3598:PMID
3590:ISSN
3551:PMID
3543:ISSN
3501:PMID
3459:PMID
3451:ISSN
3409:PMID
3401:ISSN
3359:PMID
3351:ISSN
3309:ISSN
3267:PMID
3259:ISSN
3217:PMID
3144:PMID
3126:ISSN
3085:PMID
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3026:PMID
3008:ISSN
2969:PMID
2918:PMID
2910:ISSN
2871:PMID
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2832:PMID
2824:ISSN
2783:PMID
2775:ISSN
2725:PMID
2717:ISSN
2675:PMID
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2628:PMID
2620:ISSN
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2529:PMID
2521:ISSN
2479:PMID
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2326:ISSN
2282:PMID
2264:ISSN
2212:PMID
2194:ISSN
2114:ISSN
2073:PMID
2065:ISSN
2026:ISSN
1985:ISBN
1966:help
1913:PMID
1905:ISSN
1866:PMID
1858:ISSN
1819:PMID
1811:ISSN
1772:ISSN
1725:OCLC
1700:PMID
1682:ISSN
436:and
371:HSOS
268:and
153:and
102:and
3650:PMC
3632:doi
3582:doi
3535:doi
3493:doi
3443:doi
3393:doi
3343:doi
3301:doi
3251:doi
3209:doi
3175:doi
3134:PMC
3116:doi
3075:PMC
3057:doi
3016:PMC
3000:doi
2959:PMC
2949:doi
2902:doi
2898:178
2814:doi
2810:135
2767:doi
2755:443
2709:doi
2659:doi
2612:doi
2565:doi
2513:doi
2469:PMC
2451:doi
2382:doi
2334:PMC
2316:doi
2272:PMC
2254:doi
2202:PMC
2186:doi
2145:doi
2106:doi
2057:doi
2018:doi
1897:doi
1850:doi
1803:doi
1764:doi
1690:PMC
1672:doi
378:DNA
235:Boc
157:),
66:PAs
37:of
3715::
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