{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T12:10:27Z","timestamp":1792411827662,"version":"4.4.0"},"reference-count":267,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Saturated and unsaturated pyrrolizidine alkaloids (PAs) are present in more than 6000 plant species growing in countries all over the world. They have a typical heterocyclic structure in common, but differ in their potential toxicity, depending on the presence or absence of a double bond between C1 and C2. Fortunately, most plants contain saturated PAs without this double bond and are therefore not toxic for consumption by humans or animals. In a minority of plants, however, PAs with this double bond between C1 and C2 exhibit strong hepatotoxic, genotoxic, cytotoxic, neurotoxic, and tumorigenic potentials. If consumed in error and in large emouns, plants with 1,2-unsaturated PAs induce metabolic breaking-off of the double bonds of the unsaturated PAs, generating PA radicals that may trigger severe liver injury through a process involving microsomal P450 (CYP), with preference of its isoforms CYP 2A6, CYP 3A4, and CYP 3A5. This toxifying CYP-dependent conversion occurs primarily in the endoplasmic reticulum of the hepatocytes equivalent to the microsomal fraction. Toxified PAs injure the protein membranes of hepatocytes, and after passing their plasma membranes, more so the liver sinusoidal endothelial cells (LSECs), leading to life-threatening hepatic sinusoidal obstruction syndrome (HSOS). This injury is easily diagnosed by blood pyrrolizidine protein adducts, which are perfect diagnostic biomarkers, supporting causality evaluation using the updated RUCAM (Roussel Uclaf Causality Assessment Method). HSOS is clinically characterized by weight gain due to fluid accumulation (ascites, pleural effusion, and edema), and may lead to acute liver failure, liver transplantation, or death. In conclusion, plant-derived PAs with a double bond between C1 and C2 are potentially hepatotoxic after metabolic removal of the double bond, and may cause PA-HSOS with a potential lethal outcome, even if PA consumption is stopped.<\/jats:p>","DOI":"10.3390\/ijms221910419","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T10:39:20Z","timestamp":1632739160000},"page":"10419","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Metabolic Toxification of 1,2-Unsaturated Pyrrolizidine Alkaloids Causes Human Hepatic Sinusoidal Obstruction Syndrome: The Update"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8910-1200","authenticated-orcid":false,"given":"Rolf","family":"Teschke","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt\/Main, 63450 Hanau, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9244-2003","authenticated-orcid":false,"given":"Noudeng","family":"Vongdala","sequence":"additional","affiliation":[{"name":"Laboratory of Plant Physiology and Biochemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6567-9902","authenticated-orcid":false,"given":"Nguyen Van","family":"Quan","sequence":"additional","affiliation":[{"name":"Laboratory of Plant Physiology and Biochemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9545-5929","authenticated-orcid":false,"given":"Tran Ngoc","family":"Quy","sequence":"additional","affiliation":[{"name":"Laboratory of Plant Physiology and Biochemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7103-5698","authenticated-orcid":false,"given":"Tran Dang","family":"Xuan","sequence":"additional","affiliation":[{"name":"Laboratory of Plant Physiology and Biochemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, Hiroshima 739-8529, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","unstructured":"Smith, R.L., and Bababunmi, E.A. (1980). Alkaloids and human disease. Toxicology in the Tropics, Taylor and Francis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Bhambhani, S., Kondhare, K.R., and Giri, A.P. (2021). Diversity in chemical structures and biological properties of plant alkaloids. Molecules, 26.","DOI":"10.3390\/molecules26113374"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"825","DOI":"10.18433\/J3BG7J","article-title":"Hepatotoxicity of pyrrolizidine alkaloids","volume":"18","author":"Neuman","year":"2015","journal-title":"J. Pharm. Pharm. Sci."},{"key":"ref_4","unstructured":"Debes, J. (2022). Tropical herb induced liver injury by pyrrolizidine alkaloids. Diagnosis and Management of Tropical Liver Diseases, Elsevier. in press."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"e942","DOI":"10.1097\/MD.0000000000000942","article-title":"Tusanqi-related sinusoidal obstruction syndrome in China: A systematic review of the literatures","volume":"94","author":"Wang","year":"2015","journal-title":"Medicine"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3753","DOI":"10.3748\/wjg.v25.i28.3753","article-title":"Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: Pathogenesis, clinical manifestations, diagnosis, treatment, and outcomes","volume":"25","author":"Yang","year":"2019","journal-title":"World J. Gastroent."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3560812","DOI":"10.1155\/2016\/3560812","article-title":"Systematic review on Chinese herbal medicine induced liver injury","volume":"2016","author":"Zhang","year":"2016","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1080\/17474124.2018.1427581","article-title":"Clinical characteristics and outcomes of traditional Chinese medicine-induced liver injury: A systematic review","volume":"12","author":"Wang","year":"2018","journal-title":"Exp. Rev. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Quan, N.V., Xuan, T.D., and Teschke, R. (2020). Potential hepatotoxins found in herbal medicinal products: A systematic review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145011"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"200","DOI":"10.14218\/JCTH.2020.00009","article-title":"Herb induced liver injury (HILI) in the Asian region and current role of RUCAM for causality assessment in 11,160 published cases: Analysis and outlook","volume":"8","author":"Teschke","year":"2020","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"57","DOI":"10.14218\/JCTH.2017.00033","article-title":"Traditional Chinese medicine (TCM) and herb induced liver injury: Comparison with drug induced liver injury","volume":"6","author":"Jing","year":"2018","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Jiang, Y., Zhang, T., Kusumanchi, P., Han, S., Yang, Z., and Liangpunsakul, S. (2020). Alcohol metabolizing enzymes, microsomal. ethanol oxidizing system, cytochrome P450 2E1, catalase, and aldehyde dehydrogenase in alcohol-associated liver disease. Biomedicines, 8.","DOI":"10.3390\/biomedicines8030050"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2018). Alcoholic liver disease: Alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines, 6.","DOI":"10.3390\/biomedicines6040106"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Teschke, R. (2019). Alcoholic liver disease: Current mechanistic aspects with focus on their clinical relevance. Biomedicines, 7.","DOI":"10.3390\/biomedicines7030068"},{"key":"ref_15","first-page":"5","article-title":"The mechanism of dysbiosis in alcoholic liver disease leading to liver cancer","volume":"6","author":"Abenavoli","year":"2020","journal-title":"Hepatoma Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"842","DOI":"10.3389\/fphar.2020.00842","article-title":"Knowledge mapping of drug-induced liver injury: A scientometric investigation (2010\u20132019)","volume":"11","author":"Ke","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_17","first-page":"1","article-title":"Selected highlights and controversies of drug-induced liver injury from the recent literature","volume":"1","author":"Rosenberg","year":"2020","journal-title":"World J. Gastroenterol. Hepatol. Endosc. Res."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2021). Idiosyncratic drug induced liver injury, cytochrome P450, metabolic risk factors, and lipophilicity: Highlights and controversies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073441"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2021). Idiosyncratic drug-induced liver injury (DILI) and herb-induced liver injury (HILI): Diagnostic algorithm based on the quantitative Roussel Uclaf Causality Assessment Method (RUCAM). Diagnostics, 11.","DOI":"10.3390\/diagnostics11030458"},{"key":"ref_20","first-page":"350","article-title":"Aliphatic halogenated hydrocarbons: Liver injury in 60 patients","volume":"28","author":"Teschke","year":"2018","journal-title":"J. Clin. Translat. Hepatol."},{"key":"ref_21","unstructured":"BfR. Federal institute for Risk Assessment (Bundesinstitut f\u00fcr Risikobewertung, BfR in short) (2021, July 08). Pyrrolizidinalkaloid: Gehalte in Lebensmitteln Sollen Nach Wie VOR so weit Wie M\u00f6glich Gesenkt Werden. Available online: https:\/\/www.bfr.bund.de\/cm\/343\/pyrrolizidinalkaloide-gehalte-in-lebensmitteln-sollen-nach-wie-vor-so-weit-wie-moeglich-gesenkt-werden.pdf."},{"key":"ref_22","unstructured":"EMA (European Medicines Agency) (2020, July 08). Public Statement on the Use of Herbal Medicinal Products Containing Toxic, Unsaturated Pyrrolizidine Alkaloids (PAs) Including Recommendations Regarding Contamination of Herbal Medicinal Products with Pyrrolizidine Alkaloids. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/public-statement\/public-statement-use-herbal-medicinal-products-containing-toxic-unsaturated-pyrrolizidine-alkaloids_en.pdf."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"EFSA (European Food Safety Authority) Panel on Contaminants in the Food Chain (CONTAM), Knutsen, H.K., Alexander, J., Barreg\u00e5rd, L., Bignami, M., Br\u00fcschweiler, B., Ceccatelli, S., Cottrill, B., Dinovi, M., and Edler, L. (2017). Risks for human health related to the presence of pyrrolizidine alkaloids in honey, tea, herbal infusions and food supplements. EFSA J., 15, e04908.","DOI":"10.2903\/j.efsa.2017.4908"},{"key":"ref_24","unstructured":"EU (2021, July 08). Commission Regulation (EU) 2020\/2040 of 11 December 2020 Amending Regulation (EC) No 1881\/2006 as Regards Maximum Levels of Pyrrolizidine Alkaloids in Certain Foodstuffs (Text with EEA Relevance), ELI. Available online: https:\/\/eur-lex.europa.eu\/legal-content\/EN\/TXT\/?uri=CELEX:32020R2040."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Martins, C.H.Z., Cunha, B.P., Solferini, V.N., and Trigo, J.R. (2015). Feeding on host plants with different concentrations and structures of pyrrolizidine alkaloids impacts the chemical-defense effectiveness of a specialist herbivore. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141480"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1259510","DOI":"10.1155\/2017\/1259510","article-title":"Honey, propolis, and royal jelly: A comprehensive review of their biological actions and health benefits","volume":"2017","author":"Pasupuleti","year":"2017","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1051\/apido\/2010016","article-title":"Propolis and bee health: The natural history and significance of resin use by honey bees","volume":"41","author":"Spivak","year":"2010","journal-title":"Apidologie"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1007\/s12161-017-1115-8","article-title":"Determination of pyrrolizidine alkaloids in honey with sensitive gas chromatography-mass spectrometry method","volume":"11","author":"Kowalczyk","year":"2018","journal-title":"Food Anal. Meth."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1080\/19440049.2010.541594","article-title":"Pyrrolizidine alkaloids in honey and bee pollen","volume":"28","author":"Beckh","year":"2011","journal-title":"Food Addit. Contam."},{"key":"ref_30","first-page":"300","article-title":"Pyrrolizidine alkaloids in floral honey of tropical Ghana: A health risk assessment","volume":"10","author":"Letsyo","year":"2017","journal-title":"Food Addit. Contam."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gottschalk, C., Kaltner, F., Zimmermann, M., Korten, R., Morris, O., Schwaiger, K., and Gareis, M. (2020). Spread of Jacobaea vulgaris and occurrence of pyrrolizidine alkaloids in regionally produced honeys from Northern Germany: Inter- and intra-site variations and risk assessment for special consumer groups. Toxins, 12.","DOI":"10.3390\/toxins12070441"},{"key":"ref_32","unstructured":"CBI (Centre for the Promotion of Imports) (2021, July 23). What is the Demand for Honey in Europe?. Available online: https:\/\/www.cbi.eu\/market-information\/honey-sweeteners\/trade-statistics."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2471","DOI":"10.1007\/s00217-020-03590-0","article-title":"Discriminant analysis of pyrrolizidine alkaloid contamination in bee pollen based on near-infrared data from lab-stationary and portable spectrometers","volume":"246","author":"Lanza","year":"2020","journal-title":"Eur. Food Res. Technol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1080\/19440049.2017.1382726","article-title":"Occurrence of pyrrolizidine alkaloids in animal- and plant-derived food: Results of a survey across Europe","volume":"35","author":"Mulder","year":"2018","journal-title":"Food Addit. Contam. Part A Chem. Anal. Control Expo Risk Assess."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"128384","DOI":"10.1016\/j.foodchem.2020.128384","article-title":"Pyrrolizidine alkaloids and beehive products: A review","volume":"342","author":"Brugnerotto","year":"2021","journal-title":"Food Chem."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kast, C., Kilchenmann, V., Reinhard, H., Bieri, K., and Zoller, O. (2019). Pyrrolizidine alkaloids: The botanical origin of pollen collected during the flowering period of Echium vulgare and the stability of pyrrolizidine alkaloids in bee bread. Molecules, 24.","DOI":"10.3390\/molecules24122214"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Schramm, S., K\u00f6hler, N., and Rozhon, W. (2019). Pyrrolizidine alkaloids: Biosynthesis, biological activities and occurrence in crop plants. Molecules, 24.","DOI":"10.3390\/molecules24030498"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s10886-018-0990-9","article-title":"Specific Distribution of pyrrolizidine alkaloids in floral parts of Comfrey (Symphytum officinale) and its implications for flower ecology","volume":"45","author":"Stegemann","year":"2019","journal-title":"J. Chem. Ecology"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Flade, J., Beschow, H., Wensch-Dorendorf, M., Plescher, A., and W\u00e4tjen, W. (2019). Occurrence of nine pyrrolizidine alkaloids in Senecio vulgaris L. depending on developmental stage and season. Plants, 8.","DOI":"10.3390\/plants8030054"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"EFSA (European Food Safety Authority) Panel on Contaminants in the Food Chain (CONTAM) (2011). Scientific Opinion on pyrrolizidine alkaloids in food and feed. EFSA J., 9, 2406. Available online: https:\/\/efsa.onlinelibrary.wiley.","DOI":"10.2903\/j.efsa.2011.2406"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.fct.2019.05.024","article-title":"Risk assessment of intake of pyrrolizidine alkaloids from herbal teas and medicines following realistic exposure scenarios","volume":"130","author":"Chen","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_42","first-page":"1","article-title":"Suspected herb induced liver injury by green tea extracts: Critical review and case analysis applying RUCAM for causality assessment","volume":"1","author":"Teschke","year":"2019","journal-title":"Jap. J. Gastroenterol. Hepatol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1080\/19440049.2020.1798028","article-title":"Transfer of pyrrolizidine alkaloids from ragwort, common groundsel and viper\u2019s bugloss to milk from dairy cows","volume":"37","author":"Mulder","year":"2020","journal-title":"Food Addit. Contam. Part A Chem. Anal. Control Expo Risk Assess."},{"key":"ref_44","unstructured":"Casas\u00fas, I., and Lombardi, G. (2016). Targeted and untargeted alkaloid characterisation of pasture herbs and milk from eastern Italian Alps using high resolution mass spectrometry. Mountain Pastures and Livestock Farming Facing Uncertainty: Environmental, Technical and Socio-Economic Challenges, Proceedings of the 19th Meeting of the FAO-CIHEAM Mountain Pastures Subnetwork, Zaragoza, Spain, 14\u201316 June 2016, CIHEAM. Available online: http:\/\/om.ciheam.org\/om\/pdf\/a116\/00007449.pdf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2212","DOI":"10.1080\/19440049.2017.1364432","article-title":"Fate of pyrrolizidine alkaloids during processing of milk of cows treated with ragwort","volume":"34","author":"Mulder","year":"2017","journal-title":"Food Addit. Contam. Part A"},{"key":"ref_46","unstructured":"Msomi, N.Z., and Simelane, M.B.C. (2019). Herbal Medicine, InTech."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"112","DOI":"10.7326\/M16-2977","article-title":"CONSORT Extension for Chinese Herbal Medicine Formulas 2017: Recommendations, Explanation, and Elaboration","volume":"167","author":"Cheng","year":"2017","journal-title":"Ann. Intern. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.4254\/wjh.v9.i29.1141","article-title":"Herbal Traditional Chinese Medicine and suspected liver injury: A prospective study","volume":"18","author":"Melchart","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_49","first-page":"83","article-title":"Medicinal plants in Europe containing pyrrolizidine alkaloids","volume":"50","author":"Roeder","year":"1995","journal-title":"Pharmazie"},{"key":"ref_50","first-page":"357","article-title":"Pyrrolizidine alkaloids in medicinal plants from North America","volume":"6","author":"Roeder","year":"2015","journal-title":"Pharmazie"},{"key":"ref_51","first-page":"711","article-title":"Medicinal plants in China containing pyrrolizidine alkaloids","volume":"55","author":"Roeder","year":"2000","journal-title":"Pharmazie"},{"key":"ref_52","first-page":"699","article-title":"Pyrrolizidine alkaloids in medicinal plants of Mongolia, Nepal and Tibet","volume":"64","author":"Roeder","year":"2009","journal-title":"Pharmazie"},{"key":"ref_53","first-page":"83","article-title":"Plants containing pyrrolizidine alkaloids used in the traditional Indian medicine-including ayurveda","volume":"68","author":"Roeder","year":"2013","journal-title":"Pharmazie"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/0378-8741(81)90033-7","article-title":"Studies on medicinal plants of Sri Lanka: Occurrence of pyrrolizidine alkaloids and hepatotoxic properties in some traditional medicinal herbs","volume":"4","author":"Arseculeratne","year":"1981","journal-title":"J. Ethnopharmacol."},{"key":"ref_55","first-page":"109","article-title":"Qualitative and quantitative study of pyrrolizidine alkaloids in medicinal plants sold in herb shops","volume":"30","author":"Ebrahimi","year":"2020","journal-title":"J. Maz. Univ. Med. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Kopp, T., Abdel-Tawab, M., and Mizaikoff, B. (2020). Extracting and analyzing pyrrolizidine alkaloids in medicinal plants: A review. Toxins, 12.","DOI":"10.3390\/toxins12050320"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1016\/S0305-1978(98)00028-3","article-title":"Pyrrolizidine alkaloids in members of the Boraginaceae from Sinai (Egypt)","volume":"26","author":"Witte","year":"1998","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/S0031-9422(00)85007-4","article-title":"Pyrrolizidine alkaloids from Alkanna tinctoria","volume":"23","author":"Roeder","year":"1984","journal-title":"Phytochemistry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/bms.1200170210","article-title":"Detection of Curassavine and some related pyrrolizidine alkaloids in an Anchusa officinalis strain by means of positive ion and negative ion chemical ionization GC\/MS","volume":"17","author":"Hendriks","year":"1988","journal-title":"Biol. Mass Spectrom."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1021\/np50034a045","article-title":"Unsaturated pyrrolizidines from borage (Borago officinalis), a common garden herb","volume":"47","author":"Larson","year":"1984","journal-title":"J. Nat. Prod."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1021\/np50046a045","article-title":"Pyrrolizidine alkaloids from Borage (Borago officinalis) Seeds and Flowers","volume":"49","author":"Dodson","year":"1986","journal-title":"J. Nat. Prod."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0031-9422(02)00069-9","article-title":"Thesinine-4\u2032-O-\u03b2-D-glucoside the first glycosylated plant pyrrolizidine alkaloid from Borago officinalis","volume":"60","author":"Herrmann","year":"2002","journal-title":"Phytochemistry"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1016\/j.bse.2007.05.003","article-title":"Pyrrolizidine alkaloids in the antipodean genus Brachyglottis (Asteraceae)","volume":"35","author":"Benn","year":"2007","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_64","first-page":"34","article-title":"The alkaloids of Brachyglottis hectorii","volume":"3","author":"Bai","year":"2006","journal-title":"Arkat USA"},{"key":"ref_65","first-page":"467","article-title":"Pyrrolizidine alkaloid profiles of the Senecio cineraria group (Asteraceae)","volume":"62","author":"Tundis","year":"2007","journal-title":"Z. Nat. Sect. C J. Biosci."},{"key":"ref_66","first-page":"429","article-title":"Pyrrolizidine alkaloid profiles of some Senecio species from Egypt","volume":"57","year":"2002","journal-title":"Z. Nat. Sect. C J. Biosci."},{"key":"ref_67","first-page":"559","article-title":"Pyrrolizidine alkaloid level in Senecio bicolor (Willd.) Tod, ssp. cineraria (DC.) from Middle Europe","volume":"61","author":"Wiedenfeld","year":"2006","journal-title":"Pharmazie"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.bse.2004.03.004","article-title":"Pattern of pyrrolizidine alkaloids in 12 Ethiopian Crotalaria species","volume":"32","author":"Asres","year":"2004","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/0305-1978(96)00035-X","article-title":"Pyrrolizidine alkaloids of Cynoglossum officinale and Cynoglossum amabile (Family Boraginaceae)","volume":"24","author":"Sarg","year":"1996","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1016\/S0031-9422(00)84662-2","article-title":"Lindelofine and supinine: Pyrrolizidine alkaloids from Eupatorium stoechadosmum","volume":"12","author":"Furuya","year":"1973","journal-title":"Phytochemistry"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1142\/S0192415X92000291","article-title":"Pyrrolizidine alkaloid composition of three Chinese medicinal herbs, Eupatorium cannabinum, E. japonicum and Crotalaria assamica","volume":"20","author":"Edgar","year":"1992","journal-title":"Am. J. Chin. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2086","DOI":"10.1016\/0031-9422(75)83136-0","article-title":"Echinatine and supinine: Pyrrolizidine alkaloids from Eupatorium cannabinum","volume":"14","author":"Pedersen","year":"1975","journal-title":"Phytochemistry"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1007\/BF02074855","article-title":"Pyrrolizidine alkaloids, flavonoids and volatile compounds in the genus Eupatorium\u2014Eupatorium cannabinum L., an ancient drug with new perspectives","volume":"5","author":"Hendriks","year":"1983","journal-title":"Pharm. Weekbl. Sci. Ed."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1002\/pca.2775","article-title":"Potentially toxic pyrrolizidine alkaloids in Eupatorium perfoliatum and three related species. Implications for herbal use as boneset","volume":"29","author":"Colegate","year":"2018","journal-title":"Phytochem. Anal."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1080\/19440049.2017.1378443","article-title":"Chemical fingerprinting identifies Echium vulgare, Eupatorium cannabinum and Senecio spp. as plant species mainly responsible for pyrrolizidine alkaloids in bee-collected pollen","volume":"35","author":"Kast","year":"2018","journal-title":"Food Addit. Contam. Part A Chem. Anal. Control Expo. Risk Assess."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0305-1978(00)00037-5","article-title":"Non-toxic pyrolizidine alkaloids from Eupatorium semialatum","volume":"29","author":"Lang","year":"2001","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1016\/j.phymed.2015.03.020","article-title":"Detection of pyrrolizidine alkaloids in German licensed herbal medicinal teas","volume":"22","author":"Schulz","year":"2015","journal-title":"Phytomedicine"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1021\/np980175a","article-title":"Pyrrolizidine alkaloids from Heliotropium megalanthum","volume":"61","author":"Reina","year":"1998","journal-title":"J. Nat. Prod."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1016\/0031-9422(91)84238-N","article-title":"Pyrrolizidine alkaloids of Heliotropium spathulatum","volume":"30","author":"Roeder","year":"1991","journal-title":"Phytochemistry"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1016\/0031-9422(90)89080-S","article-title":"Iso-lycopsamine, a pyrrolizidine alkaloid from Heliotropium keralense","volume":"29","author":"Ravi","year":"1990","journal-title":"Phytochemistry"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1016\/S0031-9422(82)85059-0","article-title":"Minor alkaloids of Heliotropium curassavicum","volume":"21","author":"Mohanraj","year":"1982","journal-title":"Phytochemistry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1055\/s-2000-8659","article-title":"New pyrrolizidine alkaloids from Heliotropium crassifolium","volume":"66","author":"Farsam","year":"2000","journal-title":"Planta Med."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1055\/s-2006-957984","article-title":"Pyrrolizidine alkaloids from Heliotropium esfandiarii","volume":"62","author":"Yassa","year":"1996","journal-title":"Planta Med."},{"key":"ref_84","first-page":"168","article-title":"Pyrrolizidine alkaloids from Heliotropium dissitiflorum Boiss","volume":"10","author":"Shafiee","year":"2002","journal-title":"Daru"},{"key":"ref_85","first-page":"374","article-title":"Pyrrolizidine alkaloids of Heliotropium bacciferum Forssk from Egypt","volume":"34","author":"Farrag","year":"1996","journal-title":"Int. J. Pharm."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1021\/np50006a005","article-title":"Pyrrolizidine alkaloids from Middle Eastern plants","volume":"42","author":"Zalkow","year":"1979","journal-title":"J. Nat. Prod."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0031-9422(00)97047-X","article-title":"Helibractinecine, a pyrrolizidine alkaloid from Heliotropium bracteatum","volume":"36","author":"Lakshmanan","year":"1994","journal-title":"Phytochemistry"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1016\/0031-9422(81)84051-4","article-title":"Helifoline, a pyrrolizidine alkaloid from Heliotropium ovalifolium","volume":"20","author":"Mohanraj","year":"1981","journal-title":"Phytochemistry"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/0031-9422(94)00937-O","article-title":"Heliscabine, a pyrrolizidine ester alkaloid from Heliotropium scabrum","volume":"39","author":"Lakshmanan","year":"1995","journal-title":"Phytochemistry"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/0031-9422(94)85040-2","article-title":"Pyrrolizidine alkaloids from Lithospermum officinale","volume":"37","author":"Krenn","year":"1994","journal-title":"Phytochemistry"},{"key":"ref_91","first-page":"173","article-title":"Pyrrolizidine alkaloids from Lithospermum canescens Lehm","volume":"58","author":"Wiedenfeld","year":"2003","journal-title":"Z. Nat. Sect. C J. Biosci."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1007\/s00299-006-0161-2","article-title":"The shikonin derivatives and pyrrolizidine alkaloids in hairy root cultures of Lithospermum canescens (Michx.) Lehm","volume":"25","author":"Pietrosiuk","year":"2006","journal-title":"Plant Cell Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/0031-9422(90)85153-7","article-title":"Pyrrolizidine alkaloids from Lithospermum Erythrorhizon","volume":"29","author":"Roeder","year":"1990","journal-title":"Phytochemistry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/S0021-9673(01)01498-4","article-title":"Simultaneous determination of N-oxides and free bases of pyrrolizidine alkaloids by cation-exchange solid-phase extraction and ion-pair high-performance liquid chromatography","volume":"949","author":"Mroczek","year":"2002","journal-title":"J. Chromatogr. A"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/S0021-9673(01)88166-8","article-title":"Separation and determination of macrocyclic pyrrolizidine alkaloids of the otonecine type present in the edible plant Petasites japonicus by reversed-phase high-performance liquid chromatography","volume":"257","author":"Niwa","year":"1983","journal-title":"J. Chromatogr. A"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/S0305-1978(99)00077-0","article-title":"Variability in chemical constituents in Petasites hybridus from Austria","volume":"28","author":"Chizzola","year":"2000","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1080\/01483917908060073","article-title":"Reverse phase isolation of pyrrolizidine alkaloids","volume":"2","author":"Segall","year":"1979","journal-title":"J. Liq. Chromatogr."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.jpba.2011.05.004","article-title":"Authentication of Senecio scandens and S. vulgaris based on the comprehensive secondary metabolic patterns gained by UPLC-DAD\/ESI-MS","volume":"56","author":"Yang","year":"2011","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/S0031-9422(00)97815-4","article-title":"Pyrrolizidine alkaloid patterns in populations of Senecio vulgaris, S. vernalis and their hybrids","volume":"28","author":"Borstel","year":"1989","journal-title":"Phytochemistry"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/0031-9422(92)90038-R","article-title":"Chemotypes of two pyrrolizidine alkaloid-containing Senecio species","volume":"31","author":"Witte","year":"1992","journal-title":"Phytochemistry"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/pca.715","article-title":"Evaporative light scattering detection of pyrrolizidine alkaloids","volume":"15","author":"Schaneberg","year":"2004","journal-title":"Phytochem. Anal."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.aca.2010.09.011","article-title":"A new approach for simultaneous screening and quantification of toxic pyrrolizidine alkaloids in some potential pyrrolizidine alkaloid-containing plants by using ultra performance liquid chromatography-tandem quadrupole mass spectrometry","volume":"681","author":"Zhou","year":"2010","journal-title":"Anal. Chim. Acta"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e3686","DOI":"10.7717\/peerj.3686","article-title":"Pyrrolizidine alkaloid variation in Senecio vulgaris populations from native and invasive ranges","volume":"5","author":"Cheng","year":"2017","journal-title":"PeerJ"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/j.phytochem.2005.04.015","article-title":"Frequent gain and loss of pyrrolizidine alkaloids in the evolution of Senecio section Jacobaea (Asteraceae)","volume":"66","author":"Pelser","year":"2005","journal-title":"Phytochemistry"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1021\/np50076a003","article-title":"Off-Line supercritical fluid extraction and capillary gas chromatography of pyrrolidine alkaloids in Senecio species","volume":"54","author":"Bicchi","year":"1991","journal-title":"J. Nat. Prod."},{"key":"ref_106","first-page":"300","article-title":"Alkaloid profile of Bulgarian species from genus Senecio L.","volume":"58","author":"Christov","year":"2003","journal-title":"Z. Nat. Sect. C J. Biosci."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1021\/np50075a004","article-title":"Gc-Ms determination of pyrrolizidine alkaloids in four senecio species","volume":"54","author":"Steixjes","year":"1991","journal-title":"J. Nat. Prod."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"27","DOI":"10.2298\/JSC0901027M","article-title":"Pyrrolizidine alkaloids from seven wild-growing Senecio species in Serbia and Montenegro","volume":"74","author":"Mandic","year":"2009","journal-title":"J. Serb. Chem. Soc."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1016\/S0305-1978(02)00031-5","article-title":"Pyrrolizidine alkaloids from three Spanish Senecio species","volume":"30","author":"Suau","year":"2002","journal-title":"Biochem. Syst. Ecol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/S0031-9422(00)81085-7","article-title":"Uspallatine, a pyrrolizidine alkaloid from senecio uspallatensis","volume":"24","author":"Pestchanker","year":"1985","journal-title":"Phytochemistry"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1016\/0031-9422(93)85187-V","article-title":"The pyrrolizidine alkaloids of Senecio syringifolius and S. hadiensis from Kenya","volume":"32","author":"Were","year":"1993","journal-title":"Phytochemistry"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"4132","DOI":"10.1021\/jo01059a003","article-title":"Angularine, a New Pyrrolizidine alkaloid from Senecio angulatus L.","volume":"27","author":"Porter","year":"1962","journal-title":"J. Org. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1016\/0031-9422(92)83504-R","article-title":"Ruwenine and ruzorine: Pyrrolizidine alkaloids of Senecio ruwenzoriensis","volume":"31","author":"Benn","year":"1992","journal-title":"Phytochemistry"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4000","DOI":"10.1016\/0031-9422(88)83074-7","article-title":"Doriasenine, a pyrrolizidine alkaloid from Senecio doria","volume":"27","author":"Wiedenfeld","year":"1988","journal-title":"Phytochemistry"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"5721","DOI":"10.1016\/S0040-4039(01)80930-8","article-title":"A new pyrrolizidine alkaloid N-oxide and the revised structure of sceleratine","volume":"26","author":"Bredenkamp","year":"1985","journal-title":"Tetrahedron Lett."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"2217","DOI":"10.1016\/S0031-9422(00)97225-X","article-title":"Alkaloids and triterpenoids of Symphytum officinale","volume":"10","author":"Furuya","year":"1971","journal-title":"Phytochemistry"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1021\/np0004653","article-title":"Isolation of symlandine from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography","volume":"64","author":"Kim","year":"2001","journal-title":"J. Nat. Prod."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/19960404NT3","article-title":"Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale)","volume":"4","author":"Couet","year":"1996","journal-title":"Nat. Toxins"},{"key":"ref_119","first-page":"945","article-title":"Application of Gas-Chromatography Matrix-Isolation Fourier-Transform Infrared-Spectroscopy to the Identification of Pyrrolizidine Alkaloids from Comfrey Root (Symphytum-officinale L.)","volume":"60","author":"Mossoba","year":"1994","journal-title":"J. Aoac Int."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"289","DOI":"10.5586\/asbp.2013.028","article-title":"Content of pyrrolizidine alkaloids in the leaves of coltsfoot (Tussilago farfara L.) in Poland","volume":"82","author":"Adamczak","year":"2013","journal-title":"Acta Soc. Bot. Pol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1080\/13102818.2015.1047149","article-title":"Pyrrolizidine alkaloids in Tussilago farfara from Bulgaria","volume":"29","author":"Nedelcheva","year":"2015","journal-title":"Biotechnol. Biotechnol. Equip."},{"key":"ref_122","first-page":"85","article-title":"Efficient extraction of pyrrolizidine alkaloids from plants by pressurised liquid extraction\u2014A preliminary study","volume":"86","author":"Kopp","year":"2019","journal-title":"Planta Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1007\/s10337-019-03785-y","article-title":"Determination and chemical profiling of toxic pyrrolizidine alkaloids in botanical samples with UPLC\u2013Q-TOFMS","volume":"82","author":"Jeong","year":"2019","journal-title":"Chromatographia"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"7233","DOI":"10.1007\/s00216-019-02117-1","article-title":"Development of a sensitive analytical method for determining 44 pyrrolizidine alkaloids in teas and herbal teas via LC-ESI-MS\/MS","volume":"411","author":"Kaltner","year":"2019","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"7155","DOI":"10.1007\/s00216-020-02848-6","article-title":"Development of a new LC-MS method for accurate and sensitive determination of 33 pyrrolizidine and 21 tropane alkaloids in plant-based food matrices","volume":"412","author":"Dzuman","year":"2020","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1080\/19440049.2021.1902575","article-title":"High resolution mass spectrometry workflow for the analysis of food contaminants: Application to plant toxins, mycotoxins and phytoestrogens in plant-based ingredients","volume":"38","author":"Bessaire","year":"2021","journal-title":"Food Addit. Contam. Part A"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1080\/19440049.2010.541288","article-title":"Plants containing pyrrolizidine alkaloids\u2014Toxicity and problems","volume":"28","author":"Wiedenfeld","year":"2011","journal-title":"Food Addit. Contamin. Part A"},{"key":"ref_128","first-page":"1","article-title":"An epidemiological study into the investigation of liver disease of unknown origin in a rural community of northern Ethiopia","volume":"50","author":"Mesfin","year":"2012","journal-title":"Ethiop. Med. J."},{"key":"ref_129","first-page":"9","article-title":"An outbreak of veno-occlusive liver disease in northern Ethiopia, clinical findings","volume":"50","author":"Bane","year":"2012","journal-title":"Ethiop. Med. J."},{"key":"ref_130","first-page":"17","article-title":"An outbreak of liver disease in Tahtay Koraro Woreda, Tigray region of Ethiopia: A case-control study for the identification of the etiologic agent","volume":"50","author":"Abebe","year":"2012","journal-title":"Ethiop. Med. J."},{"key":"ref_131","first-page":"27","article-title":"Toxicity study and evaluation of biochemical markers towards the identification of the causative agent for an outbreak of liver disease in Tahtay Koraro Woreda, Tigray","volume":"50","author":"Debella","year":"2012","journal-title":"Ethiop. Med. J."},{"key":"ref_132","first-page":"37","article-title":"Physico-chemical investigation of consumables and environmental samples to determine the causative agent of liver disease outbreak in Tahitay Koraro Woreda, Tiray","volume":"50","author":"Debella","year":"2012","journal-title":"Ethiop. Med. J."},{"key":"ref_133","first-page":"47","article-title":"Veno-occlusive liver disease: A case report","volume":"50","author":"Schneider","year":"2012","journal-title":"Ethiop Med. J."},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.jhep.2013.07.039","article-title":"Hirmi Valley liver disease: A disease associated with exposure to pyrrolizidine alkaloids and DDT","volume":"60","author":"Robinson","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_135","first-page":"27","article-title":"Surveillance of a chronic liver disease of unidentified cause in a rural setting of Ethiopia: A case study","volume":"54","author":"Chiu","year":"2016","journal-title":"Ethiop. Med. J."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"19784","DOI":"10.1038\/s41598-020-76586-1","article-title":"The invasive butterbur contaminates stream and seepage water in groundwater wells with toxic pyrrolizidine alkaloids","volume":"10","author":"Kisielius","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_137","first-page":"215","article-title":"Horizontal natural product transfer: A so far unconsidered source of contamination of plant-derived commodities","volume":"5","author":"Selmar","year":"2015","journal-title":"J. Environ. Anal. Toxicol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.foodchem.2016.06.069","article-title":"Interspecific transfer of pyrrolizidine alkaloids: An unconsidered source of contaminations of phytopharmaceuticals and plant derived commodities","volume":"213","author":"Nowak","year":"2016","journal-title":"Food Chem."},{"key":"ref_139","unstructured":"Merillon, J.M., and Ramawat, K. (2018). Horizontal natural product transfer: A novel attribution in allelopathy. Co-Evolution of Secondary Metabolites, Springer."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1016\/j.envpol.2019.02.026","article-title":"Transfer of pyrrolizidine alkaloids between living plants: A disregarded source of contaminations","volume":"248","author":"Selmar","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"8740","DOI":"10.1021\/acs.jafc.9b03619","article-title":"Horizontal natural product transfer: Intriguing insights into a newly discovered phenomenon","volume":"67","author":"Selmar","year":"2019","journal-title":"J. Agric. Food Chem."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"100234","DOI":"10.1016\/j.rhisph.2020.100234","article-title":"The uptake of alkaloids by plants from the soil is determined by rhizosphere pH","volume":"15","author":"Hijazin","year":"2020","journal-title":"Rhizophere"},{"key":"ref_143","doi-asserted-by":"crossref","unstructured":"Chmit, M.S., Horn, G., D\u00fcbecke, A., and Beuerle, T. (2021). Pyrrolizidine alkaloids in the food chain: Is horizontal transfer of relevance?. Foods, 10.","DOI":"10.3390\/foods10081827"},{"key":"ref_144","doi-asserted-by":"crossref","unstructured":"Vongdala, N., Tran, H.D., Xuan, T.D., Teschke, R., and Khanh, T.D. (2019). Heavy metal accumulation in water, soil, and plants of municipal solid waste landfill in Vientiane, Laos. Int. J. Environ. Res. Public Health, 16.","DOI":"10.3390\/ijerph16010022"},{"key":"ref_145","first-page":"120","article-title":"Liver injury from herbs and \u201cdietary supplements\u201d: Highlights of a literature review from 2015 to Curr","volume":"4","author":"Teschke","year":"2018","journal-title":"Pharmacol. Rep."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s12664-017-0815-8","article-title":"Clinical outcomes, histopathological patterns, and chemical analysis of Ayurveda and herbal medicine associated with severe liver injury\u2014A single-center experience from southern India","volume":"37","author":"Philips","year":"2018","journal-title":"Indian J. Gastroenterol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s40801-017-0118-5","article-title":"Use and safety of anthroposophic medicinal products: An analysis of 44,662 patients from the EvaMed pharmacovigilance network","volume":"4","author":"Hamre","year":"2017","journal-title":"Drugs Real World Outcomes"},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Jong, M.C., van Wietmarschen, H., Glockmann, A., Baars, E.W., and Hamre, H.J. (2021). Safety of anthroposophic medicinal products: An analysis of adverse drug reactions from German pharmacovigilance databases. Drugs Real World Outcomes, in press.","DOI":"10.1007\/s40801-021-00262-7"},{"key":"ref_149","unstructured":"United States Pharmacopeia (USP) (2021, June 15). USP: 2021 USP Open Forum: Pyrrolizidine Alkaloid Contaminants. Last updated on 9 January 2021. Available online: https:\/\/www.usp.org\/get-involved\/provide-input\/stakeholder-forums\/2021-pyrrolizidine-alkaloid-contaminants."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"02014","DOI":"10.1051\/e3sconf\/202125402014","article-title":"Accumulation of alkaloids in plants of the family Boraginaceae depending on environmental conditions places of growth","volume":"254","author":"Akhkubekova","year":"2021","journal-title":"E3S Web Conf."},{"key":"ref_151","doi-asserted-by":"crossref","unstructured":"Quy, T.N., Xuan, T.D., Andriana, Y., Tran, H.D., Khanh, T.D., and Teschke, R. (2019). Cordycepin Isolated from Cordyceps militaris: Its newly discovered herbicidal property and potential plant-based novel alternative to Glyphosate. Molecules, 24.","DOI":"10.3390\/molecules24162901"},{"key":"ref_152","doi-asserted-by":"crossref","unstructured":"Moreira, R., Pereira, D.M., Valent\u00e3o, P., and Andrade, P.B. (2018). Pyrrolizidine alkaloids: Chemistry, pharmacology, toxicology and food safety. Int. J. Mol.Sci., 19.","DOI":"10.3390\/ijms19061668"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1007\/s10886-018-1005-6","article-title":"Quinolizidine and pyrrolizidine alkaloid chemical ecology\u2014A mini-review on their similarities and differences","volume":"45","author":"Wink","year":"2019","journal-title":"J. Chem. Ecol."},{"key":"ref_154","doi-asserted-by":"crossref","unstructured":"Jan, R., Asaf, S., Numan, M., and Kim, K.M. (2021). Plant secondary metabolite biosynthesis and transcriptional regulation in response to biotic and abiotic stress conditions. Agronomy, 11.","DOI":"10.3390\/agronomy11050968"},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"8608","DOI":"10.1038\/srep08608","article-title":"Cross-talk between signaling pathways: The link between plant secondary metabolite production and wounding stress response","volume":"5","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s40659-019-0246-3","article-title":"Stress and defense responses in plant secondary metabolites production","volume":"52","author":"Isah","year":"2019","journal-title":"Biol. Res."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s11306-017-1184-0","article-title":"The correlation between leaf-surface and leaf-tissue secondary metabolites: A case study with pyrrolizidine alkaloids in Jacobaea hybrid plants","volume":"13","author":"Cheng","year":"2017","journal-title":"Metabolomics"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1007\/s10886-010-9772-8","article-title":"Species by environment interactions affect pyrrolizidine alkaloid expression in Senecio jacobaea, Senecio aquaticus, and their hybrids","volume":"36","author":"Kirk","year":"2010","journal-title":"J. Chem. Ecol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1104\/pp.17.00265","article-title":"Identification of a second site of pyrrolizidine alkaloid biosynthesis in Comfrey to boost plant defense in floral stage","volume":"174","author":"Kruse","year":"2017","journal-title":"Plant Physiol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s10886-018-1009-2","article-title":"Phytochemical background mediates effects of pyrrolizidine alkaloids on western flower thrips","volume":"45","author":"Liu","year":"2019","journal-title":"J. Chem. Ecol."},{"key":"ref_161","unstructured":"Akhi, M.Z., Haque, M., and Biswas, S. (2021). Role of secondary metabolites to attenuate stress damages in plants. Antioxidants, IntechOpen."},{"key":"ref_162","first-page":"779","article-title":"Editorial: Hormesis and dose-responses in herbal traditional Chinese medicine (TCM) alone are insufficient solving real clinical TCM challenges and associated herbal quality issues","volume":"19","author":"Teschke","year":"2018","journal-title":"Longhua Chin. Med."},{"key":"ref_163","first-page":"3","article-title":"Metabolomic study of diurnal variation on pyrrolizidine alkaloid from Jacobaea sp. hybrids","volume":"4","author":"Nuringtyas","year":"2015","journal-title":"Metabolomics"},{"key":"ref_164","first-page":"1212","article-title":"Seasonal variability in pyrrolizidine alkaloids in Senecio inaequidens from the Val Venosta (Northern Italy)","volume":"150","author":"Eller","year":"2016","journal-title":"Plant Biosyst. Int. J. Deal. All Asp. Plant Biol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"142822","DOI":"10.1016\/j.scitotenv.2020.142822","article-title":"Occurrence of pyrrolizidine alkaloids in ragwort plants, soils and surface waters at the field scale in grassland","volume":"755","author":"Hama","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"1","DOI":"10.12816\/0026941","article-title":"Influencing the contents of secondary metabolites in spice and medicinal plants by deliberately applying drought stress during their cultivation","volume":"8","author":"Selmar","year":"2015","journal-title":"Jordan J. Biol. Sci."},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1002\/ps.5540","article-title":"Production of pyrrolizidine alkaloids and shikonins in Echium plantagineum L. in response to various plant stressors","volume":"75","author":"Skoneczny","year":"2019","journal-title":"Pest Manag. Sci."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s11101-010-9188-7","article-title":"The effect of nutrients on pyrrolizidine alkaloids in Senecio plants and their interactions with herbivores and pathogens","volume":"10","author":"Hol","year":"2011","journal-title":"Phytochem. Rev."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1007\/BF00392159","article-title":"Sites of synthesis, translocation and accumulation of pyrrolizidine alkaloid N-oxides in Senecio vulgaris L.","volume":"177","author":"Hartmann","year":"1989","journal-title":"Planta"},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1055\/a-0998-5125","article-title":"Reduction of pyrrolizidine alkaloid levels in comfrey (Symphytum officinale) hairy roots by RNAi silencing of homospermidine synthase","volume":"85","author":"Kruse","year":"2019","journal-title":"Planta Med."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1007\/s00204-019-02499-2","article-title":"Intestinal and hepatic biotransformation of pyrrolizidine alkaloid N-oxides to toxic pyrrolizidine alkaloids","volume":"93","author":"Yang","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1917","DOI":"10.1007\/s00204-021-03060-w","article-title":"Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids","volume":"95","author":"He","year":"2021","journal-title":"Arch. Toxicol."},{"key":"ref_173","doi-asserted-by":"crossref","unstructured":"Wei, X., Ruan, W., and Vrieling, K. (2021). Current knowledge and perspectives of pyrrolizidine alkaloids in pharmacological applications: A mini-review. Molecules, 26.","DOI":"10.3390\/molecules26071970"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1081\/DMR-120028426","article-title":"Pyrrolizidine alkaloids\u2014Genotoxicity, metabolism enzymes, metabolic activation, and mechanisms","volume":"36","author":"Fu","year":"2004","journal-title":"Drug Metab. Rev."},{"key":"ref_175","first-page":"20180100","article-title":"Secondary metabolites, their structural diversity, bioactivity, and ecological functions: An overview","volume":"4","author":"Abegaz","year":"2019","journal-title":"Phys. Sci. Rev."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.phytol.2014.03.002","article-title":"Distinguishing between toxic and non-toxic pyrrolizidine alkaloids and quantification by liquid chromatography\u2013mass spectrometry","volume":"8","author":"Botha","year":"2014","journal-title":"Phytochem. Lett."},{"key":"ref_177","first-page":"11","article-title":"Opinion: Intestinal microbiome, endotoxins, cytochrome P450 2E1, and the gut-liver axis in alcoholic liver disease","volume":"5","author":"Teschke","year":"2019","journal-title":"EC Gastroenterology Dig. Syst."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1021\/tx500478q","article-title":"In silico prediction of the site of oxidation by cytochrome P450 3A4 that leads to the formation of the toxic metabolites of pyrrolizidine alkaloids","volume":"28","author":"Fashe","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/jbt.20174","article-title":"Mechanisms of cytochrome P450 substrate oxidation: MiniReview","volume":"21","author":"Guengerich","year":"2007","journal-title":"J. Biochem. Molec. Toxicol."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/toxsci\/kfq374","article-title":"Genetic polymorphism and toxicology\u2014with emphasis on cytochrome P450","volume":"120","author":"Johansson","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"837","DOI":"10.3389\/fphar.2019.00837","article-title":"Mechanistic studies of idiosyncratic DILI: Clinical implications","volume":"10","author":"Uetrecht","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"730","DOI":"10.21037\/atm-2020-ubih-05","article-title":"Idiosyncratic drug induced liver injury (DILI): Unresolved basic issues","volume":"9","author":"Teschke","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_183","doi-asserted-by":"crossref","unstructured":"Teschke, R., Eickhoff, A., Brown, A.C., Neuman, M.G., and Schulze, J. (2020). Diagnostic biomarkers in liver injury by drugs, herbs, and alcohol: Tricky dilemma after EMA correctly and officially retracted Letter of Support. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010212"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"93","DOI":"10.12970\/2308-8044.2020.08.12","article-title":"Liver injury by drugs metabolized via cytochrome PJ","volume":"8","author":"Teschke","year":"2020","journal-title":"Mod. Med. Chem."},{"key":"ref_185","doi-asserted-by":"crossref","unstructured":"Falero-Perez, J., Song, Y.-S., Zhao, Y., Teixeira, L., Sorenson, C.M., and Sheibani, N. (2018). Cyp1b1 expression impacts the angiogenic and inflammatory properties of liver sinusoidal endothelial cells. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0206756"},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.jhep.2021.02.028","article-title":"Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease","volume":"75","author":"Yang","year":"2021","journal-title":"J. Hepatol."},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1080\/26896583.2020.1769409","article-title":"Establishment of a novel CYP3A4-transduced human hepatic sinusoidal endothelial cell model and its application in screening hepatotoxicity of pyrrolizidine alkaloids","volume":"38","author":"Lu","year":"2020","journal-title":"J. Environ. Sci. Health Part C"},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1016\/S0021-9258(19)45536-1","article-title":"Reconstituted liver microsomal enzyme system that hydroxylates drugs, other foreign compounds, and endogenous substrates: II Role of the cytochrome P-450 and P-448 fractions in drug and steroid hydroxylations","volume":"247","author":"Lu","year":"1972","journal-title":"J. Biol. Chem."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"7124","DOI":"10.1016\/S0021-9258(19)66943-7","article-title":"Reconstitution of the microsomal ethanol-oxidizing system. Qualitative and quantitative changes of cytochrome P-450 after chronic ethanol consumption","volume":"52","author":"Ohnishi","year":"1977","journal-title":"J. Biol. Chem."},{"key":"ref_190","unstructured":"Ullrich, V., Roots, I., Hildebrandt, A., Estabrook, R.W., and Conney, A.H. (1977). Hepatic microsomal ethanol oxidizing system: Isolation and reconstitution. Microsomes and Drug Oxidations, Pergamon Press."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1074\/jbc.TM118.004144","article-title":"Cytochrome P450 research and The Journal of Biological Chemistry","volume":"294","author":"Guengerich","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_192","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1039\/C5NP00076A","article-title":"Pyrrolizidine alkaloids: Occurence, biology, and chemical synthesis","volume":"34","author":"Robertson","year":"2017","journal-title":"Nat. Prod. Rep."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/s00204-020-02921-0","article-title":"Lung injury induced by pyrrolizidine alkaloids depends on metabolism by hepatic cytochrome P450s and blood transport of reactive metabolites","volume":"95","author":"He","year":"2021","journal-title":"Arch. Toxicol."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1021\/tx500403t","article-title":"Pyrrolizidine alkaloids: Potential role in the etiology of cancers, pulmonary hypertension, congenital anomalies, and liver disease","volume":"28","author":"Edgar","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"1534735419869479","DOI":"10.1177\/1534735419869479","article-title":"Literature review of Traditional Chinese Medicine herbs-induced liver injury from an oncological perspective with RUCAM","volume":"18","author":"Chow","year":"2019","journal-title":"Integr. Cancer Ther."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"51","DOI":"10.21037\/tgh-20-149","article-title":"Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): An overview","volume":"6","author":"Teschke","year":"2021","journal-title":"Transl. Gastroenterol. Hepatol."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"72","DOI":"10.3389\/fphar.2015.00072","article-title":"Herbal hepatotoxicity in traditional and modern medicine: Actual key issues and new encouraging steps","volume":"6","author":"Teschke","year":"2015","journal-title":"Front. Pharmacol."},{"key":"ref_198","doi-asserted-by":"crossref","unstructured":"Frenzel, C., and Teschke, R. (2016). Herbal hepatotoxicity: Clinical characteristics and listing compilation. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050588"},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1055\/s-2002-23204","article-title":"Toxic injury to hepatic sinusoids: Sinusoidal obstruction syndrome (veno-occlusive disease)","volume":"22","author":"DeLeve","year":"2002","journal-title":"Semin. Liver Dis."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1111\/jgh.14612","article-title":"Chinese Society of Gastroenterology Committee of Hepatobiliary Disease. Expert consensus on the clinical management of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome","volume":"34","author":"Zhuge","year":"2019","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_201","doi-asserted-by":"crossref","unstructured":"Danan, G., and Teschke, R. (2016). RUCAM in drug and herb induced liver injury: The update. Int. J. Mol. Sci., 17, In Special Issue \u201cDrug, Herb, and Dietary Supplement Hepatotoxicity\u201d, Teschke, R., Ra\u00fal, J. Andrade.","DOI":"10.3390\/ijms17091488"},{"key":"ref_202","first-page":"345","article-title":"Validation of the Nanjing criteria for diagnosing pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome","volume":"9","author":"Zhang","year":"2021","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1007\/s11655-018-3000-8","article-title":"Guidelines for the Diagnosis and Management of Herb-Induced Liver Injury","volume":"24","author":"Wang","year":"2018","journal-title":"Chin. J. Integr. Med."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/s41401-018-0155-y","article-title":"Gynura rhizoma containing pyrrolizidine alkaloids induces the hepatic sinusoidal obstruction syndrome in mice via upregulating fibrosis-related factors","volume":"40","author":"Zhang","year":"2019","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_205","first-page":"962","article-title":"Research advances in the pathogenesis of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome","volume":"37","author":"Liu","year":"2021","journal-title":"J. Clin. Hepatol."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"111107","DOI":"10.1016\/j.fct.2019.111107","article-title":"Pyrrolizidine alkaloids in food and phytomedicine: Occurrence, exposure, toxicity, mechanisms, and risk assessment\u2014A review","volume":"136","author":"Schrenk","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.1007\/s00204-020-02850-y","article-title":"Hepatotoxicity of pyrrolizidine alkaloids in rats in relation to human exposure","volume":"94","author":"Bolt","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref_208","first-page":"2402","article-title":"Clinical analysis of hepatic veno-occlusive disease induced by Sedum aizoon","volume":"33","author":"Wu","year":"2008","journal-title":"Zhongguo Zhong Yao Za Zhi"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.jhep.2010.07.031","article-title":"Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum","volume":"54","author":"Lin","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_210","first-page":"311","article-title":"Analysis of alkaloids in Sedum aizoon and establishment of hepatic venoocclusive model in mice","volume":"14","author":"Gao","year":"2006","journal-title":"Chin. J. Integr. Trad. West. Elect. Microsc. Med. Digest."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1111\/j.1751-2980.2011.00552.x","article-title":"Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids","volume":"13","author":"Gao","year":"2012","journal-title":"J. Dig. Dis."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/1751-2980.12112","article-title":"Tusanqi and hepatic sinusoidal obstruction syndrome","volume":"15","author":"Wang","year":"2014","journal-title":"J. Dig. Dis."},{"key":"ref_213","first-page":"406","article-title":"Hepatic venoocclusive disease induced by Gynura segetum: Report of two cases","volume":"5","author":"Dai","year":"2006","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_214","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1016\/S0140-6736(83)91112-1","article-title":"Hepatic veno-occlusive disease due to toxic alkaloid in herbal tea","volume":"322","author":"Kumana","year":"1983","journal-title":"Lancet"},{"key":"ref_215","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1136\/gut.26.1.101","article-title":"Herbal tea induced hepatic veno-occlusive disease: Quantification of toxic alkaloid exposure in adults","volume":"26","author":"Kumana","year":"1985","journal-title":"Gut"},{"key":"ref_216","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1016\/S0140-6736(86)91084-6","article-title":"Heliotropium lasiocarpum Fisch and Mey identified as cause of veno-occlusive disease due to herbal tea","volume":"1","author":"Culvenor","year":"1986","journal-title":"Lancet"},{"key":"ref_217","doi-asserted-by":"crossref","first-page":"4861","DOI":"10.2147\/DDDT.S87858","article-title":"Blood pyrrole-protein adducts as a diagnostic and prognostic index in pyrrolizidine alkaloid-hepatic sinusoidal obstruction syndrome","volume":"9","author":"Gao","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_218","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1002\/hep.31723","article-title":"Mutational signature analysis reveals widespread contribution of pyrrolizidine alkaloid exposure to human liver cancer","volume":"74","author":"He","year":"2021","journal-title":"Hepatology"},{"key":"ref_219","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1080\/10590501.2015.1096882","article-title":"Blood pyrrole-protein adductsa\u2014Of pyrrolizidine alkaloid-induced liver injury in humans","volume":"33","author":"Ruan","year":"2015","journal-title":"J. Environ. Sci. Health Part C"},{"key":"ref_220","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1007\/s00204-020-02947-4","article-title":"Clinical application of pyrrole\u2013hemoglobin adducts as a biomarker of pyrrolizidine alkaloid exposure in humans","volume":"95","author":"Ma","year":"2021","journal-title":"Arch. Toxicol."},{"key":"ref_221","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1016\/j.jfda.2018.05.005","article-title":"Pyrrole-protein adducts\u2014A biomarker of pyrrolizidine alkaloid-induced hepatotoxicity","volume":"26","author":"Ma","year":"2018","journal-title":"J. Food Drug Anal."},{"key":"ref_222","doi-asserted-by":"crossref","first-page":"3913","DOI":"10.1007\/s00204-017-2013-y","article-title":"First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans","volume":"91","author":"Yang","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_223","doi-asserted-by":"crossref","first-page":"627126","DOI":"10.3389\/fphar.2021.627126","article-title":"Blood microRNA signatures serve as potential diagnostic biomarkers for hepatic sinusoidal obstruction syndrome caused by Gynura japonica containing pyrrolizidine alkaloids","volume":"12","author":"Wang","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_224","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.toxlet.2020.01.021","article-title":"The long persistence of pyrrolizidine alkaloid-derived pyrrole-protein adducts in vivo: Kinetic study following multiple exposures of a pyrrolizidine alkaloid containing extract of Gynura japonica","volume":"323","author":"Chen","year":"2020","journal-title":"Toxicol. Lett."},{"key":"ref_225","doi-asserted-by":"crossref","unstructured":"Teschke, R., Larrey, D., Melchart, D., and Danan, G. (2016). Traditional Chinese Medicine (TCM) and herbal hepatotoxicity: RUCAM and the role of novel diagnostic biomarkers such as microRNAs. Medicines, 3.","DOI":"10.3390\/medicines3030018"},{"key":"ref_226","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.3389\/fphar.2019.01482","article-title":"DILI: Biomarkers, requirements, candidates and validation","volume":"10","author":"Meunier","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_227","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1021\/acs.chemrestox.8b00369","article-title":"Pyrrole-hemoglobin adducts, a more feasible potential biomarker of pyrrolizidine alkaloid exposure","volume":"32","author":"Ma","year":"2019","journal-title":"Chem. Res. Toxicol."},{"key":"ref_228","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1111\/liv.13684","article-title":"Clinical characteristics and treatment of pyrrolizidine alkaloid-related hepatic vein occlusive disease","volume":"38","author":"Zhuge","year":"2018","journal-title":"Liver Int."},{"key":"ref_229","doi-asserted-by":"crossref","unstructured":"Liu, F., Rong, X., Guo, H., Xu, D., Liu, C., Meng, L., Yang, X., Guo, T., Kan, X., and Song, Y. (2020). Clinical characteristics, CT signs, and pathological findings of pyrrolizidine alkaloids-induced sinusoidal obstructive syndrome: A retrospective study. BMC Gastroenterol., 20.","DOI":"10.1186\/s12876-020-1180-0"},{"key":"ref_230","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1038\/s41598-019-38669-6","article-title":"Quantitative analysis of CT images in patients with pyrrolizidine alkaloid-induced sinusoidal obstruction syndrome","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_231","doi-asserted-by":"crossref","unstructured":"Teschke, R., and Danan, G. (2020). Worldwide use of RUCAM for causality assessment in 81,856 DILI and 14,029 HILI cases published 1993\u2014Mid 2020: A comprehensive analysis. Medicines, 7.","DOI":"10.3390\/medicines7100062"},{"key":"ref_232","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1002\/hep.510290615","article-title":"Characterization of a reproducible rat model of hepatic veno-occlusive disease","volume":"29","author":"DeLeve","year":"1999","journal-title":"Hepatology"},{"key":"ref_233","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.jceh.2018.07.002","article-title":"Critical analysis of experimental animal models of sinusoidal obstruction syndrome","volume":"9","author":"Kumar","year":"2019","journal-title":"J. Clin. Exp. Hepatol."},{"key":"ref_234","first-page":"507","article-title":"Acute veno-occlusive disease of the liver: Fine structure in Jamaican children","volume":"89","author":"Brooks","year":"1970","journal-title":"Arch. Pathol."},{"key":"ref_235","doi-asserted-by":"crossref","first-page":"1323","DOI":"10.1016\/0895-4356(93)90101-6","article-title":"Causality assessment of adverse reactions to drugs\u2014I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries","volume":"46","author":"Danan","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_236","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/0895-4356(93)90102-7","article-title":"Causality assessment of adverse reactions of drugs\u2014II. An original model for validation of drug causality assessment methods: Case reports with positive rechallenge","volume":"46","author":"Benichou","year":"1993","journal-title":"J. Clin. Epidemiol."},{"key":"ref_237","first-page":"4","article-title":"Editorial. DILI, HILI, RUCAM algorithm, and AI, the Artificial Intelligence: Provocative issues, progress, and proposals","volume":"1","author":"Teschke","year":"2020","journal-title":"Arch. Gastroenterol. Res."},{"key":"ref_238","doi-asserted-by":"crossref","first-page":"1168","DOI":"10.1097\/MEG.0000000000001630","article-title":"Clinical efficacy and safety of anticoagulation therapy for Pyrrolizidine alkaloids-induced hepatic sinusoidal obstruction syndrome: A retrospective multicenter cohort study","volume":"32","author":"Peng","year":"2020","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_239","doi-asserted-by":"crossref","first-page":"300060520961916","DOI":"10.1177\/0300060520961916","article-title":"Low molecular weight heparin in the treatment of pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: Five case reports","volume":"48","author":"Jiang","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_240","doi-asserted-by":"crossref","first-page":"1","DOI":"10.21037\/atm-20-731","article-title":"Prognostic factors for pyrrolizidine alkaloid-induced hepatic sinusoidal obstruction syndrome: A multicenter study in China","volume":"9","author":"Shang","year":"2021","journal-title":"Ann. Transl. Med."},{"key":"ref_241","doi-asserted-by":"crossref","unstructured":"Habs, M., Binder, K., Krauss, S., M\u00fcller, K., Ernst, B., Valentini, L., and Koller, M. (2017). A balanced risk\u2013benefit analysis to determine human risks associated with pyrrolizidine alkaloids (PA)\u2014The case of tea and herbal infusions. Nutrients, 9.","DOI":"10.3390\/nu9070717"},{"key":"ref_242","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1159\/000070799","article-title":"Veno-occlusive disease in a fetus caused by pyrrolizidine alkaloids of food origin","volume":"18","author":"Rasenack","year":"2003","journal-title":"Fetal Diagn. Ther."},{"key":"ref_243","doi-asserted-by":"crossref","first-page":"489","DOI":"10.12998\/wjcc.v9.i2.489","article-title":"Is sinusoidal obstructive syndrome a recurrent disease after liver transplantation? A case report","volume":"9","author":"Liu","year":"2021","journal-title":"World J. Clin. Cases"},{"key":"ref_244","doi-asserted-by":"crossref","first-page":"100138","DOI":"10.1016\/j.aohep.2019.08.009","article-title":"Sinusoidal obstruction syndrome secondary the intake of Senecio brasiliensis: A case report","volume":"20","author":"Barcelos","year":"2021","journal-title":"Ann. Hepatol."},{"key":"ref_245","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.asjsur.2021.04.015","article-title":"Letter to Editor. Hepatic sinusoidal obstruction syndrome after oral intake of Gynura segetum","volume":"44","author":"Zhang","year":"2021","journal-title":"Asian J. Surg."},{"key":"ref_246","doi-asserted-by":"crossref","first-page":"e0552","DOI":"10.1097\/MD.0000000000010552","article-title":"Hepatic veno-occlusive disease related to Gynura segetum","volume":"97","author":"Sun","year":"2018","journal-title":"Medicine"},{"key":"ref_247","first-page":"53","article-title":"Pyrrolizidine alkaloids enhance alcohol-induced hepatocytotoxicity in vitro in normal human hepatocytes","volume":"21","author":"Neuman","year":"2017","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_248","doi-asserted-by":"crossref","first-page":"300060520980649","DOI":"10.1177\/0300060520980649","article-title":"Hepatic sinusoidal obstruction syndrome caused by the ingestion of Gynura segetum in a patient with alcoholic cirrhosis: A case report","volume":"49","author":"Cen","year":"2021","journal-title":"J. Int. Med. Res."},{"key":"ref_249","doi-asserted-by":"crossref","first-page":"9","DOI":"10.26502\/fccm.92920048","article-title":"Hepatic veno-occlusive disease caused by Gynura segetum: A case report","volume":"3","author":"Ya","year":"2019","journal-title":"Cardiol. Cardiovasc. Med."},{"key":"ref_250","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1021\/acs.estlett.1c00359","article-title":"Blood pyrrole\u2013DNA adducts define the early tumorigenic risk in patients with pyrrolizidine alkaloid-induced liver injury","volume":"8","author":"He","year":"2021","journal-title":"Environ. Sci. Technol. Lett."},{"key":"ref_251","doi-asserted-by":"crossref","unstructured":"Anderson, N., and Borlak, J. (2019). Hepatobiliary events in migraine therapy with herbs\u2014The case of Petadolex, a Petasites hybridus extract. J. Clin. Med., 8.","DOI":"10.3390\/jcm8050652"},{"key":"ref_252","first-page":"154","article-title":"Petadolex\u00ae, a herbal extract for migraine prophylaxis with spontaneous case reports of disputed liver injury: Robust causality evaluation by RUCAM, the Roussel Uclaf Causality Assessment Method","volume":"3","author":"Teschke","year":"2016","journal-title":"Eur. J. Pharmaceut. Med. Res."},{"key":"ref_253","first-page":"1","article-title":"Safety profile of a special butterbur extract from Petasites hybridus in migraine prevention with emphasis on the liver","volume":"1","author":"Diener","year":"2018","journal-title":"Cephalgia Rep."},{"key":"ref_254","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/S0140-6736(76)90726-1","article-title":"An outbreak of hepatic veno-occlusive disease in north-western Afghanistan","volume":"308","author":"Mohabbat","year":"1976","journal-title":"Lancet"},{"key":"ref_255","doi-asserted-by":"crossref","unstructured":"Kakar, F., Akbarian, Z., Leslie, T., Mustafa, M.L., Watson, J., van Egmond, H.P., Omar, M.F., and Mofleh, J. (2010). An outbreak of hepatic veno-occlusive disease in western Afghanistan associated with exposure to wheat flour contaminated with pyrrolizidine alkaloids. J. Toxicol.","DOI":"10.1155\/2010\/313280"},{"key":"ref_256","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1136\/gut.17.11.849","article-title":"Study of an epidemic of venoocclusive disease in India","volume":"17","author":"Tandon","year":"1976","journal-title":"Gut"},{"key":"ref_257","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/S0140-6736(76)90727-3","article-title":"An epidemic of veno-occlusive disease of the liver in central India","volume":"308","author":"Tandon","year":"1976","journal-title":"Lancet"},{"key":"ref_258","first-page":"263","article-title":"\u00c9pid\u00e9mie d\u2019intoxication alimentaire \u00e1 l\u2019h\u00e9liotrope, tadjikistan, Novembre 1992\u2013Mars 1993","volume":"4","author":"Chauvin","year":"1994","journal-title":"Cah. \u00c9tudes Rech. Francoph. Sant\u00e9"},{"key":"ref_259","first-page":"607","article-title":"An epidemic of veno-occlusive disease of the liver in Afghanistan pathologic features","volume":"70","author":"Tandon","year":"1978","journal-title":"Am. J. Gastroenterol."},{"key":"ref_260","doi-asserted-by":"crossref","first-page":"142","DOI":"10.26719\/1998.4.1.142","article-title":"An outbreak of veno-occlusive disease of the liver in northern Iraq","volume":"4","author":"Altaee","year":"1998","journal-title":"East. Mediterr. Health J."},{"key":"ref_261","doi-asserted-by":"crossref","unstructured":"Auerbach, B.J., Reynolds, S., Lamorde, M., Merry, C., Kukunda-Byobona, C., Ocama, P., Semeere, A., Ndyanabo, A., Boaz, I., and Kiggundu, V. (2012). Traditional herbal medicine use associated with liver fibrosis in Rural Rakai, Uganda. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041737"},{"key":"ref_262","doi-asserted-by":"crossref","unstructured":"Tobyn, G., Denham, A., and Whitelegg, M. (2011). Tussilago farfara, coltsfoot. Medical Herbs, Elsevier.","DOI":"10.1016\/B978-0-443-10344-5.00035-5"},{"key":"ref_263","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jep.2013.05.048","article-title":"Senecio scandens Buch.-Ham.: A review on its ethnopharmacology, phytochemistry, pharmacology, and toxicity","volume":"149","author":"Wang","year":"2013","journal-title":"J. Ethnopharmacol."},{"key":"ref_264","first-page":"2004","article-title":"Management of nematodes and soil fertility with Sunn hemp cover crop","volume":"18","author":"Wang","year":"1969","journal-title":"EDIS"},{"key":"ref_265","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.phytochem.2013.12.004","article-title":"Chemical variation in Jacobaea vulgaris is influenced by the interaction of season and vegetation successional stage","volume":"99","author":"Carvalho","year":"2014","journal-title":"Phytochemistry"},{"key":"ref_266","doi-asserted-by":"crossref","first-page":"927","DOI":"10.13005\/bpj\/1961","article-title":"Some kinds of medicinal herbs for the treatment of sinusitis","volume":"13","author":"Hoi","year":"2020","journal-title":"Biomed. Pharm. J."},{"key":"ref_267","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.jpba.2012.11.028","article-title":"The medical plant butterbur (Petasites): Analytical and physiological (re)view","volume":"75","author":"Zerbes","year":"2013","journal-title":"J. Pharm. Biomed. Anal."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10419\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:54Z","timestamp":1760166354000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":267,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910419"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910419","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]}}}