| Reference | [1]. Food Chem Toxicol. 2021 May;151:112151. doi: 10.1016/j.fct.2021.112151. Epub 2021 Mar 25.<br />
Analysis of pyrrolizidine alkaloids in Eupatorium fortunei Turcz. and their in vitro neurotoxicity.<br />
Zhang Y(1), Yang FF(2), Chen H(2), Qi YD(2), Si JY(2), Wu Q(3), Liao YH(4).<br />
Author information: (1)Beijing University of Chinese Medicine, Yangguang South Street, Fangshan District, Beijing, 102488, PR China; Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing, 100193, PR China. (2)Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing, 100193, PR China. (3)Beijing University of Chinese Medicine, Yangguang South Street, Fangshan District, Beijing, 102488, PR China. Electronic address: [email protected]. (4)Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Institute of Medicinal Plant Development (IMPLAD), Chinese Academy of Medical Sciences & Peking Union Medical College, No. 151 Malianwa North Road, Haidian District, Beijing, 100193, PR China. Electronic address: [email protected].<br />
This study was to analyze the pyrrolizidine alkaloids (PAs) in Eupatorium fortunei herbs and its derived finished products with a view to evaluating their effects on the proliferation and oligodendrogenesis of neural progenitor cells (NPCs). Using a LC-MS/MS method with 32 PAs reference standards, 8 PAs including intermedine, intermedine N-oxide, lycopsamine, lycopsamine N-oxide, retronecine, seneciphylline and senkirkine and 7-acetylintermedine N-oxide were identified with intermedine N-oxide and lycopsamine N-oxide being most abundant. The total PA amounts were found to vary from 0.18 to 61.81 μg/g in 30 batches of herbs and from 0.86 to 36.96 μg/g in 4 commercial finished products, respectively. Risk assessments indicated that the short-term intake seemed unlikely lead to acute toxic effects but the chronic use warranted cautions. Using NPCs derived from mouse induced pluripotent stem cells as an in vitro testing model, intermedine, intermedine N-oxide and lycopsamine N-oxide appeared to decrease cell viability at 30 μM whereas intermedine N-oxide inhibited oligodendrogenesis of NPCs at 10 μM. The present results suggested that the PAs in the majority of E. fortunei herbs and the derived products not only resulted in their exposure far exceeding the acceptable intake limit (i. e. 1.0 μg PA per day for adults) in herbal medicinal products recommended by the European Medicines Agency but also induced neurotoxicity to NPCs in vitro.<br />
DOI: 10.1016/j.fct.2021.112151 PMID: 33774095<br />
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[2]. J Ethnopharmacol. 2015 Aug 22;172:179-94. doi: 10.1016/j.jep.2015.06.012. Epub 2015 Jun 16.<br />
Pro-toxic dehydropyrrolizidine alkaloids in the traditional Andean herbal medicine "asmachilca".<br />
Colegate SM(1), Boppré M(2), Monzón J(2), Betz JM(3).<br />
Author information: (1)USDA, ARS, Poisonous Plant Research Laboratory, Logan, UT 84341, USA; Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT 84322, USA. Electronic address: [email protected]. (2)Forstzoologie und Entomologie, Albert-Ludwigs-Universität, D-79085 Freiburg, Germany. (3)Office of Dietary Supplements, National Institutes of Health, 6100 Executive Blvd., Room 3B01, Bethesda, MD 20892, USA.<br />
ETHNOPHARMACOLOGICAL RELEVANCE: Asmachilca is a Peruvian medicinal herb preparation ostensibly derived from Aristeguietia gayana (Wedd.) R.M. King & H. Rob. (Asteraceae: Eupatorieae). Decoctions of the plant have a reported bronchodilation effect that is purported to be useful in the treatment of respiratory allergies, common cold and bronchial asthma. However, its attractiveness to pyrrolizidine alkaloid-pharmacophagous insects indicated a potential for toxicity for human consumers. AIM OF THE STUDY: To determine if commercial asmachilca samples, including fully processed herbal teas, contain potentially toxic 1,2-dehydropyrrolizidine alkaloids. MATERIALS AND METHODS: Two brands of "Asmachilca" herbal tea bags and four other commercial samples of botanical materials for preparing asmachilca medicine were extracted and analyzed using HPLC-esi(+)MS and MS/MS for the characteristic retention times and mass spectra of known dehydropyrrolizidine alkaloids. Other suspected dehydropyrrolizidine alkaloids were tentatively identified based on MS/MS profiles and high resolution molecular weight determinations. Further structure elucidation of isolated alkaloids was based on 1D and 2D NMR spectroscopy. RESULTS: Asmachilca attracted many species of moths which are known to pharmacophagously gather dehydropyrrolizidine alkaloids. Analysis of 5 of the asmachilca samples revealed the major presence of the dehydropyrrolizidine alkaloid monoesters rinderine and supinine, and their N-oxides. The 6th sample was very similar but did not contain supinine or its N-oxide. Small quantities of other dehydropyrrolizidine alkaloid monoesters, including echinatine and intermedine, were also detected. In addition, two major metabolites, previously undescribed, were isolated and identified as dehydropyrrolizidine alkaloid monoesters with two "head-to-tail" linked viridifloric and/or trachelanthic acids. Estimates of total pyrrolizidine alkaloid and N-oxide content in the botanical components of asmachilca varied from 0.4% to 0.9% (w/dw, dry weight) based on equivalents of lycopsamine. The mean pyrrolizidine alkaloid content of a hot water infusion of a commercial asmachilca herbal tea bag was 2.2±0.5mg lycopsamine equivalents. Morphological and chemical evidence showed that asmachilca is prepared from different plant species. CONCLUSIONS: All asmachilca samples and the herbal tea infusions contained toxicologically-relevant concentrations of pro-toxic 1,2-dehydropyrrolizidine alkaloid esters and, therefore, present a risk to the health of humans. This raises questions concerning the ongoing unrestricted availability of such products on the Peruvian and international market. In addition to medical surveys of consumers of asmachilca, in the context of chronic disease potentially associated with ingestion of the dehydropyrrolizidine alkaloids, the botanical origins of asmachilca preparations require detailed elucidation.<br />
DOI: 10.1016/j.jep.2015.06.012 PMCID: PMC4523498 PMID: 26087231 [Indexed for MEDLINE]<br />
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[3]. Toxicon. 2015 Apr;97:36-45. doi: 10.1016/j.toxicon.2015.02.001. Epub 2015 Feb 7.<br />
An in vitro comparison of the cytotoxic potential of selected dehydropyrrolizidine alkaloids and some N-oxides.<br />
Field RA(1), Stegelmeier BL(2), Colegate SM(1), Brown AW(1), Green BT(1).<br />
Author information: (1)United States Department of Agriculture, Agricultural Research Service, Poisonous Plant Research Laboratory, Logan, UT 84332, USA. (2)United States Department of Agriculture, Agricultural Research Service, Poisonous Plant Research Laboratory, Logan, UT 84332, USA. Electronic address: [email protected].<br />
Plants producing dehydropyrrolizidine alkaloids (DHPAs) are found throughout the world and they are dangerous to human and animal health. Several DHPAs are carcinogenic but only riddelliine has been classified as a potential human carcinogen by the National Toxicology Program. As DHPA-related carcinogenicity is probably linked to cytotoxicity, a model of CRL-2118 chicken hepatocyte cytotoxicity was developed to compare equimolar DHPA exposures between 19 and 300 μM. Alkaloid-related cytotoxicity was estimated using cytomorphology, cell viability reflected by mitochondrial function and cellular degeneration reflected by media lactate dehydrogenase activity. Lasiocarpine induced cytotoxicity and decreased cell viability in a concentration dependent manner at 24 h. At similar concentrations and exposures of 48 and 72 h, seneciphylline, senecionine, monocrotaline and riddelliine were cytotoxic. None of the DHPA-N-oxides were significantly cytotoxic at these concentrations. Using graphic analyses the median cytotoxic concentration (DHPA concentration that produced ½ the maximum response) were estimated. The estimated descending order of cytotoxicity was lasiocarpine, seneciphylline, senecionine, heliotrine, riddelliine, monocrotaline, riddelliine-N-oxide, lycopsamine, intermedine, lasiocarpine-N-oxide and senecionine-N-oxide. This comparison identifies DHPAs that were more cytotoxic than carcinogenic riddelliine. Additional studies to better characterize the carcinogenic potential of these alkaloids are essential to better determine the risk they each may pose for human and animal health.<br />
DOI: 10.1016/j.toxicon.2015.02.001 PMID: 25666399 [Indexed for MEDLINE]<br />
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[4]. J Med Chem. 1985 Jun;28(6):687-94. doi: 10.1021/jm00383a001.<br />
Synthesis of pyrrolizidine alkaloids indicine, intermedine, lycopsamine, and analogues and their N-oxides. Potential antitumor agents.<br />
Zalkow LH, Glinski JA, Gelbaum LT, Fleischmann TJ, McGowan LS, Gordon MM.<br />
(-)- and (+)-trachelanthic and (-)- and (+)-viridifloric acids were synthesized and their isopropylidene derivatives were regiospecifically coupled, at C-9, with (-)-retronecine obtained by hydrolysis of monocrotaline, isolated from Crotalaria spectabilis. Hydrolysis, followed by oxidation, led to the N-oxides of indicine, intermedine, lycopsamine, and the new nonnatural product, respectively. Each of these analogues was screened in the P388 lymphocytic leukemia system at the same time as indicine N-oxide, and the results were compared. Other related analogues were prepared and similarly screened and the results compared with those from indicine N-oxide.<br />
DOI: 10.1021/jm00383a001 PMID: 4009589 [Indexed for MEDLINE]
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