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Qingsu Xia - One of the best experts on this subject based on the ideXlab platform.
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Detection of Pyrrolizidine Alkaloid DNA Adducts in Livers of Cattle Poisoned with Heliotropium europaeum
2017Co-Authors: Qingsu Xia, Nir Edery, Shimon Barel, Frederick A Beland, Jakob A. ShimshoniAbstract:Pyrrolizidine alkaloids are among the most common poisonous plants affecting livestock, wildlife, and humans. Exposure of humans and livestock to toxic Pyrrolizidine alkaloids through the intake of contaminated food and feed may result in poisoning, leading to devastating epidemics. During February 2014, 73 mixed breed female beef cows from the Galilee region of Israel were accidently fed Pyrrolizidine alkaloid contaminated hay for 42 days, resulting in the sudden death of 24 cows over a period of 63 days. The remaining cows were slaughtered 2.5 months after the last ingestion of the contaminated hay. In this study, we report the histopathological analysis of the livers from five of the slaughtered cows and quantitation of Pyrrolizidine alkaloid-derived DNA adducts from their livers and three livers of control cows fed with feed free of weeds producing Pyrrolizidine alkaloids. Histopathological examination revealed that the five cows suffered from varying degrees of bile duct proliferation, fibrosis, and megalocytosis. Selected reaction monitoring HPLC–ES-MS/MS analysis indicated that (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts were formed in all five livers. The livers from the three control cows did not have any liver damage nor any indication of DHP–DNA adduct formed. These results confirm that the toxicity observed in these cattle was caused by Pyrrolizidine alkaloid poisoning and that Pyrrolizidine alkaloid-derived DNA adducts could still be detected and quantified in the livers of the chronically poisoned cows 2.5 months after their last exposure to the contaminated feed, suggesting that DHP-derived DNA adducts can serve as biomarkers for Pyrrolizidine alkaloid exposure and poisoning
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Pyrrolizidine Alkaloid-Derived DNA Adducts as a Common Biological Biomarker of Pyrrolizidine Alkaloid-Induced Tumorigenicity
2016Co-Authors: Qingsu Xia, Yuewei Zhao, Linda S. Von Tungeln, Daniel R. Doerge, Ge Lin, Lining CaiAbstract:Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic Pyrrolizidine alkaloid, as “reasonably anticipated to be a human carcinogen” in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N2-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N6-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic Pyrrolizidine alkaloid, platyphylliine, a Pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic Pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic Pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8–10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic Pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic Pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of Pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics
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Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of Pyrrolizidine alkaloid-induced tumorigenicity.
Chemical Research in Toxicology, 2013Co-Authors: Qingsu Xia, Yuewei Zhao, Linda S. Von Tungeln, Daniel R. Doerge, Ge Lin, Lining CaiAbstract:Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic Pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic Pyrrolizidine alkaloid, platyphylliine, a Pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic Pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic Pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic Pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic Pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of Pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics.
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full structure assignments of Pyrrolizidine alkaloid dna adducts and mechanism of tumor initiation
Chemical Research in Toxicology, 2012Co-Authors: Yuewei Zhao, Qingsu Xia, Goncalo Gamboa Da Costa, Lining CaiAbstract:Pyrrolizidine alkaloid-containing plants are widespread in the world and are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids are among the first chemical carcinogens identified in plants. Previously, we determined that metabolism of Pyrrolizidine alkaloids in vivo and in vitro generated a common set of DNA adducts that are responsible for tumor induction. Using LC-ESI/MS/MS analysis, we previously determined that four DNA adducts (DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4) were formed in rats dosed with riddelliine, a tumorigenic Pyrrolizidine alkaloid. Because of the lack of an adequate amount of authentic standards, the structures of DHP-dA-3 and DHP-dA-4 were not elucidated, and the structural assignment for DHP-dG-4 warranted further validation. In this study, we developed an improved synthetic methodology for these DNA adducts, enabling their full structural elucidation by mass spectrometry and NMR spectroscopy. We determined that DHP-dA-3...
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formation of dhp derived dna adducts from metabolic activation of the prototype heliotridine type Pyrrolizidine alkaloid heliotrine
Toxicology Letters, 2008Co-Authors: Qingsu Xia, Jian Yan, Ming W. ChouAbstract:Abstract Pyrrolizidine alkaloid-containing plants are widespread in the world and may be the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolism to exert their genotoxicity and tumorigenicity. Our mechanistic studies have determined that metabolism of the retronecine-type (riddelliine, retrorsine, and monocrotaline), heliotridine-type (lasiocarpine), and otonecine-type (clivorine) tumorigenic Pyrrolizidine alkaloids in vivo and/or in vitro all generates a common set of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts responsible for tumor induction. All the Pyrrolizidine alkaloids studied previously are diesters with an ester linkage at the C7 and C9 positions of the necine base. In this study, we report that F344 rat liver microsomal metabolism of heliotrine, a tumorigenic monoester bearing a hydroxyl group at the C7 of the necine base, resulted in the formation of the dehydroheliotridine (DHH) metabolite. When incubations of heliotrine were carried out in the presence of calf thymus DNA, the same set of DHP-derived DNA adducts was formed. These results support that DHP-derived DNA adducts are potential common biomarkers of Pyrrolizidine alkaloid exposure and tumorigenicity. For comparison, the dehydroretronecine (DHR)-derived DNA adducts formed from metabolism of riddleiine, retrorsine, monocrotaline, riddelleiine N-oxide, and retrorsine N-oxide were measured in parallel; the levels of DHP-derived DNA adduct formation were in the order: riddelliine ≈ retrorsine > monocrotaline > retrorsine N-oxide ≥ riddelliine N-oxide > heliotrine.
Zhengtao Wang - One of the best experts on this subject based on the ideXlab platform.
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mass spectrometry directed analysis and purification of Pyrrolizidine alkaloid cis trans isomers in gynura japonica
IEEE Journal of Solid-state Circuits, 2014Co-Authors: Lianxiang Fang, Aizhen Xiong, Xiao Yang, Wenzhi Cheng, Li Yang, Zhengtao WangAbstract:Pyrrolizidine alkaloids are highly hepatotoxic natural chemicals that produce irreversible chronic and acute hepatotoxic effects on human beings. Purification of large amounts of Pyrrolizidine alkaloids is necessary for toxicity studies. In this study, an efficient method for targeted analysis and purification of Pyrrolizidine alkaloid cis/trans isomers from herbal materials was developed for the first time. Targeted analysis of the hepatotoxic Pyrrolizidine alkaloids was performed by liquid chromatography with tandem mass spectrometry (precursor ion scan and daughter ion scan), and the purification of Pyrrolizidine alkaloids was achieved with a mass-directed auto purification system. The extraction and preparative liquid chromatography conditions were optimized. The developed method was applied to analysis of Gynura japonica (Thunb.) Juel., a herbal medicine traditionally used for detumescence and relieving pain but is potentially hepatotoxic as it contains Pyrrolizidine alkaloids. Twelve Pyrrolizidine alkaloids (six cis/trans isomer pairs) were identified with reference compounds or characterized by liquid chromatography with tandem mass spectrometry, and five individual Pyrrolizidine alkaloids, including (E)-seneciphylline, seneciphylline, integerrimine, senecionine, and seneciphyllinine, were prepared from G. japonica roots with high efficiency. The results of this work provide a new technique for the preparation of large amounts of Pyrrolizidine alkaloid reference substances, which will also benefit toxicological studies of Pyrrolizidine alkaloids and treatments for Pyrrolizidine alkaloid-induced toxicity.
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Mass-spectrometry-directed analysis and purification of Pyrrolizidine alkaloid cis/trans isomers in Gynura japonica.
IEEE Journal of Solid-state Circuits, 2014Co-Authors: Lianxiang Fang, Aizhen Xiong, Xiao Yang, Wenzhi Cheng, Li Yang, Zhengtao WangAbstract:Pyrrolizidine alkaloids are highly hepatotoxic natural chemicals that produce irreversible chronic and acute hepatotoxic effects on human beings. Purification of large amounts of Pyrrolizidine alkaloids is necessary for toxicity studies. In this study, an efficient method for targeted analysis and purification of Pyrrolizidine alkaloid cis/trans isomers from herbal materials was developed for the first time. Targeted analysis of the hepatotoxic Pyrrolizidine alkaloids was performed by liquid chromatography with tandem mass spectrometry (precursor ion scan and daughter ion scan), and the purification of Pyrrolizidine alkaloids was achieved with a mass-directed auto purification system. The extraction and preparative liquid chromatography conditions were optimized. The developed method was applied to analysis of Gynura japonica (Thunb.) Juel., a herbal medicine traditionally used for detumescence and relieving pain but is potentially hepatotoxic as it contains Pyrrolizidine alkaloids. Twelve Pyrrolizidine alkaloids (six cis/trans isomer pairs) were identified with reference compounds or characterized by liquid chromatography with tandem mass spectrometry, and five individual Pyrrolizidine alkaloids, including (E)-seneciphylline, seneciphylline, integerrimine, senecionine, and seneciphyllinine, were prepared from G. japonica roots with high efficiency. The results of this work provide a new technique for the preparation of large amounts of Pyrrolizidine alkaloid reference substances, which will also benefit toxicological studies of Pyrrolizidine alkaloids and treatments for Pyrrolizidine alkaloid-induced toxicity.
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Advance on pharmacologic actions, toxicity and pharmacokinetics of Pyrrolizidine alkaloids
Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica, 2009Co-Authors: Jiangguo Gao, Changhong Wang, Zhengtao WangAbstract:Plants containing Pyrrolizidine alkaloids were widely used in traditional medicine. Its hepatotoxicity is main toxicity as well known internationally. In order to providing some foundation for the future studies, the advancement on the pharmacologic actions, toxicity, and pharmacokinetics or toxicokinetics of Pyrrolizidine alkaloids was reviewed.
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Pyrrolizidine alkaloid clivorine inhibits human normal liver l 02 cells growth and activates p38 mitogen activated protein kinase in l 02 cells
Toxicon, 2002Co-Authors: Xianguo Zhao, Li Chen, Mian Zhang, Zhengtao WangAbstract:Clivorine, a Pyrrolizidine alkaloid extracted from Chinese medicinal plant Ligularia hodgsonii Hook significantly inhibited human normal liver L-02 cells proliferation and decreased L-02 cells viability. The results of western blot showed that clivorine strongly evoked phosphorylation of p38 mitogen-activated protein (MAP) Kinase in L-02 cells, but had no effect on extracellular signal-related kinases MAP Kinase phosphorylation. Moreover, another Pyrrolizidine alkaloid monocrotaline had no effect on phosphorylation of p38 MAP Kinase in L-02 cells. These studies document the effects of Pyrrolizidine alkaloid clivorine on the MAPK cascade and on the growth of human normal liver L-02 cells for the first time, which may be a possible reason for the toxic effects observed in those plants containing Pyrrolizidine alkaloids.
John A. Edgar - One of the best experts on this subject based on the ideXlab platform.
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Pyrrolizidine alkaloids sequestered by Solomon Island Danaine butterflies. The feeding preferences of the Danainae and Ithomiinae
Journal of Zoology, 2009Co-Authors: John A. EdgarAbstract:The plant sources and identity of Pyrrolizidine alkaloids sequestered by six species of Solomon Island Danainae have been investigated. The secretions of the pheromone-disseminating hairpencils of the males have also been analysed and the componenets, including Pyrrolizidine metabolites, have been identified. The first confirmed example of Danaine larvae, rather than adults, acquiring Pyrrolizidine alkaloids is reported and its relevance to hypotheses concerning the origin of the requirement of Danaine and Ithomiine butterflies for Pyrrolizidine alkaloids is discussed.
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Pyrrolizidine alkaloids of Echium vulgare honey found in pure pollen
Journal of agricultural and food chemistry, 2005Co-Authors: Michael Boppré, Steve M Colegate, John A. EdgarAbstract:The Pyrrolizidine alkaloids previously identified in floral honey attributed to Echium vulgare (Boraginaceae) have been detected (8000-14 000 ppm) in pure pollen collected from the anthers of Echium vulgare. Pyrrolizidine alkaloids and/or their N-oxides were isolated from the aqueous acid extracts of pollen by use of strong cation-exchange, solid-phase extraction and identified by liquid chromatographic/mass spectrometric (LCMS) analysis. The Pyrrolizidine alkaloids in the pollen are present mainly as the N-oxides. In addition to seven previously described Pyrrolizidine alkaloids and/or their N-oxides (echimidine, acetylechimidine, uplandicine, 9-O-angelylretronecine, echiuplatine, leptanthine, and echimiplatine), one unidentified (echivulgarine), but previously found in honey, and two previously undescribed (vulgarine and 7-O-acetylvulgarine) Pyrrolizidine alkaloids and/or their N-oxides were identified in the pollen. Tentative structures for these unidentified Pyrrolizidine alkaloids are proposed on the basis of the mass spectrometric data and biogenetic considerations. The implications of these results for identifying the source and subsequent concentrations of Pyrrolizidine alkaloids in honeys and commercial bee pollen are briefly discussed.
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Solid-phase extraction and HPLC-MS profiling of Pyrrolizidine alkaloids and their N-oxides: a case study of Echium plantagineum.
Phytochemical analysis : PCA, 2005Co-Authors: Steve M Colegate, John A. Edgar, Andrew M. Knill, Stephen T. LeeAbstract:Pyrrolizidine alkaloids and their N-oxides can be extracted from the dried methanolic extracts of plant material using dilute aqueous acid. The subsequent integration of solid-phase extraction (with a strong cation exchanger) of the alkaloids and N-oxides from the aqueous acid solution, together with analysis using HPLC-ESI/MS, provides a method for the simultaneous profiling of the Pyrrolizidine alkaloids and their N-oxides in plant samples and the collection of useful structural data as an aid in their identification. The N-oxide character of the analytes may be confirmed by treating analytical samples with a redox resin and observing the formation of the corresponding parent Pyrrolizidine alkaloids. The present case study of Echium plantagineum highlighted a higher ratio of N-oxides to the parent tertiary bases than has been previously reported. Furthermore, a higher proportion of acetylated Pyrrolizidine-N-oxides was observed in the flower heads relative to the leaves. Six Pyrrolizidine alkaloids or Pyrrolizidine-N-oxides, not previously reported from E. plantagineum, were tentatively identified on the basis of MS and biogenetic considerations. Three of these, 3'-O-acetylintermedine/lycopsamine, leptanthine-N-oxide and 9-O-angelylretronecine-N-oxide, have been reported elsewhere, whilst three others, 3'-O-acetylechiumine-N-oxide, echimiplatine-N-oxide and echiuplatine-N-oxide, appear unreported from any other source.
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Solid-phase extraction and LC-MS analysis of Pyrrolizidine alkaloids in honeys
Journal of Agricultural and Food Chemistry, 2004Co-Authors: Kerrie A. Beales, Keith Betteridge, Steve M Colegate, John A. EdgarAbstract:Strong-cation-exchange, solid-phase extraction of Pyrrolizidine alkaloids and theirN-oxides from honey samples was followed by reduction of the N-oxides and subsequent analysis of total Pyrrolizidine alkaloids using high-performance liquid chromatography-atmospheric pressure chemical ionization mass spectrometry. A limited survey of 63 preprocessing samples of honey, purposefully biased toward honeys attributed to floral sources known to produce Pyrrolizidine alkaloids, demonstrated levels of Pyrrolizidine alkaloids up to approximately 2000 parts per billion (ppb) in a sample attributed to Echium plantagineum. Up to 800 ppb Pyrrolizidine alkaloids was detected in some honeys not attributed by the collector to any Pyrrolizidine alkaloid-producing floral source. No Pyrrolizidine alkaloids were detected in approximately 30% of the samples in this limited study, while some honeys showed the copresence of Pyrrolizidine alkaloids from multiple floral sources such as E. plantagineum and Heliotropium europaeum. In addition, retail samples of blended honeys (with no labeling to suggest that Pyrrolizidine alkaloid-producing floral sources were used in the blends) have been shown to contain up to approximately 250 ppb Pyrrolizidine alkaloids.
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Honey from plants containing Pyrrolizidine alkaloids: a potential threat to health.
Journal of agricultural and food chemistry, 2002Co-Authors: John A. Edgar, E Roeder, Russell J. MolyneuxAbstract:Following scientific risk assessments, several countries have imposed strict regulations on herbal medicines containing 1,2-dehydro-Pyrrolizidine alkaloids. Using published data on the plants used in honey production, Pyrrolizidine alkaloid-containing plants are shown in this review to represent a significant source of honey worldwide. This observation, honey consumption data, reported levels of Pyrrolizidine alkaloids in honeys, and consideration of tolerable exposure levels determined for Pyrrolizidine alkaloids in herbal medicines, leads to the conclusion that some honey is a potential threat to health, especially for infants and fetuses, and further investigation is warranted.
Steve M Colegate - One of the best experts on this subject based on the ideXlab platform.
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Recognition of Pyrrolizidine Alkaloid Esters in the Invasive Aquatic Plant Gymnocoronis spilanthoides (Asteraceae)
Phytochemical analysis : PCA, 2015Co-Authors: Michael Boppré, Steve M ColegateAbstract:Introduction The freshwater aquatic plant Gymnocoronis spilanthoides (Senegal tea plant, jazmin del banado, Falscher Wasserfreund) is an invasive plant in many countries. Behavioural observations of Pyrrolizidine alkaloid-pharmacophagous butterflies suggested the presence of Pyrrolizidine alkaloids in the plant. Objective To determine whether the attraction of the butterflies to the plant is an accurate indicator of Pyrrolizidine alkaloids in G. spilanthoides. Methods The alkaloid fraction of a methanolic extract of G. spilanthoides was analysed using HPLC with electrospray ionisation MS and MS/MS. Two HPLC approaches were used, that is, a C18 reversed-phase column with an acidic mobile phase, and a porous graphitic carbon column with a basic mobile phase. Results Pyrrolizidine alkaloids were confirmed, with the free base forms more prevalent than the N-oxides. The major alkaloids detected were lycopsamine and intermedine. The porous graphitic carbon HPLC column, with basic mobile phase conditions, resulted in better resolution of more Pyrrolizidine alkaloids including rinderine, the heliotridine-based epimer of intermedine. Based on the MS/MS and high-resolution MS data, gymnocoronine was tentatively identified as an unusual C9 retronecine ester with 2,3-dihydroxy-2-propenylbutanoic acid. Among several minor-abundance monoester Pyrrolizidines recognised, spilanthine was tentatively identified as an ester of isoretronecanol with the unusual 2-acetoxymethylbutanoic acid. Conclusions The butterflies proved to be reliable indicators for the presence of pro-toxic 1,2-dehydroPyrrolizidine alkaloids in G. spilanthoides, the first aquatic plant shown to produce these alkaloids. The presence of the anti-herbivory alkaloids may contribute to the plant's invasive capabilities and would certainly be a consideration in any risk assessment of deliberate utilisation of the plant. The prolific growth of the plant and the structural diversity of its Pyrrolizidine alkaloids may make it ideal for investigating biosynthetic pathways or for large-scale production of specific alkaloids. Copyright © 2015 John Wiley & Sons, Ltd.
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improved method for extraction and lc ms analysis of Pyrrolizidine alkaloids and their n oxides in honey application to echium vulgare honeys
Journal of Agricultural and Food Chemistry, 2005Co-Authors: Keith Betteridge, Yu Cao, Steve M ColegateAbstract:A method for analyzing honey samples was developed that enabled the simultaneous detection and identification of Pyrrolizidine alkaloids and their N-oxides. Honey samples were treated with methanol or dilute sulfuric acid and then centrifuged to remove insoluble material. Subsequent strong cation exchange, solid-phase extraction of the supernatant provided a fraction that was analyzed for the presence of Pyrrolizidine alkaloids and their N-oxides using high-pressure liquid chromatography coupled to electrospray ionization mass spectrometry. The procedure was validated using extracts of Echium plantagineum and authenticated standards of Pyrrolizidine alkaloids and their N-oxides from other plant sources. Of several variations of the solid-phase extraction method assessed in this study, the best combination for generic use involved the dilution of honey with 0.05 M sulfuric acid and the subsequent application of the centrifuged solution to solid-phase extraction columns at the rate of a maximum of 10 g of honey per solid-phase extraction column. The method was applied to the analysis of nine floral honeys, five of which were attributed by the apiarist to Echium vulgare. Seven of the honey samples were positive for Pyrrolizidine alkaloids and N-oxides characteristic of E. vulgare.
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Pyrrolizidine alkaloids of Echium vulgare honey found in pure pollen
Journal of agricultural and food chemistry, 2005Co-Authors: Michael Boppré, Steve M Colegate, John A. EdgarAbstract:The Pyrrolizidine alkaloids previously identified in floral honey attributed to Echium vulgare (Boraginaceae) have been detected (8000-14 000 ppm) in pure pollen collected from the anthers of Echium vulgare. Pyrrolizidine alkaloids and/or their N-oxides were isolated from the aqueous acid extracts of pollen by use of strong cation-exchange, solid-phase extraction and identified by liquid chromatographic/mass spectrometric (LCMS) analysis. The Pyrrolizidine alkaloids in the pollen are present mainly as the N-oxides. In addition to seven previously described Pyrrolizidine alkaloids and/or their N-oxides (echimidine, acetylechimidine, uplandicine, 9-O-angelylretronecine, echiuplatine, leptanthine, and echimiplatine), one unidentified (echivulgarine), but previously found in honey, and two previously undescribed (vulgarine and 7-O-acetylvulgarine) Pyrrolizidine alkaloids and/or their N-oxides were identified in the pollen. Tentative structures for these unidentified Pyrrolizidine alkaloids are proposed on the basis of the mass spectrometric data and biogenetic considerations. The implications of these results for identifying the source and subsequent concentrations of Pyrrolizidine alkaloids in honeys and commercial bee pollen are briefly discussed.
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Solid-phase extraction and HPLC-MS profiling of Pyrrolizidine alkaloids and their N-oxides: a case study of Echium plantagineum.
Phytochemical analysis : PCA, 2005Co-Authors: Steve M Colegate, John A. Edgar, Andrew M. Knill, Stephen T. LeeAbstract:Pyrrolizidine alkaloids and their N-oxides can be extracted from the dried methanolic extracts of plant material using dilute aqueous acid. The subsequent integration of solid-phase extraction (with a strong cation exchanger) of the alkaloids and N-oxides from the aqueous acid solution, together with analysis using HPLC-ESI/MS, provides a method for the simultaneous profiling of the Pyrrolizidine alkaloids and their N-oxides in plant samples and the collection of useful structural data as an aid in their identification. The N-oxide character of the analytes may be confirmed by treating analytical samples with a redox resin and observing the formation of the corresponding parent Pyrrolizidine alkaloids. The present case study of Echium plantagineum highlighted a higher ratio of N-oxides to the parent tertiary bases than has been previously reported. Furthermore, a higher proportion of acetylated Pyrrolizidine-N-oxides was observed in the flower heads relative to the leaves. Six Pyrrolizidine alkaloids or Pyrrolizidine-N-oxides, not previously reported from E. plantagineum, were tentatively identified on the basis of MS and biogenetic considerations. Three of these, 3'-O-acetylintermedine/lycopsamine, leptanthine-N-oxide and 9-O-angelylretronecine-N-oxide, have been reported elsewhere, whilst three others, 3'-O-acetylechiumine-N-oxide, echimiplatine-N-oxide and echiuplatine-N-oxide, appear unreported from any other source.
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Solid-phase extraction and LC-MS analysis of Pyrrolizidine alkaloids in honeys
Journal of Agricultural and Food Chemistry, 2004Co-Authors: Kerrie A. Beales, Keith Betteridge, Steve M Colegate, John A. EdgarAbstract:Strong-cation-exchange, solid-phase extraction of Pyrrolizidine alkaloids and theirN-oxides from honey samples was followed by reduction of the N-oxides and subsequent analysis of total Pyrrolizidine alkaloids using high-performance liquid chromatography-atmospheric pressure chemical ionization mass spectrometry. A limited survey of 63 preprocessing samples of honey, purposefully biased toward honeys attributed to floral sources known to produce Pyrrolizidine alkaloids, demonstrated levels of Pyrrolizidine alkaloids up to approximately 2000 parts per billion (ppb) in a sample attributed to Echium plantagineum. Up to 800 ppb Pyrrolizidine alkaloids was detected in some honeys not attributed by the collector to any Pyrrolizidine alkaloid-producing floral source. No Pyrrolizidine alkaloids were detected in approximately 30% of the samples in this limited study, while some honeys showed the copresence of Pyrrolizidine alkaloids from multiple floral sources such as E. plantagineum and Heliotropium europaeum. In addition, retail samples of blended honeys (with no labeling to suggest that Pyrrolizidine alkaloid-producing floral sources were used in the blends) have been shown to contain up to approximately 250 ppb Pyrrolizidine alkaloids.
Lining Cai - One of the best experts on this subject based on the ideXlab platform.
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Pyrrolizidine Alkaloid-Derived DNA Adducts as a Common Biological Biomarker of Pyrrolizidine Alkaloid-Induced Tumorigenicity
2016Co-Authors: Qingsu Xia, Yuewei Zhao, Linda S. Von Tungeln, Daniel R. Doerge, Ge Lin, Lining CaiAbstract:Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic Pyrrolizidine alkaloid, as “reasonably anticipated to be a human carcinogen” in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N2-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N6-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic Pyrrolizidine alkaloid, platyphylliine, a Pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic Pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic Pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8–10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic Pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic Pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of Pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics
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Pyrrolizidine alkaloid-derived DNA adducts as a common biological biomarker of Pyrrolizidine alkaloid-induced tumorigenicity.
Chemical Research in Toxicology, 2013Co-Authors: Qingsu Xia, Yuewei Zhao, Linda S. Von Tungeln, Daniel R. Doerge, Ge Lin, Lining CaiAbstract:Pyrrolizidine alkaloid-containing plants are the most common poisonous plants affecting livestock, wildlife, and humans. The U.S. National Toxicology Program (NTP) classified riddelliine, a tumorigenic Pyrrolizidine alkaloid, as "reasonably anticipated to be a human carcinogen" in the NTP 12th Report on Carcinogens in 2011. We previously determined that four DNA adducts were formed in rats dosed with riddelliine. The structures of the four DNA adducts were elucidated as (i) a pair of epimers of 7-hydroxy-9-(deoxyguanosin-N(2)-yl)dehydrosupinidine adducts (termed as DHP-dG-3 and DHP-dG-4) as the predominant adducts; and (ii) a pair of epimers of 7-hydroxy-9-(deoxyadenosin-N(6)-yl)dehydrosupinidine adducts (termed as DHP-dA-3 and DHP-dA-4 adducts). In this study, we selected a nontumorigenic Pyrrolizidine alkaloid, platyphylliine, a Pyrrolizidine alkaloid N-oxide, riddelliine N-oxide, and nine tumorigenic Pyrrolizidine alkaloids (riddelliine, retrorsine, monocrotaline, lycopsamine, retronecine, lasiocarpine, heliotrine, clivorine, and senkirkine) for study in animals. Seven of the nine tumorigenic Pyrrolizidine alkaloids, with the exception of lycopsamine and retronecine, are liver carcinogens. At 8-10 weeks of age, female F344 rats were orally gavaged for 3 consecutive days with 4.5 and 24 μmol/kg body weight test article in 0.5 mL of 10% DMSO in water. Twenty-four hours after the last dose, the rats were sacrificed, livers were removed, and liver DNA was isolated for DNA adduct analysis. DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4 adducts were formed in the liver of rats treated with the individual seven hepatocarcinogenic Pyrrolizidine alkaloids and riddelliine N-oxide. These DNA adducts were not formed in the liver of rats administered retronecine, the nontumorigenic Pyrrolizidine alkaloid, platyphylliine, or vehicle control. These results indicate that this set of DNA adducts, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, is a common biological biomarker of Pyrrolizidine alkaloid-induced liver tumor formation. To date, this is the first finding that a set of exogenous DNA adducts are commonly formed from a series of tumorigenic xenobiotics.
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full structure assignments of Pyrrolizidine alkaloid dna adducts and mechanism of tumor initiation
Chemical Research in Toxicology, 2012Co-Authors: Yuewei Zhao, Qingsu Xia, Goncalo Gamboa Da Costa, Lining CaiAbstract:Pyrrolizidine alkaloid-containing plants are widespread in the world and are probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids are among the first chemical carcinogens identified in plants. Previously, we determined that metabolism of Pyrrolizidine alkaloids in vivo and in vitro generated a common set of DNA adducts that are responsible for tumor induction. Using LC-ESI/MS/MS analysis, we previously determined that four DNA adducts (DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4) were formed in rats dosed with riddelliine, a tumorigenic Pyrrolizidine alkaloid. Because of the lack of an adequate amount of authentic standards, the structures of DHP-dA-3 and DHP-dA-4 were not elucidated, and the structural assignment for DHP-dG-4 warranted further validation. In this study, we developed an improved synthetic methodology for these DNA adducts, enabling their full structural elucidation by mass spectrometry and NMR spectroscopy. We determined that DHP-dA-3...
