紫草中的吡咯里西啶类成分及其代谢毒性研究进展
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摘要
吡咯里西啶生物碱(pyrrolizidine alkaloids, PAs)是植物中较常见的一类肝毒性成分。紫草为我国常用中药之一,因具有抗炎、促进伤口愈合等作用而广泛应用于临床,但研究表明含有PAs。这类成分在体内大量暴露及代谢活化可致肝窦阻塞综合征,故被认为是许多含PAs中草药引起肝损伤作用的潜在物质基础。尽管有关紫草的临床毒害未见报道,但PAs的存在无疑为其安全用药埋下了隐患,揭示和控制其毒性风险已成为紫草研究的一个重要方向。本文拟从吡咯里西啶类成分及其代谢毒性两个方面对紫草及其相关品种的安全性研究进展及存在的主要问题做一概述,并对进一步的研究提出建议,以期为全面系统评价紫草的用药风险和指导其临床合理用药提供参考。
Pyrrolizidine alkaloids(PAs) are a class of hepatotoxic compounds that are largely found in plants. "Zicao" is one of the most commonly-used Chinese herbal medicines from multiple sources, owing to its antiinflammatory and wound healing effects. However, many studies have shown that this herb and its relative species contain hepatotoxic PAs. These PAs may cause hepatic sinusoidal obstruction syndrome following metabolic activation, and are therefore considered as potential toxic substances. Even though the toxicity of "Zicao" in clinical use has not been reported, the existence of PAs will undoubtedly post a threat for its safety in long-term use. It has now become the focus of many researchers to disclose and prevent its potential risk of intoxication. This review summarizes recent progress and key scientific evidence found in the research of pyrrolizidine alkaloids from "Zicao" and its relative species, including their metabolic toxicity. We comment on the need of future studies,such as providing a reference or guidance for safety evaluation of this medicinal herb in clinical practice.
Pyrrolizidine alkaloids(PAs) are a class of hepatotoxic compounds that are largely found in plants. "Zicao" is one of the most commonly-used Chinese herbal medicines from multiple sources, owing to its antiinflammatory and wound healing effects. However, many studies have shown that this herb and its relative species contain hepatotoxic PAs. These PAs may cause hepatic sinusoidal obstruction syndrome following metabolic activation, and are therefore considered as potential toxic substances. Even though the toxicity of "Zicao" in clinical use has not been reported, the existence of PAs will undoubtedly post a threat for its safety in long-term use. It has now become the focus of many researchers to disclose and prevent its potential risk of intoxication. This review summarizes recent progress and key scientific evidence found in the research of pyrrolizidine alkaloids from "Zicao" and its relative species, including their metabolic toxicity. We comment on the need of future studies,such as providing a reference or guidance for safety evaluation of this medicinal herb in clinical practice.
引文
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[11]Hartmann T,Ober D.Biosynthesis and metabolism of pyrroli‐zidine alkaloids in plants and specialized insect herbivores[J].Top Curr Chem,2000,209:207-243.
[12]Lin G,Wang JY,Li N,et al.Hepatic sinusoidal obstruction syndrome associated with consumption of Gynura segetum[J].JHepatol,2011,54:666-673.
[13]Li H,Zhang M.Research advances in sinusoidal obstruction syndrome[J].J Clin Hepatol(临床肝胆病杂志),2016,32:1429-1432.
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[16]Liu QH,Yuan JQ,Yang JS.Chemical constituents and pharmaco‐logical activities of pyrrolizidine alkaloids in Boraginaceae[J].Chin Pharm J(中国药学杂志),2005,40:561-564.
[17]Smyrska-Wieleba N,Wojtanowski KK,Mroczek T.Comparative HILIC/ESI-QTOF-MS and HPTLC studies of pyrrolizidine alkaloids in flowers of Tussilago farfara,and roots of Arnebia euchroma[J].Phytochem Lett,2016,20:339-349.
[18]Ahmad L,He Y,Hao JC,et al.Toxic pyrrolizidine alkaloids provide a warning sign to overuse of the ethnomedicine Arnebia benthamii[J].J Ethnopharmacol,2017,210:88-94.
[19]Krenn L,Wiedenfeld H,Roeder E.Pyrrolizidine alkaloids from Lithospermum officinale[J].Phytochemistry,1994,37:275-277.
[20]Wiedenfeld H,Pietrosiuk A,Furmanowa M,et al.Pyrrolizidine alkaloids from Lithospermum canescens Lehm[J].Z Natur‐forsch C,2003,58:173-176.
[21]El-Shazly A,Abdel-Ghani A,Wink M.Pyrrolizidine alkaloids from Onosma arenaria(Boraginaceae)[J].Biochem Syst Eco,2003,31:477-485.
[22]Kretsi O,Aligiannis N,Skaltsounis AL,et al.Pyrrolizidine alka‐loids from Onosma leptantha[J].Helv Chim Acta,2003,86:3136-3140.
[23]Damianakos H,Sotiroudis G,Chinou I.Pyrrolizidine alkaloids from Onosma erecta[J].J Nat Prod,2013,76:1829-1835.
[24]Orfanou IM,Damianakos H,Bazos I,et al.Pyrrolizidine alka‐loids from Onosma kaheirei Teppner(Boraginaceae)[J].Rec Nat Prod,2016,10:221-227.
[25]Mellidis AS,Papageorgiou VP.Pyrrolizidine alkaloids of the plant Onosma heterophylla[J].Chem Chron,1988,17:67-73.
[26]Roeder E,Wiedenfeld H,Kroeger R.Pyrrolizidine alkaloids of three taxa of Onosma(Boraginaceae-Lithospermeae)[J].Phyton(Horn,Austria),1993,33:41-49.
[27]Mroczek T,Ndjoko K,G?owniak K,et al.On-line structure char‐acterization of pyrrolizidine alkaloids in Onosma stellulatum and Emilia coccinea by liquid chromatography-ion-trap mass spec‐trometry[J].J Chromatogr A,2004,1056:91-97.
[28]Damianakos H,Jeziorek M,Pietrosiuk A,et al.The chemical profile of pyrrolizidine alkaloids from selected Greek endemic Boraginaceae plants determined by gas chromatography/mass spectrometry[J].J AOAC Int,2014,97:1244-1249.
[29]Tang J,Cheng M,Wei JX,et al.Identification of pyrrolizidine alkaloids in two major commercial sources of Zicao,a commonly used Chinese medicinal herb,by liquid chromatography coupled to triple tandem quadrupole mass spectrometry[C]//Brochure/Abstract of 2013 International Symposium of New Drug Discov‐ery and Medicinal Chemistry.Wuhan:Chinese Pharmaceutical Association Hubei Branch,2013:40.
[30]Edgar JA,Molyneux RJ,Colegate SM.Pyrrolizidine alkaloids:potential role in the etiology of cancers,pulmonary hyperten‐sion,congenital anomalies,and liver disease[J].Chem Res Toxicol,2015,28:4-20.
[31]Fu PP.Pyrrolizidine alkaloids:metabolic activation pathways leading to liver tumor initiation[J].Chem Res Toxicol,2017,30:81-93.
[32]Lin G,Tang J,Liu XQ,et al.Deacetylclivorine:a gender-selec‐tive metabolite of clivorine formed in female Sprague-Dawley rat liver microsomes[J].Drug Metab Dispos,2007,35:607-613.
[33]Liang Q,Sheng Y,Jiang P,et al.The gender-dependent difference of liver GSH antioxidant system in mice and its influence on isoline-induced liver injury[J].Toxicology,2011,280:61-69.
[34]Ruan J,Yang M,Fu PP,et al.Metabolic activation of pyrroli‐zidine alkaloids:insights into the structural and enzymatic basis[J].Chem Res Toxicol,2014,27:1030-1039.
[35]Kolrep F,Numata J,Kneuer C,et al.In vitro biotransformation of pyrrolizidine alkaloids in different species.Part I:Microsomal degradation[J].Arch Toxicol,2018,92:1089-1097.
[36]Wen JX.Isolation,Purification and Hepatoprotective Effects of Polysaccharides from Ligularia hodgsonii(川紫菀多糖的分离纯化及保肝作用研究)[D].Wuhan:Wuhan University,2018.
[37]Gao H,Li N,Wang JY,et al.Definitive diagnosis of hepatic sinusoidal obstruction syndrome induced by pyrrolizidine alkaloids[J].J Dig Dis,2015,13:33-39.
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