川紫菀水提取物中主要生物碱成分clivorine分析及其对大鼠肝毒性初步研究

目的 考察川紫菀水提取物对大鼠的肝毒性,并探讨其肝毒性与水提取物中吡咯里西啶生物碱成分之间的关系.方法 采用HPLC法分析川紫菀水提取物中主要吡咯里西啶生物碱成分,并结合文献报道设定水提取物的给药剂量.将水提取物ig给予SD大鼠,通过测定血清丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)的活性、肝组织中结合吡咯和还原型谷胱甘肽(GSH)水平及观察肝组织病理改变,考察水提取物的肝毒性.结果 川紫菀水提取物中主要吡咯里西啶生物碱成分为clivorine (3.94 mg/g).单次给予水提取物无论剂量高低,ALT和AST均未见明显改变,但肝组织GSH水平显著下降;多次给药时水提取物高剂量组ALT和AST显著升高(P＜0.05).各给药组肝组织中均可检出结合吡咯,其量与给药剂量大小及次数呈正相关.组织病理学观察未见肝组织有明显病变.结论 川紫菀水提取物具有潜在的肝毒性,大剂量的毒性尤为明显.Clivorine是水提取物中的主要生物碱成分,可能是川紫菀肝毒性的主要毒效物质.     

含吡咯里西啶生物碱植物的特殊毒性及致毒机制研究进展

吡咯里西啶类生物碱(pyrrolizidine alkaloids,PAs)是一类在植物中广泛分布的成分,含有吡咯里西啶类生物碱的植物在民间被作为草药和植物茶饮品应用的现象极为普遍.然而,研究发现吡咯里西啶类生物碱具有明确的毒性作用,其中的肝毒性早已引起人们的关注,而生殖毒性、致突变和致癌性方面的毒性却研究较少.本文主要就PAs的生殖毒性、致突变和致癌方面的特殊毒性进行综述,主要总结了20世纪50年代以来关于PAs特殊毒性的临床报道及动物实验研究,并对现有研究所认为的影响PAs特殊毒性的因素及PAs特殊毒性产生的机制进行了归纳.     

吡咯里西啶生物碱的药理作用、毒性及药(毒) 物代谢动力学研究进展

含有吡咯里西啶生物碱的植物在传统医药中有广泛使用,其肝毒性引起广泛关注.作者综述了吡咯里西啶生物碱的药理作用、毒性和药(毒)物代谢动力学等方面的研究进展,以便为后期研究提供基础.     

含吡咯里西啶生物碱的山紫菀类药材的分子鉴别

目的：采用分子生物学的方法对含吡咯里西啶生物碱(HPAs)与不含吡咯里西啶生物碱的山紫菀类药材(橐吾属植物)进行鉴剐。方法：采用CTAB法提取9种不同基源的山紫菀类药材的总DNA，进行PCR扩增和测序，并对序列进行系统分析。结果：通过提取、扩增和测序，得到了9种橐吾属植物的nrDNA ITS区间序列，统计分析结果得到了9种植物的遗传距离和转换、颠换数，分支分类结果得到了系统树。结论：9种橐吾属植物nrDNA ITS区间序列的分析结果表明了两类山紫菀类药材有着明显的区别，是两类药材鉴别的有效方法之一。     

含吡咯里西啶生物碱中成药潜在风险评估

吡咯里西啶生物碱(pyrrolizidine alkaloids,PAs)是一种双环吡咯啶生物碱,因多数具有肝毒性,又称肝毒性吡咯里西啶生物碱(hepatotoxic PAs)。PAs广泛存在于菊科、豆科、紫草科的多种药用植物中。《中国药典》2020年版共收载含有PAs的药材8种,包括千里光Senecionis Scandentis Herba、款冬花Farfarae Flos、佩兰Eupatorii Herba、紫草Arnebiae Radix等,涉及成方制剂数十种。此外,《卫生部药品标准》《药品注册标准》等收载含PAs制剂尚有200余种。除千里光药材外,其他含PAs中药及其制剂均没有关于PAs类成分的安全限量标准,其临床用药安全存在极大的风险。对含PAs中成药的研究概况进行了系统总结、分析,以期为此类中成药的临床用药安全提供警示和参考。     

千里光属植物的毒性研究进展

对千里光属植物的毒性成分,毒性特点及其致毒机制,临床中毒报道,其主要毒性成分吡咯里西啶类生物碱pyrrolizidine alkaloids(PAs)在中草药中的分布,以及我国千里光属的应用情况进行了综述,对千里光属中草药的应用和开发提出建议。     

千里光属植物的化学成分研究进展

查阅国内外文献33篇,综述近年来有关千里光属植物在化学成分及其特征成分吡咯里西啶类生物碱的提取、分离和鉴定方法等方面的研究进展。千里光属植物由于所含的吡咯里西啶类生物碱具有肝毒作用,故在对该属植物进行开发研究新药时,安全性评价应放在首位。今后在化学成分、构效关系、药理、临床和质量控制等方面均需进一步深入研究并加以充分开发和利用。     

单麻叶千里光中肝毒吡咯里西啶生物碱的分离与鉴定

目的:研究菊科千里光属植物单麻叶千里光Senecio cannabifolius var.integrilifolius的肝毒性吡咯里西啶生物碱.方法:运用多种色谱方法进行分离纯化,应用现代波谱学分析方法进行结构鉴定.结果:从单麻叶千里光的总碱部位中分离得到4个吡咯里西啶生物碱,分别鉴定为:jacobine(1),jacoline(2),jaconine(3),senecicannabine(4).结论:化合物1～4均为首次从该植物中分离得到.     

肝毒吡咯里西啶生物碱与中草药

结合研究工作，就含肝毒吡咯里西啶生物碱中草药的安全性、质量控制、合理开发利用及从中草药中寻找拮抗、治疗吡咯里西啶生物碱肝脏毒的活性成分等方面提出了一些思路。     

自消容子水提取物对大鼠的毒性作用及肝损伤机制的初步研究

目的:研究含吡咯里西啶生物碱中草药自消容子的水提取物对大鼠的急性毒性、主要毒性靶器官及其肝损伤作用的初步机制,探讨该药材临床用药的安全性.方法:按传统水提醇沉法制备自消容子水提取物,进行急性毒性试验,采用寇氏法计算该提取物对大鼠的LD50.设定高、中、低3个剂量组和对照组对大鼠进行灌胃给药,单次给药后观察7d,7d末进行生化指标测定和组织病理学检查.进一步采用体外肝微粒体代谢方法进行实验,结合以上研究探讨其肝毒性机制.结果:自消容子水提取物灌服Wistar大鼠的LD50为(2.36 ±0.26)g·kg-1.不同剂量给药组大鼠均出现毒性反应,其中,血清转氨酶(ALT和AST)较对照组均有显著升高,组织病理学检查显示大鼠肝、肺脏有明显损伤,其程度亦呈剂量依赖性.研究还发现,肝组织结合吡咯在给药组大鼠均有形成且呈剂量依赖性的增加,同时,体外肝微粒体代谢实验也检测出吡咯代谢物,提示了肝代谢与毒性的发生具有一定的相关性.结论:自消容子具有较强的急性毒性作用;肝、肺是其主要的毒性靶器官;肝损伤作用机制与药材所含吡咯里西啶生物碱的代谢活化及其组织共价结合有关.     

Characterization of two structural forms of otonecine-type pyrrolizidine alkaloids from Ligularia hodgsonii by NMR spectroscopy

Clivorine (1) and ligularine (2), two hepatotoxic otonecine-type pyrrolizidine alkaloids isolated from Ligularia hodgsonii, an antitussive traditional Chinese medicine, were investigated in CDCl(3) and D(2)O by various NMR techniques to delineate why this type of alkaloid displays uncharacteristic solubility properties by dissolving in both nonpolar organic and aqueous solutions. The results demonstrated that both alkaloids exist in a non-ionized form in CDCl(3), but in an ionized form in D(2)O, suggesting that this unique dual solubility may play a role in the intoxication resultant from consumption of water extracts of herbs, including herbal teas, containing otonecine-type pyrrolizidine alkaloids.     

黄药子二萜内酯类成分对肝细胞毒性的实验研究(英文)

目的:考察黄药子二萜内酯成分体外实验中对肝细胞的毒性。方法:MTT法检测了黄药子二萜内酯成分对人正常肝细胞株细胞活性的影响。利用酶活法检测了肝酶在黄药子二萜内酯成分作用下细胞内释放水平,从而进一步确证其毒性。分别利用荧光比色法和流式细胞仪荧光法检测黄药子二萜内酯成分作用下细胞内谷胱甘肽和活性氧水平。结果:黄药子二萜内酯对肝细胞具有强烈的毒性作用,在黄药子二萜内酯成分作用下细胞内测谷胱甘肽下降同活性氧的上升呈相关性,而NAC能明显抑制二萜内酯对肝细胞的毒性作用。结论:黄药子二萜内酯体外对肝细胞具有毒性作用,其机制可能与该成分引起肝细胞氧化应激有关。     

The effect of Senecio latifolius a plant used as a South African traditional medicine, on a human hepatoma cell line

A number of traditional remedies used in South Africa contain pyrrolizidine alkaloids, some of which are hepatotoxic. We investigated the effect on human HuH-7 cells of Senecio latifolius DC., a plant that is a component of some traditional remedies and which is known to contain toxic pyrrolizidine alkaloids. Cells were also treated with extracts of a standard pyrrolizidine, retrorsine. The changes in the gross morphology of the cells were studied using light microscopy after haematoxylin and eosin staining. The cytoskeleton was investigated using fluorescence-labelled anti-beta-tubulin antibody and the nuclear organisation was studied using fluorescence-labelled antinuclear antibodies. The plant extracts gave rise to dose-dependent gross morphological changes. At high doses, we observed necrosis and at lower doses, destruction of the cytoskeleton, nuclear fragmentation and apoptosis. Doses of less than the equivalent of 330 ng/ml retrorsine led to multinucleated cells with failure in spindle formation and clumping of nuclear chromatin. This latter finding suggests that chronic low-dose treatment with such traditional remedies could give rise to teratogenic and/or carcinogenic effects.     

Studies of medicinal plants of Sri Lanka. Part 14: Toxicity of some traditional medicinal herbs

Seventy five medicinal plants of the traditional Ayurvedic pharmacopoeia of Sri Lanka have been screened chemically for alkaloids and pyrrolizidine alkaloids. Of these, Crotolaria juncea L. was found to contain pyrrolizidine alkaloids with biological effects consistent with pyrrolizidine alkaloid toxicity. Feeding trials in rats with three plants lacking pyrrolizidine alkaloids, namely Aegle marmelos (L.) Corr., Hemidesmus indicus (L.) Ait. F. and Terminalia chebula Retz. produced hepatic lesions which included central vein abnormalities while Terminalia chebula and Withania somnifera (L.) dunal produced marked renal lesions.     

Studies on medicinal plants of Sri Lanka: Occurrence of pyrrolizidine alkaloids and hepatotoxic properties in some traditional medicinal herbs

There is a paucity of data on the occurrence of hepatotoxic and hepatocarcinogenic pyrrolizidine alkaloids in medicinal plants, and there are no data on the hepatotoxic properties of herbal medicines that are used in the traditional pharmacopoiea of Sri Lanka and other Asian and African countries. In view of the extensive consumption of these herbs and the occurrence of chronic liver diseases including hepatocellular cancer in this and other countries of South Asia, we have screened fifty medicinal plants for pyrrolizidine alkaloids and have obtained positive results with three species, namely Crotalaria verrucosa L., Holarrhena antidysenterica (L.) Br., and Cassia auriculata L. Feeding trials in rats with materials from these three species produced liver lesions — disruption of the centrilobular veins, congestion or haemorrhage in the centrilobular sinusoids, centrilobular or focal hepatocellular necrosis — and histopathology in the lungs and kidneys which were compatible with the action of pyrrolizidine alkaloids. The presence of alkaloids in C. auriculata has not been previously reported nor has the presence of pyrrolizidine alkaloids in H. antidysenterica. It is suggested that the consumption of herbal medicines that contain pyrrólizidine alkaloids could contribute to the high incidence of chronic liver disease including primary hepatocellular cancer in Asian and African countries.     

Evaluation of Athrixia bush tea for cytotoxicity, antioxidant activity, caffeine content and presence of pyrrolizidine alkaloids

In South Africa, Athrixia phylicoides DC. (bush tea) is widely used as a beverage, cough remedy and purgative. The commercialization of this tea in a similar vein to rooibos (Aspalathus linearis), is being considered. Traditional infusions and decoctions, as well as water and ethanol extracts, were prepared and screened. A related species, Athrixia elata Sond. (daisy tea), was included in many of the assays as a comparison. Extracts of Athrixia phylicoides and Athrixia elata were tested for toxic effects to brine shrimp larvae and the Vero kidney cell line. In both assays, the traditional preparations and aqueous extracts had little effect, but the ethanol extracts were relatively toxic. Antioxidant activity comparable to that found in rooibos was established. No detectable levels of caffeine were present in the Athrixia extracts following analysis using TLC and I/HCl spray reagent. Neither screening using spectrophotometry nor confirmation using gas chromatography-mass spectrometry analyses showed evidence of pyrrolizidine alkaloids in Athrixia phylicoides. Although a wider range of studies needs to be conducted prior to commercialization, these results support the development of bush tea as a healthy alternative to caffeine-containing beverages.     

民族药铁棒锤炮制减毒原理初步研究

目的:研究铁棒锤不同炮制方法的炮制减毒原理。方法:采用高效液相色谱法和急性毒性试验比较铁棒锤炮制前后化学成分和毒性的变化。结果:生品中的主要毒性成分为乌头碱、去氧乌头碱和3-乙酰乌头碱,炮制品中这3种生物碱的含量降低,苯甲酰乌头原碱的含量增加,新出现了polyschistine-D,beyzoyldeoxyaconine,16-epi-pyroaconitine,16-epi-pyrodeoxya-conitine等生品中所不含的生物碱,从结构上分析,这些新增的成分由乌头碱等毒性成分转化而来。结论:铁棒锤的炮制减毒原理与乌头碱等有毒成分通过酯键水解和高温热解的方式转化成毒性小的成分有关,不同炮制方法均能够达到减毒的目的。     

Chemical Diversity Investigation of Hepatotoxic Pyrrolizidine Alkaloids in Qianliguang (Senecio scandens) and Related Species by UHPLC-QTOF-MS1

Objective: Qianliguang (Senecio scandens) is a common Chinese medicinal herb. Qianliguang-containing herbal proprietary products are registered as over-the-counter remedies in China and exported to Western countries. The presence of hepatotoxic pyrrolizidine alkaloids (PAs) has raised concerns about the safety of using Qianliguang and its products. The present study aims at investigation of different types of PAs present in Qianliguang collected from representative locations in China. Methods: In this study, a simple but specific UHPLC-QTOF-MS method for the determination of toxic PAs was developed, based on the characteristic fragment ions specific to different types of PAs. It was successfully applied for the identification and distinguishing of PAs present in Qianliguang and related Senecio species growing in different locations of China. Results: Significant diversity of the PA types and quantities were revealed among the samples tested. The estimated total amounts of toxic PAs in three of the samples exceed the toxic limits of PA intake restricted by WHO, demonstrating the timely and highly demand for regulating both types and quantities of PAs present in Qianliguang. Conclusions: This study provides the methodology for simultaneous identification and quantification of PAs present in herbs without requiring corresponding standards, which could be further used for more systematic investigations of the PA distribution in Qianliguang and other PA-containing herbs.