Journal of Ethnopharmacology 193 (2016) 566–573 Contents lists available at ScienceDirect Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep Review Toxic polyacetylenes in the genus Bupleurum (Apiaceae) – Distribution, toxicity, molecular mechanism and analysis crossmark ⁎ Meiyu Lin, Weidong Zhang, Juan Su School of Pharmacy, Second Military Medical University, Shanghai 200433, China ARTICLE INFO ABSTRACT Keywords: Ethnopharmacological relevance: The genus Bupleurum includes approximately 200 species that are widely Polyacetylenes distributed in the Northern Hemisphere, Eurasia and North Africa. Certain species of this genus have long been Bupleurum used as antiphlogistic, antipyretic and analgesic agents in traditional folk medicine. As described in the Chinese Toxicity Pharmacopoeia, the roots of Bupleurum chinense DC. and B. scorzonerifolium Willd. are the herbal materials Mechanism that compose Chaihu (Radix Bupleuri), a well-known TCM herb. Quality analyses Aim of the review: This review aims to provide up-to-date and comprehensive information regarding the distribution, toxicity, molecular mechanism and relatively new methods for the qualitative and quantitative determination of polyacetylenes in different Bupleurum species. Method: The information needed for this paper were sourced from publishing sites such as Elsevier, science Direct, PubMed; electronic search engines such as Scopus and Web of Science, Google scholar; other scientific database sites for chemicals such as ChemSpider, PubChem, SciFinder, and also from on line books. Results: Polyacetylenes, which are widely distributed in genus Bupleurum of the Apiaceae family, have high toxicity. Among polyacetylenes, bupleurotoxin, acetylbupleurotoxin and oenanthotoxin have strong neurotoxi- city. Through previous research, it was found that the toxicity of Bupleurum polyacetylenes manifested as epileptic seizures, with the target of toxicity being the brain. The neurotoxicity of polyacetylenes exhibits a relationship with the γ-aminobutyric acid (GABA) receptor pathway, and polyacetylenes have been shown to inhibit GABA-induced currents (IGABA) in a competitive manner. Conclusions: The plants of genus Bupleurum have been used in traditional medicine for thousands of years. However, certain species of this genus are poisonous, and it was attributed to the high content of polyacetylenes. The present review indicates that certain polyacetylenes in the genus Bupleurum have highly neurotoxic effects. The major challenge with regard to toxic polyacetylenes is to test their neurotoxic effects in vivo as well as in further preclinical studies, which will require large amounts of purified polyacetylenes. More reference substances should be prepared, and sophisticated analytical technologies should be developed to comprehen- sively assess the quality of Radix Bupleuri herbs. These investigations will be helpful for further utilization of the plants of genus Bupleurum. 1. Introduction undesirable due to their toxic properties. Certain polyacetylenes are known to be potent skin sensitizers and have a pronounced selective Polyacetylenes are widely distributed among the families cytotoxic activity against cancer cells (Machado et al., 2002; Murdoch Umbelliferae, Araliaceae, and Asteraceae. They form a distinct group and Dempster, 2000; Ahn and Kim, 1988; Matsunaga et al., 1989; of relatively reactive natural products, and more than 1400 different Matsunaga et al., 1990). Some studies have focused on the neurotoxi- polyacetylenes and related compounds have been isolated from plants city of polyacetylenes. Polyacetylenes isolated from the roots of poison (Christensen and Brandt, 2006). Some of the polyacetylenes isolated hemlock and Oenanthe fistulosa have high neurotoxicity (Anet et al., from food plants such as carrot, celery and parsley have received much 1953; Wittstock et al., 1995; Uwai et al., 2000), and some species of the attention due to their extensive physiological impact, including anti- genus of Bupleurum have also been shown to be neurotoxic at high inflammatory, antibacterial, antifungal, anticancer, antiplatelet aggre- concentrations (Vetter, 2004; Wittstock et al., 1997). gation activities. Still, some polyacetylenes have been considered The genus Bupleurum (Family: Apiaceae) includes approximately ⁎ Corresponding author. E-mail addresses: [email protected] (W. Zhang), [email protected] (J. Su). http://dx.doi.org/10.1016/j.jep.2016.09.052 Received 12 July 2016; Received in revised form 28 September 2016; Accepted 28 September 2016 Available online 30 September 2016 0378-8741/ © 2016 Elsevier Ireland Ltd. All rights reserved. M. Lin et al. Journal of Ethnopharmacology 193 (2016) 566–573 200 species, a number of which have been pharmaceutically used for authentic Chaihu samples (Huang et al., 2011). These results indicated thousands of years, mainly in Asia and Europe (Pan, 2006; Chang and that the distribution and the contents of the tested polyacetylenes in But, 1987). Preparations containing the roots of Bupleurum species different Bupleurum species vary significantly, and they were much have been prescribed for more than 2000 years in China, where the first higher in the B. longiradiatum than in the other samples. The toxicity record about their use appeared in Shen-Nong's Herbal (Yao et al., of B. longiradiatum could readily be distinguished from other medic- 2013). Certain Bupleurum species have been used in traditional inal Bupleurum species based on polyacetylene profile. medicine in Asia for the treatment of the common cold, inflammatory Thus, in order to ensure its safety clinical use, the commercially disorders, hepatitis, cancer and fever. Radix Bupleuri, with the Chinese prepared crude drugs of Chaihu in herb markets should be labeled name Chaihu, has been widely used to treat influenza, fever, inflam- before circulation, and the qualitative and quantitative determination mation, malaria as well as menstrual disorders and is recorded as being of polyacetylenes is useful for the assessment of the toxicity of crude prepared from the roots of Bupleurum Chinense and B. scorzoner- herbal material. ifolium (Family: Apiaceae) in the Chinese Pharmacopoeia (Ikegami et al., 2006; National Commission of Chinese Pharmacopoeia, 2015). 3. Toxicity of polyacetylenes However, there are at least ten species of the genus Bupleurum (Apiaceae) that are also used locally under the name Chaihu (Pan, In general, polyacetylenes which distributed in B. falcatum, B. 2006). Even worse, B. longiradiatum, widely distributed in north- spinosum, B. salicifolium, and B. acutifolium exhibit antibacterial, eastern mainland China, is a poisonous plant that has been found in anti-inflammatory, antifungal, and anti-platelet aggregatory effects herb markets (National Commission of Chinese Pharmacopoeia, 2015). (Alanko et al., 1994; Kobaisy et al., 1997; Fujimoto et al., 1998). The misuse of B. longiradiatum as Chaihu has caused several cases of However, some polyacetylenes have been considered undesirable in human poisoning, and at least three people died after administration of Bupleurum species to their toxicant properties. Polyacetylenes are this plant, showing symptoms such as serious nausea, vomiting, known to be neurotoxic in high concentrations (Anet et al., 1953), and twitching, and opisthotonus (Pan, 2006). they have also been shown to have a pronounced selective cytotoxic The investigation of the acute toxicity of B. longiradiatum extract activity against cancer cells (Matsunaga et al., 1990). uncovered strong toxicity in mice, which was attributed to its high Radix Bupleuri represents one of the most successful and widely content of polyacetylenes (Chen, 1981; You et al., 2002). This review used herbal drugs in Asia for treatment of many diseases over the past highlights the present state of knowledge on polyacetylenes in the 2000 years. There are many adulterants of Radix Bupleuri in the herb genus Bupleurum, including their distribution, toxicity, mechanism, market (Yao, 2006; Li, et al., 2012). Among them, B. longiradiatum is quality analysis and possible relevance to human health. a representative poisonous plant which contains high concentrations of polyacetylenes. And B. longiradiatum is prohibited to be used in herb 2. Distribution of polyacetylenes in the genus Bupleurum market according to the Chinese Pharmacopoeia (2015 Edition). The misuse of B. longiradiatum as Chaihu had caused several cases of The genus Bupleurum (Family: Apiaceae) includes approximately human poisoning, and at least three people died after administration of 200 species that are widely distributed in the Northern Hemisphere, this plant, which showed symptoms such as serious nausea, vomiting, Eurasia and North Africa (Su et al., 1998). In addition to the South twitching, opisthotonus, and so on (Pan, 2006; Zhao et al., 1987). The Bupleurum and the North Bupleurum described in the Chinese surveys on B. longiradiatum demonstrated that polyacetylenes were of Pharmacopoeia, there are also other species of this genus, such as B. particular abundance in root of this plant and proved to be responsible smithivar. parvifolium, B. marginatum vat. stenophyllum, B. margin- for the toxicity of B. longiradiatum (Huang et al., 2009). As major toxic atum, B. bicaule, B.smithii, B. longiradiatum Turcz, and others. ingredients of B. longiradiatum, bupleurotoxin (1), acetylbupleurotox- Certain species of this genus, such as B. chinense, B. scorzonerifolium in (2) and oenanthotoxin (5) attracted the