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Review
A review of traditional use, phytoconstituents and biological activities of Himalayan yew, Taxus wallichiana Hitender Sharma, Munish Garg Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, Haryana, India ABSTRACT Plants synthesize certain phytoconstituents for their protection, which, because they are not of primary need, are known as secondary metabolites. These secondary metabolites of plants, have often been found to have medicinal uses for human beings. One such gymnosperm having secondary metabolites of medicinal potential for humans is Taxus wallichiana (Himalayan yew). Besides being the source of taxol, this plant has been investigated for its essential oil, diterpenoids, lignans, steroids, sterols and biflavonoids. Traditionally, it is used to treat disorders of the digestive, respiratory, nervous and skeletal systems. Although pharmacologically underexplored, it has been used for antiepileptic, anti-inflammatory, anticancer, antipyretic, analgesic, immunomodulatory and antimicrobial activities. The present review compiles traditional uses, phytochemical constituents (specifically the secondary metabolites) pharmacological activities and the toxicity of T. wallichiana. Keywords: Taxus wallichiana; plants, medicinal; diterpenes; lignans; biflavonoids; pharmacological effect; review Citation: Sharma H, Garg M. A review of traditional use, phytoconstituents and biological activities of Himalayan yew, Taxus wallichiana. J Integr Med. 2015; 13(2): 80–90.
1 Introduction
Pakistan, India, Nepal, Bhutan, China, Indonesia, Malaysia, Myanmar, Vietnam and the Philippines[5]. In the Indian subcontinent, Himalayan yew is widely distributed in the temperate Himalayan region and in the hills of the northern, north eastern and eastern states (i.e., Jammu & Kashmir, Himachal Pradesh, Uttaranchal, Sikkim, Arunachal Pradesh, Assam Meghalaya, Nagaland and Manipur) at an altitude range of 1 800–3 300 m[5,6]. Morphologically, it is a dioecious evergreen tree reaching nearly 6 m in height with reddish brown bark, distichously arranged leaves, with flowers arising from the axils of the leaves, 6–14 stamens and solitary female strobili[7]. As mentioned above some ethnobotanical works use the classification suggested by Pilger (1903), where all species of Taxus have been classified as subspecies of Taxus baccata L[8]. However, some literature
Taxus is a genus of morphologically similar looking yew, distributed in the Northern Hemisphere[1,2]. The taxonomy of these yews is not well defined, and although taxonomists had previously divided the genus Taxus into one species with seven subspecies, it has recently been proposed that the genus should be separated into 24 species with 55 varieties; neither approach has gained universal acceptance[3]. Probably due to this reason, geographic location is also often used for the identification and naming of different populations. For example, European yew grows in Europe, Canadian yew is distributed within North America and Himalayan yew is the species found in Asia[4]. Himalayan yew has a wide distribution in Asia, ranging across Afghanistan,
http://dx.doi.org/10.1016/S2095-4964(15)60161-3 Received September 6, 2014; accepted December 3, 2014. Correspondence: Munish Garg, PhD, Associate Professor; Tel: +91-9812588857; E-mail: [email protected]
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also suggests that Himalayan yew is a separate species[9]. The yews of Hindu Kush-Himalaya and adjacent regions have been divided into two species, on the basis of morphological, molecular and climatic data. T. contorta is found in the Western Himalaya, distributed from Afghanistan to central Nepal, and T. wallichiana in the Eastern Himalaya, distributed from central Nepal to Yunnan Province in China. The habitat in which T. contorta is found includes the Himalayan region that receives low summer rainfall and high winter rainfall, whereas, T. wallichiana habitat is characterized by high summer and low winter rainfall[10]. Other authors have named the Western Himalayan yew as T. fuana Nan Li & R.R. Mill, which is an evergreen non-resinous gymnosperm, endemic to the Western Himalaya region of Pakistan, North India, and Southwest Xizang, China and Nepal[11]. Indeed, using modern techniques to verify the taxonomy of this genus is an area that deserves further attention. Despite the problematic nomenclature of Himalayan yew, there have been phytochemical and pharmacological investigations based on its widespread traditional uses during the last few decades. Uniformly, these literature has used the name T. wallichiana Zucc. for Himalayan yew. These studies, in addition to the ethanobotanical uses, suggest that the Himalayan yew has outstanding pharmacological potential because of its secondary metabolites. Nevertheless, a review summarizing the current understanding of the secondary metabolites of Himalayan yew is lacking. The present review compiles chemical constituents and pharmacological activities reported in published literature on yew identified as T. wallichiana, using Google, Google Scholar, ScienceDirect and PubMed databases. Unfortunately, because of taxonomic ambiguity, Himalayan yew is identified as T. baccata L. in some reports. Thus, in the present review only literature employing traditional taxonomic methods has been included, considering the fact that it may be helpful in further phytochemical and pharmacological exploration. Finally, the toxicity of Himalayan yew is also discussed briefly.
Himalayan yew is used in Indian folk medicine called “Zarnab” for its aphrodisiac and sedative properties, as well as in the treatment of bronchitis, asthma, epilepsy, snakebites and scorpion stings[5]. Various preparations and parts of the plant have specific uses. Juice from the leaves is used to treat cancer and bronchitis; bark and leaf juice is used for asthma, bronchitis and cancer, whereas dried leaves are considered to be useful for asthma, bronchitis, hiccough, epilepsy, diarrhoea and headache[17]. A tincture made from the young shoots is used for treatment of feeble and falling pulse, coldness of extremities, headache, giddiness, diarrhoea and severe biliousness[7]. A decoction prepared from the bark is used in the management of pain associated with muscles, joints and rheumatism whereas a decoction of the leaves is used for treating liver problems[18]. A decoction prepared from the bark, filtered and mixed with jaggary (a sweetener) is taken twice a day for 14 d in case of hysteria[19] and a decoction prepared from the stem is taken early in the morning to treat tuberculosis[20]. Some written works attribute antirheumatic, anticatarrhal, insecticidal and wound-healing properties to Himalayan yew and recommend the use of the drug in powder form for treatment of several disorders including vitiated blood, tumors, dermatosis and helminthiasis[8]. Himalayan yew is also an important ingredient of several Ayurvedic formulations such as lavanbhaskar churna, talisadivati, and sudarshan churna[7]. 3 Phytoconstituents 3.1 Essential oils T. wallichiana leaves are rich in essential oils[2]. Terpenes and alcohol, aldehyde, organic acid, acid esters, alkanes and alkenes are the main constituents that give it its characteristic flavor and fragrance. The major constituents of the oils are reported in Table 1[2]. 3.2 Diterpenes Diterpenes have been the most important phytocompounds of genus Taxus. These taxane diterpenoids are biosynthesized from pyruvate and glyceraldehyde-3-phosphate to form isopentenyl diphosphate and dimethylallyl diphosphate, through the 2-C-methyl-D-erythritol phosphate pathway. The isopentenyl diphosphate and dimethylallyl diphosphate act as substrate for geranylgeranyl diphosphate synthase to form geranylgeranyl diphosphate. Further, cyclization of geranylgeranyl diphosphate by taxadiene synthetase results in the formation of taxane core, which through extensive oxidative modification leads to the formation of taxol[21]. After the isolation of taxol, every species of the Taxus genus was screened for cytotoxic dipterpenes. In fact, every part of each species was investigated and diterpenes of anticancer potential have been isolated from almost every species. T. wallichiana has also been the
2 Traditional use and medicinal importance For centuries, the stem bark of Himalayan yew has been used to make tea by the Bhotiya tribal community in the Garhwal region of Himalayas[12] and to cure colds, coughs, hypertension and cancer in the buffer zone villages of Nanda Devi Biosphere Reserve[13–15]. Himalayan yew was in such demand that the use in the buffer zone of the Nanda Devi Biosphere Reserve was about 1.7 (±0.3) kg dry weight per family per year[16]. Poor families relied on the bark of this species for preparing tea for their own consumption throughout the year, whereas wealthy families also distributed bark to their relatives living elsewhere[16]. Journal of Integrative Medicine
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www.jcimjournal.com/jim Table 1 Essential oil composition of Taxus wallichiana Zucc. leaves. Essential oil
Chemical constituents
Alkane
n-Eicosane, docosane, n-pentacosane.
Alkene
Santolina triene.
Alcohol
1-Hepten-3-ol, (E)-2-hexenol, n-hexenol, n-heptan-2-ol, n-heptanol, (E)-2-octen-1-ol, (Z)-2-octen1-ol, 1-octanol, (E)-verbenol, (E)-2-nonenol, myrtenol, geraniol, eugenol, globulol.
Aldehyde
n-Heptanal, benzaldehyde, n-octanal, (E)-2-octenal, n-nonanal, (E)-2-nonenal, dodecanal, n-nonanal, anisaldehyde.
Ketones
(Z)-3-Hexenone.
Organic acid
Hexanoic acid, benzoic acid.
Organic acid esters
(Z)-3-Hexenyl formate, (Z)-3-hexenyl acetate, (E)-2-gexenyl acetate, methyl benzoate, (E)-3heptenyl acetate, octyl formate, benzyl acetate, methyl salicylate, n-octyl acetate, isopropyl-noctanoate, sabinyl acetate, (E)-2-hexenyl-n-hexanoate, anisyl acetate, (Z)-3-hexenyl benzoate, geranyl tiglate, n-amyl anisoate, geranyl-n-heptanoate, (Z)-3-hexenyl benzoate, geranyl tiglate, n-amyl anisoate, geranyl-n-heptanoate, geranyl benzoate.
Monoterpenes/monoterpene hydrates
α-Pinene, β-pinene, camphor, β-caryophyllene, (Z)-β-ocimene, (Z)-sabinene hydrate, pinene hydrate.
Sesquiterpene
β-Caryophyllene, (E)-α-bergamotene, α-humulenen, (E)-β-farnesene, caryophyllene oxide, (E,E)farnesol.
Taxaceae and Ginkgoaceae, biflavonoids have provided chemotaxonomic markers. A number of bioflavonoids have already been reported from genus Taxus[55,56]. Specifically, amentoflavone and sciadopitysin are bioflavonoids that have been isolated from T. wallichiana (Figure 3); reports also include the partial isolation of mono- and o-dimethylamentoflavone[57]. 3.5 Phytosterols and phytoecdysteroids The biosynthesis of sterols in plants not only regulates fluidity and permeability of membranes to maintain various functions of membranes, but also modulates the activities of membrane-associated proteins including enzymes, receptors and signal transduction components[58]. The sterols reported from T. wallichiana belonging to the 4-desmethylsterol type, β-sitosterol and daucosterol (β-glucosylated form of β-sitosterol; Figure 4), have been obtained from the ethanolic extract of bark[25]. β-Sitosterol has shown antiviral, antiinflammatory, antifebrile and uterotrophic effects, whereas daucosterol has been investigated for its cytotoxic effect[59]. The other steroids present in Himalayan yew are phytoecdysteroids. These phytoecdysteroids are C27, C28 or C29 compounds possessing a 14α-hydroxy-7-en6-one chromophore and A/B-cis ring fusion[60]. Plants synthesise ecdysteroids as a defence mechanism[61]. Two phytoecdysteroids isolated from the T. wallichiana are ponasterone and ecdysone (Figure 4)[62,63].
source of number of diterpenes that have been isolated from leaves, bark, roots and heartwood (Table 2 and Figure 1). Several reviews have compiled the diterpenes obtained from genus Taxus, and classified on the basis of diterpene ring[4,45]. 3.3 Lignans Lignans constitute a class of phenylpropanoid that are often biosynthesized and deposited in significant amounts in the heartwood region of the trees [46]. The isolation of lignans from T. wallichiana was first reported by Miller et al[47] during their investigation of an extract prepared from a combination of roots, stem, and needles for diterpenes. The first reported lignans were identified as α-conidendrin, β-conidendrin, hydroxymatairesinol and isoliovil [47]. Subsequent lignans isolated from the heartwood of this plant were identified as texiresinol, isotexiresinol and (–)-secoisolariciresinol[48,18] (Figure 2). Recently, these lignans have drawn considerable attention due to experimental studies in which they reduced the incidence of the certain chronic diseases[49]. Lignans such as hydroxymatairesinol and secoisolariciresinol have been found to have anticancer activities[50,51]. Texiresinol, another lignin, has also shown anticancer as well as antiulcer activities[48,52]. Another example is isotaxiresinol, which is useful for the treatment of postmenopausal osteoporosis by increasing bone formation and inhibiting bone resorption[53]. 3.4 Biflavonoids The biflavonoids are secondary metabolites that are formed through phenol-oxidative coupling of flavones, flavonols, dihydroflavonols, flavanones, isoflavones, aurones, auronols or chalcones [54]. For the majority of families belonging to Gymnospermae, including the families March 2015, Vol.13, No.2
4 Pharmacological effects 4.1 Analgesic and antipyretic effects Himalayan yew is used traditionally to relieve acute
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www.jcimjournal.com/jim Table 2 Reported diterpenes from Taxus wallichiana Part of plant Name of chemical constituents Stem, needles and roots combined Cephalomannine Taxol Baccatin III 1β-Hydroxybaccatin I 10-Deacetylcephalomannine 10-Deacetyltaxol 19-Hydroxybaccatin III Bark Taxol 7β-Xylosyltaxol 10-Deacetyl-7-xylosyltaxol 10-Deacetyl-7-Xylosyltaxol C Cephalomannine 2′-Decetoxytaxinine J 2′-Deacetoxy-5-decinnamoyltaxinine J 1-Hydroxy-2-deacetoxytaxinine J ( Taxawallin A) 2′-Deacetoxyaustrospicatine 7,2′-Bisdeacetoxyaustrospicatine Taxacustin Taxayuntin 2α-Acetoxybrevifoliol 5α,7β,10β,13α-Tetrahydroxy-2,9,15-triacetoxy-11(15-1)abeotaxa-4(20),11-diene. 5α,9α,10β,13α-Tetraacetoxy-15-hydroxy-11(15-1)abeotaxa-4(20),11-diene Taxawallin I 7,9-Dideacetyltaxayuntin Taxawallin K Tasumatrol B 4-Deacetylbaccatin III 1,13-Diacetyl-10-deacetylbaccatin III Taxamairin F Taxusabietane C Taxusabietane A Leaves/Needles 14-β-Hydroxy-10-deacetylbaccatin III 14-β-Hydroxy-10-deacetylbaccatin V 2-Debenzoyl-14β-benzoyloxy-10-deacetylbaccatin III Taxol Cephalomannine 10-Deacetylbaccatin III Brevifoliol 2-Acetoxybrevifoliol (Taxchinin) Wallifoliol 19-Debenzoyl-19-acetyltaxinine M 10,13-Deacetylabeobaccatin IV 5-Deacetyl-1-hydroxybaccatin I 2-Deacetoxytaxinine B 5αO-(3′-dimethylamino-3′-phenylpropionyl) taxinine M 7-O-acetyltaxine A 2α-Acetoxy-2′β-deacetylaustrospicatine 1-Hydroxy-2-deacetoxy-5-decinnamoyl-taxinine J Heartwood Taxusin 7-Xylosyltaxol-10-deacetyltaxol C-14 oxygenated taxoid Dibenzoylated taxoid 13-Acetyl-13-decinnamoyltaxchinin B Roots Paclitaxel 1β-Hydroxy-baccatin 1 Baccatin III Taxusin 7-Xylosyl-10-deacetyltaxol C Baccatin IV C-14 Oxygenated taxoid *
Structure number* 1 2 3 4 5 6 7 2 8 9 10 1 11 12 13 14 15 16 17 18
Reference
19
[26]
20
[26]
21 22 23 24 25 26 40 41 42 27 28 29 2 1 44 45 18 30 31 32 33 34 35 36 37 38 43 9 46 48 39 2 4 3 43 9 47 46
[27]
[22] [22] [22] [22] [23] [23] [23] [24] [24] [24] [25] [24] [24,25] [24,25] [24] [24] [24] [24] [24] [25]
[27] [27] [28] [28,29] [28] [30] [30] [31] [32] [33] [33] [34] [34] [34,35] [34] [34,35] [34] [36] [37] [38] [39] [40] [40] [40] [41] [42] [42] [42] [42] [43] [44] [44] [44] [44] [44] [44] [44]
Structure numbers are corresponding to numbers in Figure 1.
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Figure 1 (to be continued) Chemical structure of diterpenes reported from Taxus wallichiana Zucc OAc: acetyloxy; Cinn: cinnamoyl; OBz: benzyloxy; Me: methyl; Ph: phenyl.
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Figure 1 (continuation) Chemical structure of diterpenes reported from Taxus wallichiana Zucc OAc: acetyloxy; Cinn: cinnamoyl; OBz: benzyloxy; Me: methyl; Ph: phenyl.
Figure 2 Chemical structure of lignans from Taxus wallichiana Journal of Integrative Medicine
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Figure 3 Flavonoids from Taxus wallichiana
Figure 4 Sterol and phytosteroids from Taxus wallichiana
pain[12]. The antinociceptive activity of the methanolic leaf extract of T. wallichiana was investigated against induced nociception and pyrexia in rodents. This study was carried out using acetic acid-induced nociception in mice and formalin and yeast-induced pyrexia in rats. Significant analgesic effect was found in acetic acid-induced pain model at doses of 100 and 200 mg/kg i.p., respectively. Crude extract also exhibited significant inhibition of the formalin-induced noxious stimulation on both early and late phases of pain at both 100 and 200 mg/kg doses. In case of yeast-induced pyrexia model 200 mg/kg dose showed highly significant (P < 0.01) inhibition of pain, while 50 and 100 mg/kg doses also showed significant (P < 0.05) inhibition[64]. In another study, tasumatrol B, isolated from the bark of T. wallichiana, was found to have significant analgesic activity relative to the control in an acetic acid-induced pain model[28]. 4.2 Anticonvulsant effects In an experimental study, the methanol leaf extract of the T. wallichiana plant was found to control pentylenetetrazole-induced convulsions in mice at doses of 100 and 200 mg/kg i.p. The extract showed significant (P < 0.05) inhibition of the mioclonus and clonus, while inhibition of tonus and hind limb tonic extension was highly significant (P < 0.01)[64]. 4.3 Anticancer activity The diterpenoid alkaloid taxol, also called paclitaxel, was first isolated from the bark of T. brevifolia Nutt.[65] and subsequently extracted from T. wallichiana Zucc.[22,34]. It is currently used for the treatment of several forms of breast, liver, lung, blood and gynaecological cancers[66–70]. Apart from taxane diterpenes, the other phytoconstituents of T. wallichiana that have shown some potential for March 2015, Vol.13, No.2
anticancer activity in in vitro studies are lignans. Lignan taxiresinol 1, isolated from the heartwood of T. wallichiana, has shown anticancer activity in an in vitro bioassay against colon, liver, ovarian and breast cancer cell lines[48]. In addition to lignans, the taxoid taxawallin I, isolated from methanolic bark extract of T. wallichiana Zucc., exhibited significant in vitro anticancer activity against HepG2, A498, NCI-H226 and MDR 2780AD cancer cell lines[27]. Another taxoid, 1-hydroxy-2-deacetoxy-5-decinnamoyltaxinine J, has shown dose-dependent cytotoxic activity against MCF-7, WRL-68, KB PA-1, Colo 320DM human cancer cell lines as determined by MTT and clonogenic assays[41]. 4.4 Immunomodulatory activity T. wallichiana has shown immunomodulatory properties. In the experimental study, the well known immunopressant agent, cyclophosphamide, was used to suppress the proliferation of human lymphocytes. These cyclophosphamidetreated human lymphocytes showed proliferation when treated with concanavaline A (5 μg/mL), a well known immunostimulant. Cyclophosphamide-treated human lymphocytes when treated with taxoid, 1-hydroxy-2deacetoxy-5-decinnamoyl-taxinine J (1 μg/mL), also showed proliferation. Furthermore, when human lymphocytes were treated with different concentrations of 1-hydroxy2-deacetoxy-5-decinnamoyl-taxinine J (0.01–10 μg/mL), combined independently with concanavaline A (5 μg/mL), it was observed that significant proliferation of human lymphocytes occurred at concentrations of 1.0 and 2.0 μg/mL of experimental taxoid compared to the concanavaline A treatment alone. This experimental study suggested that the experimental taxoid, 1-hydroxy-2-deacetoxy-5decinnamoyl-taxinine J, had immunomodulating activity,
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which had synergistic action with concanavaline A[41]. 4.5 Anti-inflammatory activity Inflammation is an immediate response of the body to tissue and cell damage caused by pathogens, noxious substances or physical injury. The 5-lipoxygenase (5LOX) pathway plays an important role in inflammation because it synthesize leucotrienes that have direct action on endothelial cells and promote plasmatic exudation in asthmatic and other pathological conditions[71]. Himalayan yew has traditionally been used as an anti-inflammatory agent and some of these uses have been scientifically investigated. In an experimental study taxoid and taxusabietane A, isolated from the bark extract of T. wallichiana, revealed considerable 5-LOX inhibitory activity with an IC50 of (57.00 ± 0.31) μmol/L in the carrageenan-induced paw edema model of inflammation. This was more than twice the IC50 of baicalein (22.10 ± 0.03 μmol/L), a reference standard. Taxusabietane A also showed significant anti-inflammatory activity in an in vivo study at the doses of 5 and 10 mg/kg, which was comparable to 5 mg/kg dose of indomethacin[31]. In another study, taxoid tasumatrol B, although found to have anti-inflammatory activity in an acetic acid-induced model, failed to exhibit any activity in a hot-plate test or in an in vitro lipoxygenase inhibitory assay[28]. In another experimental study using the lipoxygenase inhibitory assay, abietane diterpenoids, namely taxusabietane C and taxamairin F, isolated from the bark of this plant, had an IC50 of (69.00 ± 0.31) μmol/L and (73.00 ± 0.14) μmol/L, respectively, which were significantly relative to reference standards of baicalein and tenidap sodium[30]. 4.6 Antibacterial and antifungal activity Methanol extracts of the leaf, bark and heartwood of T. wallichiana Zucc. showed antibacterial effect against Staphylococcus aureus, Pseudomonas aerugenosa and Salmonella typhi with minimum inhibitory concentrations (MICs) ranging from 0.08 to 200 mg/mL. Antifungal effects were found against Trichophyton longifusus, Microsporum canis and Fusarium solani fungal strains[72]. In another study, the ethanolic extract of bark from T. wallichiana was found to have antifungal effects against Blastoschizomyces capitatus[73]. 4.7 Toxicological status of Himalayan yew As mentioned earlier, Himalayan yew is widely used for its medicinal potential. These traditional uses are in contrast to European yew, which is reported to be toxic. In fact, reports of human fatalities related to the consumption of Taxus baccata L. are found as early as first century B.C. One of the most cited examples is of Catuvolcus, the king of Eburones, who while at war with Julius Caesar, committed suicide by taking yew[74]. In recent literature, it has been reported that all yew varieties that are grown in gardens, such as English yew (T. baccata), Pacific or Western yew (T. brevifolia), American yew (T. canadensis), Journal of Integrative Medicine
and Japanese yew (Taxus cuspidata), are toxic and have been implicated in human and animal poisonings[75]. The chemical constituents responsible for the toxicity are the basic, or alkaloid diterpenes. These white, noncrystalline, alkaloid diterpenes were first recovered by Lucas (1856), from the foliage of T. baccata L. during the phytochemical analysis of alkaloid content, and were named “taxines”. The identification of taxines based on the presence of β-dimethylamino-βphenylpropionic acid was first reported by Winterstein et al (1921), while studying the degradation of taxines. The poisonous taxines of European yew such as taxine A, 2-deacetyltaxine A, isotaxine B, and 1-deoxytaxine B, derived from p-dimethylaminohydroxycinnamic acid, have not been reported in T. wallichiana. These taxines are so toxic that an infusion made from 50 to 100 g of needles can be fatal, with symptoms manifesting after 30 to 90 min of the time of consumption[75,76]. Himalayan yew appears to have little or no toxicity. This opinion has been echoed by some researchers, suggesting either low content of taxines or their easy degradation during storage[35,45]. In fact, it is reported that taxines are unstable in a neutral or alkaline environment, and are sensitive to photodegradation[77]. This instability may play a critical role in making Himalayan yew a medicinally important plant. Nevertheless, three taxines have been found in the leaves of this plant[38]. It has been observed that the polarity of the solvent used for extraction plays a role in toxicity of the extract[78]. Presently, the toxicity and stability of the taxines found in T. wallichiana pose important research questions that need to be addressed before sanctioning the use of Himalayan yew in medicine. Broadly, the presence of taxines may also provide a tool for chemotaxonomic classification of yews of the Himalayan region. This added information might enhance the climatic, morphological and genetic approach to taxonomy in the Himalayan region. 5 Conclusion Himalayan yew is a gymnosperm that has widespread traditional use. During the early and late 1990’s there was intense focus on the cytotoxic chemical constituents from this plant, and there was little interest in experimental validation of its traditional uses. During the last decade traditional uses have received increased scrutiny in suitable in vitro and in vivo animal models. Although recent studies have contributed to confusion in the taxonomy of the genus, the species in western and eastern Himalaya have been argued to show morphological diversification due to environmental and climatic effects. This re-enforces the need of further experimentation beyond ethanopharmacological screening, focusing on the chemotaxonomical
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difference between these species. Identifying distinctions in morphological characters may be a useful tool for proper identification of these two species, and may be further useful for ethanopharmacological and phytochemical studies. Furthermore, the widespread traditional uses of Himalayan yew suggest a difference in toxicity between Himalayan and European yew, emphasizing the need for further investigation. In the present review, chemical, pharmacological and toxicological studies of Himalayan yew have been discussed, in addition to a review of its traditional uses and taxonomic ambiguities, suggesting several avenues for further study.
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6 Acknowledgements
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The authors acknowledge the anonymous reviewers for their valuable comments. 7 Conflict of interests
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The authors declare that they have no competing interests. References
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SM. Molecular simulations of Taxawallin I inside classical taxol binding site of β-tubulin. Fitoterapia. 2011; 82(2): 276–281. Qayum M, Nisar M, Shah MR, Adhikari A, Kaleem WA, Khan I, Khan N, Gul F, Khan IA, Zia-Ul-Haq M, Khan A. Analgesic and anti-inflammatory activities of taxoids from Taxus wallichiana Zucc. Phytother Res. 2012; 26(4): 552– 556. Nisar M, Qayum M, Adhikari A, Khan I, Kaleem WA, Ali Z, Choudhary MI. 4-Deacetylbaccatin III: a proposed biosynthetic precursor of paclitaxel from the bark of Taxus wallichiana. Nat Prod Commun. 2010; 5(11): 1727–1728. Khan I, Nisar M, Zarrelli A, Fabio GD, Gul F, Gilani SN, Shah MR, Khan AZ, Samiullah, Amin H. Molecular insights to explore abietane diterpenes as new LOX inhibitors. Med Chem Res. 2013; 22(12): 5809–5813. Khan I, Nisar M, Shah MR, Shah H, Gilani SN, Gul F, Abdullah SM, Ismail M, Khan N, Kaleem WA, Qayum M, Khan H, Obaidullah, Samiullah, Ullah M. Anti-inflammatory activities of taxusabietane A isolated from Taxus wallichiana Zucc. Fitoterapia. 2011; 82(7): 1003–1007. Appendino G, Gariboldi P, Gabetta B, Pace R, Bombardelli E, Viterbo D. 14β-Hydroxy-10-deacetylbaccatin III, a new taxane from Himalayan yew (Taxus wallichiana Zucc.). J Chem Soc. 1992; 21: 2925–2929. Appendino G, Özen HÇ, Gariboldi P, Torregiani E, Gabetta B, Nizzola R, Bombardelli E. New oxetane type taxane from Taxus wallichiana Zucc. J Chem Soc Perkin Trans. 1993; (14): 1563–1566. Vander Velde DG, Georg GI, Gollapudi SR, Jampani HB, Liang XZ, Mitscher LA, Ye QM. Wallifoliol, a taxol congener with a novel carbon skeleton, from Himalayan Taxus wallichiana. J Nat Prod. 1994; 56(6): 861–867. Bala S, Uniyal GC, Chattopadhyay SK, Tripathi V, Sashidhara KV, Kulshrestha M, Sharma RP, Jain SP, Kukreja AK, Kumar S. Analysis of taxol and major taxoids in Himalayan yew, Taxus wallichiana. J Chromatogr A. 1999; 858(2): 239–244. Barboni L, Gariboldi P, Torregiani E, Appendino G, Varese M, Gabetta B, Bombardelli E. Minor taxoid from Taxus wallichiana. J Nat Prod. 1995; 58(6): 934–939. Chattopadhyay SK, Sharma RP, Appendino G, Gariboldi P. A rearranged taxane from the Himalayan yew. Phytochemistry. 1995; 39: 869–870. Barboni L, Lambertucci C, Appendino G, Gabetta B. A taxane epoxide from Taxus wallichiana. Phytochemistry. 1997; 46(1): 179–180. Shrestha TB, Khatri Chetri SK, Banskota AH, Manandhar MD. 2-Deacetoxytaxinine B: a new taxane from Taxus wallichiana. J Nat Prod. 1997; 60(8): 820–821. Prasain JK, Stefanowicz P, Kiyota T, Habeichi F, Konishi Y. Taxines from the needles of Taxus wallichiana. Phytochemistry. 2001; 58(8): 1167–1170. Chattopadhyay SK, Pal A, Maulik PR, Kaur T, Garg A, Khanuja SPS. Taxoid from the needles of the Himalayan yew Taxus wallichiana with cytotoxic and immunomodulatory activities. Bioorg Med Chem Lett. 2006; 16(9): 2446–2449. Chattopadhyay SK, Kulshrestha M, Saha GC, Sharma RP, Jain SP, Kumar S. The taxoid constituents of the heartwood of Taxus wallichiana. Planta Med. 1996; 62(5): 482.
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www.jcimjournal.com/jim 2001; 57(3): 325–339. 61 Schmelz EA, Grebenok RJ, Ohnmeiss TS, Bowers WS. Interaction between Spinacia oleracea and Bradysia impatiens: a role for phytoecdysteroids. Arch Insect Biochem Physiol. 2000; 51(4): 204–221. 62 Chattopadhyay SK, Tripathi V, Shawl AS, Roy R, Joshi BS. Studies on the Himalayan yew Taxus wallichiana: Part VIII ― Isolation of additional taxoids and ponasterone from the leaves of T. wallichiana. Indian J Chem. 1999; 38B(7): 874–876. 63 Rufaie ZH, Munshi NA, Sharma RK, Ahmad K, Malik GN, Raja TA. Occurrence of insect moulting hormone (β-ecdysone) in some locally available plants. Int J Adv Biol Res. 2011; 1(1): 104–107. 64 Nisar M, Khan I, Simjee SU, Gilani AH, Obaidullah, Perveen H. Anticonvulsant, analgesic and antipyretic activities of Taxus wallichiana Zucc. J Ethnopharmacol. 2008; 116(3): 490–494. 65 Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc. 1971; 93: 2325–2327. 66 McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC. Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med. 1989; 111(4): 273–279. 67 Rowinsky EK, Cazenave LA, Donehower RC. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst. 1990; 82(15): 283–304. 68 Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortabagyi GN. Phase II trial of taxol, an active drug in the treatment of
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Review
A review of traditional use, phytoconstituents and biological activities of Himalayan yew, Taxus wallichiana Hitender Sharma, Munish Garg Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak-124001, Haryana, India ABSTRACT Plants synthesize certain phytoconstituents for their protection, which, because they are not of primary need, are known as secondary metabolites. These secondary metabolites of plants, have often been found to have medicinal uses for human beings. One such gymnosperm having secondary metabolites of medicinal potential for humans is Taxus wallichiana (Himalayan yew). Besides being the source of taxol, this plant has been investigated for its essential oil, diterpenoids, lignans, steroids, sterols and biflavonoids. Traditionally, it is used to treat disorders of the digestive, respiratory, nervous and skeletal systems. Although pharmacologically underexplored, it has been used for antiepileptic, anti-inflammatory, anticancer, antipyretic, analgesic, immunomodulatory and antimicrobial activities. The present review compiles traditional uses, phytochemical constituents (specifically the secondary metabolites) pharmacological activities and the toxicity of T. wallichiana. Keywords: Taxus wallichiana; plants, medicinal; diterpenes; lignans; biflavonoids; pharmacological effect; review Citation: Sharma H, Garg M. A review of traditional use, phytoconstituents and biological activities of Himalayan yew, Taxus wallichiana. J Integr Med. 2015; 13(2): 80–90.
1 Introduction
Pakistan, India, Nepal, Bhutan, China, Indonesia, Malaysia, Myanmar, Vietnam and the Philippines[5]. In the Indian subcontinent, Himalayan yew is widely distributed in the temperate Himalayan region and in the hills of the northern, north eastern and eastern states (i.e., Jammu & Kashmir, Himachal Pradesh, Uttaranchal, Sikkim, Arunachal Pradesh, Assam Meghalaya, Nagaland and Manipur) at an altitude range of 1 800–3 300 m[5,6]. Morphologically, it is a dioecious evergreen tree reaching nearly 6 m in height with reddish brown bark, distichously arranged leaves, with flowers arising from the axils of the leaves, 6–14 stamens and solitary female strobili[7]. As mentioned above some ethnobotanical works use the classification suggested by Pilger (1903), where all species of Taxus have been classified as subspecies of Taxus baccata L[8]. However, some literature
Taxus is a genus of morphologically similar looking yew, distributed in the Northern Hemisphere[1,2]. The taxonomy of these yews is not well defined, and although taxonomists had previously divided the genus Taxus into one species with seven subspecies, it has recently been proposed that the genus should be separated into 24 species with 55 varieties; neither approach has gained universal acceptance[3]. Probably due to this reason, geographic location is also often used for the identification and naming of different populations. For example, European yew grows in Europe, Canadian yew is distributed within North America and Himalayan yew is the species found in Asia[4]. Himalayan yew has a wide distribution in Asia, ranging across Afghanistan,
http://dx.doi.org/10.1016/S2095-4964(15)60161-3 Received September 6, 2014; accepted December 3, 2014. Correspondence: Munish Garg, PhD, Associate Professor; Tel: +91-9812588857; E-mail: [email protected]
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also suggests that Himalayan yew is a separate species[9]. The yews of Hindu Kush-Himalaya and adjacent regions have been divided into two species, on the basis of morphological, molecular and climatic data. T. contorta is found in the Western Himalaya, distributed from Afghanistan to central Nepal, and T. wallichiana in the Eastern Himalaya, distributed from central Nepal to Yunnan Province in China. The habitat in which T. contorta is found includes the Himalayan region that receives low summer rainfall and high winter rainfall, whereas, T. wallichiana habitat is characterized by high summer and low winter rainfall[10]. Other authors have named the Western Himalayan yew as T. fuana Nan Li & R.R. Mill, which is an evergreen non-resinous gymnosperm, endemic to the Western Himalaya region of Pakistan, North India, and Southwest Xizang, China and Nepal[11]. Indeed, using modern techniques to verify the taxonomy of this genus is an area that deserves further attention. Despite the problematic nomenclature of Himalayan yew, there have been phytochemical and pharmacological investigations based on its widespread traditional uses during the last few decades. Uniformly, these literature has used the name T. wallichiana Zucc. for Himalayan yew. These studies, in addition to the ethanobotanical uses, suggest that the Himalayan yew has outstanding pharmacological potential because of its secondary metabolites. Nevertheless, a review summarizing the current understanding of the secondary metabolites of Himalayan yew is lacking. The present review compiles chemical constituents and pharmacological activities reported in published literature on yew identified as T. wallichiana, using Google, Google Scholar, ScienceDirect and PubMed databases. Unfortunately, because of taxonomic ambiguity, Himalayan yew is identified as T. baccata L. in some reports. Thus, in the present review only literature employing traditional taxonomic methods has been included, considering the fact that it may be helpful in further phytochemical and pharmacological exploration. Finally, the toxicity of Himalayan yew is also discussed briefly.
Himalayan yew is used in Indian folk medicine called “Zarnab” for its aphrodisiac and sedative properties, as well as in the treatment of bronchitis, asthma, epilepsy, snakebites and scorpion stings[5]. Various preparations and parts of the plant have specific uses. Juice from the leaves is used to treat cancer and bronchitis; bark and leaf juice is used for asthma, bronchitis and cancer, whereas dried leaves are considered to be useful for asthma, bronchitis, hiccough, epilepsy, diarrhoea and headache[17]. A tincture made from the young shoots is used for treatment of feeble and falling pulse, coldness of extremities, headache, giddiness, diarrhoea and severe biliousness[7]. A decoction prepared from the bark is used in the management of pain associated with muscles, joints and rheumatism whereas a decoction of the leaves is used for treating liver problems[18]. A decoction prepared from the bark, filtered and mixed with jaggary (a sweetener) is taken twice a day for 14 d in case of hysteria[19] and a decoction prepared from the stem is taken early in the morning to treat tuberculosis[20]. Some written works attribute antirheumatic, anticatarrhal, insecticidal and wound-healing properties to Himalayan yew and recommend the use of the drug in powder form for treatment of several disorders including vitiated blood, tumors, dermatosis and helminthiasis[8]. Himalayan yew is also an important ingredient of several Ayurvedic formulations such as lavanbhaskar churna, talisadivati, and sudarshan churna[7]. 3 Phytoconstituents 3.1 Essential oils T. wallichiana leaves are rich in essential oils[2]. Terpenes and alcohol, aldehyde, organic acid, acid esters, alkanes and alkenes are the main constituents that give it its characteristic flavor and fragrance. The major constituents of the oils are reported in Table 1[2]. 3.2 Diterpenes Diterpenes have been the most important phytocompounds of genus Taxus. These taxane diterpenoids are biosynthesized from pyruvate and glyceraldehyde-3-phosphate to form isopentenyl diphosphate and dimethylallyl diphosphate, through the 2-C-methyl-D-erythritol phosphate pathway. The isopentenyl diphosphate and dimethylallyl diphosphate act as substrate for geranylgeranyl diphosphate synthase to form geranylgeranyl diphosphate. Further, cyclization of geranylgeranyl diphosphate by taxadiene synthetase results in the formation of taxane core, which through extensive oxidative modification leads to the formation of taxol[21]. After the isolation of taxol, every species of the Taxus genus was screened for cytotoxic dipterpenes. In fact, every part of each species was investigated and diterpenes of anticancer potential have been isolated from almost every species. T. wallichiana has also been the
2 Traditional use and medicinal importance For centuries, the stem bark of Himalayan yew has been used to make tea by the Bhotiya tribal community in the Garhwal region of Himalayas[12] and to cure colds, coughs, hypertension and cancer in the buffer zone villages of Nanda Devi Biosphere Reserve[13–15]. Himalayan yew was in such demand that the use in the buffer zone of the Nanda Devi Biosphere Reserve was about 1.7 (±0.3) kg dry weight per family per year[16]. Poor families relied on the bark of this species for preparing tea for their own consumption throughout the year, whereas wealthy families also distributed bark to their relatives living elsewhere[16]. Journal of Integrative Medicine
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www.jcimjournal.com/jim Table 1 Essential oil composition of Taxus wallichiana Zucc. leaves. Essential oil
Chemical constituents
Alkane
n-Eicosane, docosane, n-pentacosane.
Alkene
Santolina triene.
Alcohol
1-Hepten-3-ol, (E)-2-hexenol, n-hexenol, n-heptan-2-ol, n-heptanol, (E)-2-octen-1-ol, (Z)-2-octen1-ol, 1-octanol, (E)-verbenol, (E)-2-nonenol, myrtenol, geraniol, eugenol, globulol.
Aldehyde
n-Heptanal, benzaldehyde, n-octanal, (E)-2-octenal, n-nonanal, (E)-2-nonenal, dodecanal, n-nonanal, anisaldehyde.
Ketones
(Z)-3-Hexenone.
Organic acid
Hexanoic acid, benzoic acid.
Organic acid esters
(Z)-3-Hexenyl formate, (Z)-3-hexenyl acetate, (E)-2-gexenyl acetate, methyl benzoate, (E)-3heptenyl acetate, octyl formate, benzyl acetate, methyl salicylate, n-octyl acetate, isopropyl-noctanoate, sabinyl acetate, (E)-2-hexenyl-n-hexanoate, anisyl acetate, (Z)-3-hexenyl benzoate, geranyl tiglate, n-amyl anisoate, geranyl-n-heptanoate, (Z)-3-hexenyl benzoate, geranyl tiglate, n-amyl anisoate, geranyl-n-heptanoate, geranyl benzoate.
Monoterpenes/monoterpene hydrates
α-Pinene, β-pinene, camphor, β-caryophyllene, (Z)-β-ocimene, (Z)-sabinene hydrate, pinene hydrate.
Sesquiterpene
β-Caryophyllene, (E)-α-bergamotene, α-humulenen, (E)-β-farnesene, caryophyllene oxide, (E,E)farnesol.
Taxaceae and Ginkgoaceae, biflavonoids have provided chemotaxonomic markers. A number of bioflavonoids have already been reported from genus Taxus[55,56]. Specifically, amentoflavone and sciadopitysin are bioflavonoids that have been isolated from T. wallichiana (Figure 3); reports also include the partial isolation of mono- and o-dimethylamentoflavone[57]. 3.5 Phytosterols and phytoecdysteroids The biosynthesis of sterols in plants not only regulates fluidity and permeability of membranes to maintain various functions of membranes, but also modulates the activities of membrane-associated proteins including enzymes, receptors and signal transduction components[58]. The sterols reported from T. wallichiana belonging to the 4-desmethylsterol type, β-sitosterol and daucosterol (β-glucosylated form of β-sitosterol; Figure 4), have been obtained from the ethanolic extract of bark[25]. β-Sitosterol has shown antiviral, antiinflammatory, antifebrile and uterotrophic effects, whereas daucosterol has been investigated for its cytotoxic effect[59]. The other steroids present in Himalayan yew are phytoecdysteroids. These phytoecdysteroids are C27, C28 or C29 compounds possessing a 14α-hydroxy-7-en6-one chromophore and A/B-cis ring fusion[60]. Plants synthesise ecdysteroids as a defence mechanism[61]. Two phytoecdysteroids isolated from the T. wallichiana are ponasterone and ecdysone (Figure 4)[62,63].
source of number of diterpenes that have been isolated from leaves, bark, roots and heartwood (Table 2 and Figure 1). Several reviews have compiled the diterpenes obtained from genus Taxus, and classified on the basis of diterpene ring[4,45]. 3.3 Lignans Lignans constitute a class of phenylpropanoid that are often biosynthesized and deposited in significant amounts in the heartwood region of the trees [46]. The isolation of lignans from T. wallichiana was first reported by Miller et al[47] during their investigation of an extract prepared from a combination of roots, stem, and needles for diterpenes. The first reported lignans were identified as α-conidendrin, β-conidendrin, hydroxymatairesinol and isoliovil [47]. Subsequent lignans isolated from the heartwood of this plant were identified as texiresinol, isotexiresinol and (–)-secoisolariciresinol[48,18] (Figure 2). Recently, these lignans have drawn considerable attention due to experimental studies in which they reduced the incidence of the certain chronic diseases[49]. Lignans such as hydroxymatairesinol and secoisolariciresinol have been found to have anticancer activities[50,51]. Texiresinol, another lignin, has also shown anticancer as well as antiulcer activities[48,52]. Another example is isotaxiresinol, which is useful for the treatment of postmenopausal osteoporosis by increasing bone formation and inhibiting bone resorption[53]. 3.4 Biflavonoids The biflavonoids are secondary metabolites that are formed through phenol-oxidative coupling of flavones, flavonols, dihydroflavonols, flavanones, isoflavones, aurones, auronols or chalcones [54]. For the majority of families belonging to Gymnospermae, including the families March 2015, Vol.13, No.2
4 Pharmacological effects 4.1 Analgesic and antipyretic effects Himalayan yew is used traditionally to relieve acute
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www.jcimjournal.com/jim Table 2 Reported diterpenes from Taxus wallichiana Part of plant Name of chemical constituents Stem, needles and roots combined Cephalomannine Taxol Baccatin III 1β-Hydroxybaccatin I 10-Deacetylcephalomannine 10-Deacetyltaxol 19-Hydroxybaccatin III Bark Taxol 7β-Xylosyltaxol 10-Deacetyl-7-xylosyltaxol 10-Deacetyl-7-Xylosyltaxol C Cephalomannine 2′-Decetoxytaxinine J 2′-Deacetoxy-5-decinnamoyltaxinine J 1-Hydroxy-2-deacetoxytaxinine J ( Taxawallin A) 2′-Deacetoxyaustrospicatine 7,2′-Bisdeacetoxyaustrospicatine Taxacustin Taxayuntin 2α-Acetoxybrevifoliol 5α,7β,10β,13α-Tetrahydroxy-2,9,15-triacetoxy-11(15-1)abeotaxa-4(20),11-diene. 5α,9α,10β,13α-Tetraacetoxy-15-hydroxy-11(15-1)abeotaxa-4(20),11-diene Taxawallin I 7,9-Dideacetyltaxayuntin Taxawallin K Tasumatrol B 4-Deacetylbaccatin III 1,13-Diacetyl-10-deacetylbaccatin III Taxamairin F Taxusabietane C Taxusabietane A Leaves/Needles 14-β-Hydroxy-10-deacetylbaccatin III 14-β-Hydroxy-10-deacetylbaccatin V 2-Debenzoyl-14β-benzoyloxy-10-deacetylbaccatin III Taxol Cephalomannine 10-Deacetylbaccatin III Brevifoliol 2-Acetoxybrevifoliol (Taxchinin) Wallifoliol 19-Debenzoyl-19-acetyltaxinine M 10,13-Deacetylabeobaccatin IV 5-Deacetyl-1-hydroxybaccatin I 2-Deacetoxytaxinine B 5αO-(3′-dimethylamino-3′-phenylpropionyl) taxinine M 7-O-acetyltaxine A 2α-Acetoxy-2′β-deacetylaustrospicatine 1-Hydroxy-2-deacetoxy-5-decinnamoyl-taxinine J Heartwood Taxusin 7-Xylosyltaxol-10-deacetyltaxol C-14 oxygenated taxoid Dibenzoylated taxoid 13-Acetyl-13-decinnamoyltaxchinin B Roots Paclitaxel 1β-Hydroxy-baccatin 1 Baccatin III Taxusin 7-Xylosyl-10-deacetyltaxol C Baccatin IV C-14 Oxygenated taxoid *
Structure number* 1 2 3 4 5 6 7 2 8 9 10 1 11 12 13 14 15 16 17 18
Reference
19
[26]
20
[26]
21 22 23 24 25 26 40 41 42 27 28 29 2 1 44 45 18 30 31 32 33 34 35 36 37 38 43 9 46 48 39 2 4 3 43 9 47 46
[27]
[22] [22] [22] [22] [23] [23] [23] [24] [24] [24] [25] [24] [24,25] [24,25] [24] [24] [24] [24] [24] [25]
[27] [27] [28] [28,29] [28] [30] [30] [31] [32] [33] [33] [34] [34] [34,35] [34] [34,35] [34] [36] [37] [38] [39] [40] [40] [40] [41] [42] [42] [42] [42] [43] [44] [44] [44] [44] [44] [44] [44]
Structure numbers are corresponding to numbers in Figure 1.
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Figure 1 (to be continued) Chemical structure of diterpenes reported from Taxus wallichiana Zucc OAc: acetyloxy; Cinn: cinnamoyl; OBz: benzyloxy; Me: methyl; Ph: phenyl.
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Figure 1 (continuation) Chemical structure of diterpenes reported from Taxus wallichiana Zucc OAc: acetyloxy; Cinn: cinnamoyl; OBz: benzyloxy; Me: methyl; Ph: phenyl.
Figure 2 Chemical structure of lignans from Taxus wallichiana Journal of Integrative Medicine
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Figure 3 Flavonoids from Taxus wallichiana
Figure 4 Sterol and phytosteroids from Taxus wallichiana
pain[12]. The antinociceptive activity of the methanolic leaf extract of T. wallichiana was investigated against induced nociception and pyrexia in rodents. This study was carried out using acetic acid-induced nociception in mice and formalin and yeast-induced pyrexia in rats. Significant analgesic effect was found in acetic acid-induced pain model at doses of 100 and 200 mg/kg i.p., respectively. Crude extract also exhibited significant inhibition of the formalin-induced noxious stimulation on both early and late phases of pain at both 100 and 200 mg/kg doses. In case of yeast-induced pyrexia model 200 mg/kg dose showed highly significant (P < 0.01) inhibition of pain, while 50 and 100 mg/kg doses also showed significant (P < 0.05) inhibition[64]. In another study, tasumatrol B, isolated from the bark of T. wallichiana, was found to have significant analgesic activity relative to the control in an acetic acid-induced pain model[28]. 4.2 Anticonvulsant effects In an experimental study, the methanol leaf extract of the T. wallichiana plant was found to control pentylenetetrazole-induced convulsions in mice at doses of 100 and 200 mg/kg i.p. The extract showed significant (P < 0.05) inhibition of the mioclonus and clonus, while inhibition of tonus and hind limb tonic extension was highly significant (P < 0.01)[64]. 4.3 Anticancer activity The diterpenoid alkaloid taxol, also called paclitaxel, was first isolated from the bark of T. brevifolia Nutt.[65] and subsequently extracted from T. wallichiana Zucc.[22,34]. It is currently used for the treatment of several forms of breast, liver, lung, blood and gynaecological cancers[66–70]. Apart from taxane diterpenes, the other phytoconstituents of T. wallichiana that have shown some potential for March 2015, Vol.13, No.2
anticancer activity in in vitro studies are lignans. Lignan taxiresinol 1, isolated from the heartwood of T. wallichiana, has shown anticancer activity in an in vitro bioassay against colon, liver, ovarian and breast cancer cell lines[48]. In addition to lignans, the taxoid taxawallin I, isolated from methanolic bark extract of T. wallichiana Zucc., exhibited significant in vitro anticancer activity against HepG2, A498, NCI-H226 and MDR 2780AD cancer cell lines[27]. Another taxoid, 1-hydroxy-2-deacetoxy-5-decinnamoyltaxinine J, has shown dose-dependent cytotoxic activity against MCF-7, WRL-68, KB PA-1, Colo 320DM human cancer cell lines as determined by MTT and clonogenic assays[41]. 4.4 Immunomodulatory activity T. wallichiana has shown immunomodulatory properties. In the experimental study, the well known immunopressant agent, cyclophosphamide, was used to suppress the proliferation of human lymphocytes. These cyclophosphamidetreated human lymphocytes showed proliferation when treated with concanavaline A (5 μg/mL), a well known immunostimulant. Cyclophosphamide-treated human lymphocytes when treated with taxoid, 1-hydroxy-2deacetoxy-5-decinnamoyl-taxinine J (1 μg/mL), also showed proliferation. Furthermore, when human lymphocytes were treated with different concentrations of 1-hydroxy2-deacetoxy-5-decinnamoyl-taxinine J (0.01–10 μg/mL), combined independently with concanavaline A (5 μg/mL), it was observed that significant proliferation of human lymphocytes occurred at concentrations of 1.0 and 2.0 μg/mL of experimental taxoid compared to the concanavaline A treatment alone. This experimental study suggested that the experimental taxoid, 1-hydroxy-2-deacetoxy-5decinnamoyl-taxinine J, had immunomodulating activity,
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which had synergistic action with concanavaline A[41]. 4.5 Anti-inflammatory activity Inflammation is an immediate response of the body to tissue and cell damage caused by pathogens, noxious substances or physical injury. The 5-lipoxygenase (5LOX) pathway plays an important role in inflammation because it synthesize leucotrienes that have direct action on endothelial cells and promote plasmatic exudation in asthmatic and other pathological conditions[71]. Himalayan yew has traditionally been used as an anti-inflammatory agent and some of these uses have been scientifically investigated. In an experimental study taxoid and taxusabietane A, isolated from the bark extract of T. wallichiana, revealed considerable 5-LOX inhibitory activity with an IC50 of (57.00 ± 0.31) μmol/L in the carrageenan-induced paw edema model of inflammation. This was more than twice the IC50 of baicalein (22.10 ± 0.03 μmol/L), a reference standard. Taxusabietane A also showed significant anti-inflammatory activity in an in vivo study at the doses of 5 and 10 mg/kg, which was comparable to 5 mg/kg dose of indomethacin[31]. In another study, taxoid tasumatrol B, although found to have anti-inflammatory activity in an acetic acid-induced model, failed to exhibit any activity in a hot-plate test or in an in vitro lipoxygenase inhibitory assay[28]. In another experimental study using the lipoxygenase inhibitory assay, abietane diterpenoids, namely taxusabietane C and taxamairin F, isolated from the bark of this plant, had an IC50 of (69.00 ± 0.31) μmol/L and (73.00 ± 0.14) μmol/L, respectively, which were significantly relative to reference standards of baicalein and tenidap sodium[30]. 4.6 Antibacterial and antifungal activity Methanol extracts of the leaf, bark and heartwood of T. wallichiana Zucc. showed antibacterial effect against Staphylococcus aureus, Pseudomonas aerugenosa and Salmonella typhi with minimum inhibitory concentrations (MICs) ranging from 0.08 to 200 mg/mL. Antifungal effects were found against Trichophyton longifusus, Microsporum canis and Fusarium solani fungal strains[72]. In another study, the ethanolic extract of bark from T. wallichiana was found to have antifungal effects against Blastoschizomyces capitatus[73]. 4.7 Toxicological status of Himalayan yew As mentioned earlier, Himalayan yew is widely used for its medicinal potential. These traditional uses are in contrast to European yew, which is reported to be toxic. In fact, reports of human fatalities related to the consumption of Taxus baccata L. are found as early as first century B.C. One of the most cited examples is of Catuvolcus, the king of Eburones, who while at war with Julius Caesar, committed suicide by taking yew[74]. In recent literature, it has been reported that all yew varieties that are grown in gardens, such as English yew (T. baccata), Pacific or Western yew (T. brevifolia), American yew (T. canadensis), Journal of Integrative Medicine
and Japanese yew (Taxus cuspidata), are toxic and have been implicated in human and animal poisonings[75]. The chemical constituents responsible for the toxicity are the basic, or alkaloid diterpenes. These white, noncrystalline, alkaloid diterpenes were first recovered by Lucas (1856), from the foliage of T. baccata L. during the phytochemical analysis of alkaloid content, and were named “taxines”. The identification of taxines based on the presence of β-dimethylamino-βphenylpropionic acid was first reported by Winterstein et al (1921), while studying the degradation of taxines. The poisonous taxines of European yew such as taxine A, 2-deacetyltaxine A, isotaxine B, and 1-deoxytaxine B, derived from p-dimethylaminohydroxycinnamic acid, have not been reported in T. wallichiana. These taxines are so toxic that an infusion made from 50 to 100 g of needles can be fatal, with symptoms manifesting after 30 to 90 min of the time of consumption[75,76]. Himalayan yew appears to have little or no toxicity. This opinion has been echoed by some researchers, suggesting either low content of taxines or their easy degradation during storage[35,45]. In fact, it is reported that taxines are unstable in a neutral or alkaline environment, and are sensitive to photodegradation[77]. This instability may play a critical role in making Himalayan yew a medicinally important plant. Nevertheless, three taxines have been found in the leaves of this plant[38]. It has been observed that the polarity of the solvent used for extraction plays a role in toxicity of the extract[78]. Presently, the toxicity and stability of the taxines found in T. wallichiana pose important research questions that need to be addressed before sanctioning the use of Himalayan yew in medicine. Broadly, the presence of taxines may also provide a tool for chemotaxonomic classification of yews of the Himalayan region. This added information might enhance the climatic, morphological and genetic approach to taxonomy in the Himalayan region. 5 Conclusion Himalayan yew is a gymnosperm that has widespread traditional use. During the early and late 1990’s there was intense focus on the cytotoxic chemical constituents from this plant, and there was little interest in experimental validation of its traditional uses. During the last decade traditional uses have received increased scrutiny in suitable in vitro and in vivo animal models. Although recent studies have contributed to confusion in the taxonomy of the genus, the species in western and eastern Himalaya have been argued to show morphological diversification due to environmental and climatic effects. This re-enforces the need of further experimentation beyond ethanopharmacological screening, focusing on the chemotaxonomical
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difference between these species. Identifying distinctions in morphological characters may be a useful tool for proper identification of these two species, and may be further useful for ethanopharmacological and phytochemical studies. Furthermore, the widespread traditional uses of Himalayan yew suggest a difference in toxicity between Himalayan and European yew, emphasizing the need for further investigation. In the present review, chemical, pharmacological and toxicological studies of Himalayan yew have been discussed, in addition to a review of its traditional uses and taxonomic ambiguities, suggesting several avenues for further study.
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6 Acknowledgements
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The authors acknowledge the anonymous reviewers for their valuable comments. 7 Conflict of interests
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The authors declare that they have no competing interests. References
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