Phytochemical, Pharmacological and Toxical Proprieties of Euphorbia Helioscopia: Review

Abstract

Euphorbia helioscopia L. (Euphorbiaceae), also known as “Sun spurge” is one of used herbs in most parts of the world since thousands of years. This work aims to provide updated comprehensive and categorized information on chemical composition, pharmacological and toxical properties of this plant. To achieve this purpose, several scientific databases were used, including Wiley, PubMed, Web of Science, Springer, Science Direct, Elsevier, and Google Scholar and related books published up to December 2019 were also used as references. After description of its history, botanical characteristics and distribution, this review highlights the different types of secondary metabolites, such as diterpenoids, tannins, glucosides and steroids, which have been isolated from E. helioscopia L. in several researches over the last four decades. Related Twenty five pharmacological activities (among them: antibacterial, antiviral, antioxidant, antifungal, phytotoxic, anthelmintic, antitumor, anti-allergic, anti-asthmatic, cytotoxic, anticancer, allelopathic, anti-nociceptive, anti-inflammatory, anti-pyretic, vasodepressor, antileishmanial, lipid-lowering activity, and triglyceride-lowering activity) are presented and discussed. E. helioscopia L. toxicity related studies against Humans, snails and some herbs are summarised and presented with correspondent references. This study can be used by researches interested by this plant since it resumes all relevant published papers in link with E. helioscopia L.

Keywords

Euphorbia Helioscopia; Chemical composition; Pharmacological properties; Toxicity

INTRODUCTION

Euphorbiaceae is the largest family of Anthophyta with 300 genera and 5,000 species [1]. Euphorbia, is one of the largest angiosperms’ genera, with about 2,000 species, and has long been known for its wide variety of growth forms, including many xerophytic species. Despite its great vegetative diversity, the genus is morphological united by the possession of a cyathium which is a very small inflorescence that looks like a single flower [1-3].

Euphorbia helioscopia L., also called Sun spurge, is an annual plant with a tall between 10 and 50 cm high, with a rich latex stem, oval alternate leaves and small yellow-green flowers. The plant is native to temperate regions of Eurasia but has been adapted to subtropical conditions. It behaves as a winter annual in Japan that is blooming from April to May. In Morocco, this plant blooms from December to April in plains and up to May in mountainous areas [4]. Most E. helioscopia L. compounds are biologically active; for example: Antibacterial [1, 5-8], antitumor/anticancer [9-12] antioxidant [1, 13-15], Antifungal [16] plus other types of activities. Plants in Euphorbiaceae family are also promising sources of high quality tanning agents for leather industry [17]. E. helioscopia L. has been considered as a medicinal plant and is used in traditional medicine in various countries of the world [3, 18-20]. For Maghrebian traditional medicine, E. helioscopia L. is locally called "Bou Labeena" (in reference to the plant’s milky latex). However, Euphorbia stems are an irritant drug that cause severe toxicity like phytotoxic effects [21], Molluscicidal activity [22-24] and skin irritant [25].

The objective of this review is to present an evaluation of art state of E. helioscopia L., in particular chemical compounds identified and characterized in its different parts, in one hand; in the other hand, to examine pharmacological and toxic properties of this plant, based on a comprehensive and in-depth analysis of relevant literature.

MATERIALS AND METHODS

In this work we collected literatures published documents up to December 2019 on phytochemistry, botany, pharmacology and toxicity of E. helioscopia L. All available information on this plant was retrieved by Internet databases (Springer, PubMed, Web of Science, Wiley, Science Direct, Elsevier, and Google Scholar) and a number of books and PhD dissertations were also used. Used key words in the search were: “Euphorbia helioscopia L.”, “Traditional uses of Euphorbia helioscopia L.”, “Chemical composition of Euphorbia helioscopia L.”, “pharmalogical activity”, “toxicity”. Scientific name of the plant has been identified and validated by the Scientific Institute of Rabat (Morocco) and through www.theplantlist.org.

Traditional uses of Euphorbia L. (Euphorbiaceae)

Historically, natural extract from plants have showed a significant role in humans live, whether for food or for drugs [26]. Euphorbia L. (Euphorbiaceae) has attracted human interest around the world since the earliest and even prehistoric times [27-29]. Euphorbia species are easily identified especially by their milky latex and unique inflorescences (cyathia) [30]. They are known for their use as ornamental and domestic plants [31], and their latex has contributed to the economic interest for certain species such as Euphorbia antisyphilitica Zucc [31] and Euphorbia Intisy Drake (intisy rubber) [31]. According to Hippocrates, Galen and Dioscorides [32, 33], Sumerians and Akkadians knew the toxic properties of E. helioscopia L. [34], the medicinal properties of "euphorbium" (gum from E. resinifera Berg [32] and the presence of active natural products in the latex [35,36]. In 1752 Carl Linnaeus presented Euphorbia genus with various medicinal uses, including topical treatments and purging of the gastrointestinal tract [37-39]. E. helioscopia L. takes her name from a Greek origin, deriving from ‘‘helioscopion’’ used first by Dioscorides to describe this species and meaning ‘‘sun gazer’’. In fact, according to the Roman naturalist Pliny, the plant moves its flowers round to follow the sunlight [40, 41]. Furthermore, as reported for other species belonging to the Euphorbiae genus, the plant was used by Greeks and Romans to take away all kinds of warts, knobs, and the hard calluses of fistulas, hot swelling and carbonucles. Nowadays, the plant is still used in China for a variety of ailments: as a cure for boils, to get rid of worms, and to bring down high temperatures [41].

Botanical characteristics

E. helioscopia L. (Figure 1) is a fleshy annual plant, glossy green and glabrous, up to 50 cm tall but more commonly between 10 to 30 cm. All parts of the plant emit a milky sap, once cut. E. helioscopia L.’s stems are clearly tinged with red and radiate outward from a central point. All leaves (1 to 2 mm long) are usually attached directly to the stem and do not appear on petioles. Not very visible, light green to pale yellow, inflorescences (cyathias) occur at stems’ ends and have 4 lobes. Each lobe has a round yellowish gland [42, 43].

E. helioscopia L. is classified in reign: Plantae, under reign: Tracheobionta, Super division: Spermatophyta, Division: Magnoliophyta, Class: Magnoliopsida, Subclass: Rosidae, Order: Malpighiales, Family Euphorbiaceae, Genus: Euphorbia and Species: Euphorbia helioscopia [43].

Distribution

Euphorbia helioscopia is native to North Africa, Europe, and some parts of Asia. It was introduced in North and South America as shown in the cart below (Figure 2). African native countries are Algeria, Egypt, Libya, Morocco and Tunisia, European ones are: Albania, Belgium, Bulgaria, Cyprus, Czech, Finland, France, Germany, Great Britain, Greece, Hungary, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Romania. Asian ones are: Afghanistan, Bangladesh, Belarus, China, India, Iran, Iraq, Japan, Kazakhstan, Kirgizstan, South Korea, Lebanon, Syria, Mongolia, Pakistan, Palestine, Saudi Arabia, Tadzhikistan, Taiwan, Turkey, Turkmenistan and Vietnam. While introduced countries are: Canada, United States of America and Argentina [44-52].

Chemical composition

Euphorbia is the largest genus of Euphorbiaceae family, which is well known for the chemical diversity of terpenoids [35]. Diterpenoids are particularly rich and diversified in Euphorbia species, with more than 650 diterpenoids that have been isolated and identified, including jatrophanes, lathyranes, ingenanes, tiglianes, abietanes, kauranes, pimaranes, daphnanes, casbbanes and myrsinanes [35- 36, 53]. A large number of secondary metabolites have been reported from E. helioscopia L. plant including diterpenoid, triterpenoid, tannins, glucosides and lipids [3,54-59] which offer to E. helioscopia L. a wide array of bioactive functions.

More than 133 diterpenoids have been isolated and structurally characterized from E. helioscopia L. [57, 60], which present the main class components studied in this plant (table 1), e.g Euphohelin A [61], Euphornin A-K (1-11), Euphoscopin A-L, Euphorpin A- F [62], Euphorbiapene A-D [63, 62] and Helioscopianoids A–Q [64].

Oil content of Euphorbia helioscopia’s seeds is equal to 30.33 % with a d15: 0.9346, nD: 1.4847, Iodine index, % J2: 176.6–204.4, and saponification value is 191.1mg KOH [65]. According to [64], E. helioscopia L. contains diterpenoid esters of jatrophane, helioscopianoides A–Q and euphornin N [66-67, 115]. Triterpenes like Euphorbatrine A-G [68]. Four hydrolysable tannins named: heliscopinins A & B, and helioscopins A & B were found in all parts of E. helioscopia L. [55-17, 69]. Other studies have revealed the presence of flavonoids like, Heliosin [70,71], glycosides such as quercetin-3-pglucoside, quercetin-3-β-galactoside, quercetin-3-β-galactoside-2"-galla [72] and aryl glycoside, 300-O-galloyl-benzyl-O-α-L-rhamnopyranosyl-(1→6)-β-D-glucopyranoside [57-73,74], Hyperoside and Quercetin [75], steroids and lipids like Glucoclionasterol [54, 59] and other secondary metabolites such as 24-methylene cycloartanol, 24-methylenecycloart-3-one, cycloartanol, and stigmast-4-ene-3-one [3]. Diversity in secondary metabolites in all parts of E. helioscopia L. would explain their various uses in several areas.

Details related to extraction methods used can be found in mentioned references. Throughout this review, it is seen that chemical proprieties are deeply investigated by researchers from different countries from 1968 up to nowadays (2019). Some substances are present in all parts of the plant while other are located in some of them (table3). Further studies about the use of these chemical constituents can be envisaged. E. helioscopia L. diterpenoids have been extensively studied over the years. However, for many other classes of compounds, with have nteresting pharmacological affects possibilities, investigations are scarce. Examples of these compounds include saponins especially in E. helioscopia L. roots, and tannins isolated from E. helioscopia L. where there is still much to be explored and published.

Pharmacological properties

In literature, twenty five pharmacological activities (table 2) were reported in relation with E. helioscopia L. References of studies describing these activities are summarized in table 3 below and are chronologically classified as described in the literature.

The most interesting active compounds from E. helioscopia L. belongs to diterpenoids [9, 12]. For example, the bioactive jatrophane diterpenoides, heliosterpenoids A & B were found to be potent inhibitors of P-glycoprotein (ABCB1) and exhibited cytotoxicity against MDA-MB-231 cell lines [85]. The same Helioscopianoids A–Q showed neuroprotective activities against serum deprivation-induced PC12 cell damage [80], euphelionolides F and L diterpenoids exhibited significant cytotoxicity against MCF-7 and PANC-1 cell lines [86]. Triterpenoids Euphorbatrine E and F increased Hela−/− cell death via activating apoptosis pathway other than necroptosis [68]. And the most relevant activities are antibacterial [1-5-7-66-91, 93], antioxidant [1-13-14, 15] and anticancer [12-41-92-91, 94]. As previously described, E. helioscopia L. has several properties, among them its antioxidant activity E. helioscopia L. flowers extracts have the highest levels of phenolics and flavonoids, as well as highest antioxidant compared to leaf and stem extracts, regardless of the solvent used [14].Another study reported that methanolic extracts of E. helioscopia L. leaves possess significant antioxidant activity in vivo by increasing biomarkers of oxidative stress in tissue and homogenates serum enzymes [15].

Among bioactive functions of E. helioscopia L., some studies mentioned an antiviral and antibacterial effect [6-7, 8]. In addition, it has been reported that antibacterial activity of dichloromethane and methanol extracts from aerial parts of E. helioscopia L. was performed against Eschericha Coli, Bacillus Subtilis, Shigella Flexenari, Staphylococcus Aureu, Pseudomonas Aeruginosa and Salmonella Typhi [1]. E. helioscopia L. was active against Bacillus Anthracis [5]. As well as extracts from E. helioscopia L. had an inhibition of more than 90% against Botrytis Cinerea, Rhizoctonia, Solani, Fusarium Oxysporum, Cladosporium Cucumerinum and Alternaria Solani Fungi [16].

Isolated compounds (Euphornin L. and Euphoscopin) of E. helioscopia L. exhibited cytotoxicity against HL-60 [10]. Extracts of E. helioscopia L. from Turkey showed a vasodepressor effect which could be due to its vasorelaxant activity [3]. E. helioscopia L. also showed an anticancer effect; indeed, ethyl acetate and chloroform extracts could inhibit the proliferation of five human cancer cell lines over a range of concentrations from 50 to 200 μg / mL [12]. Park's study [76] indicates that polyphenol compound known as helioscopinin-A has shown some inhibitory activity of capillary permeability in responses to passive cutaneous anaphylaxis in rats. The whole plant of E. helioscopia L. has significant anthelmintic activity, which may be a potential alternative to treating helminth infections in ruminants [96]. Studies showed that E. helioscopia L. have innumerable benefits especially from aerial parts, such as antioxidant, antiviral, antitumoral, antibacterial, antifungal, anti-allergic, anti-asthmatic allelopathic, lipid and triglyceride lowering activity and other effects, it is very promising as anthelmintic.

Table 3 below provides a summary of reported pharmacological activities, details of extracts, application type (in vivo or in vitro), test objective, used control; doses tested for drugs and found results. Among the thirty nine studies about pharmacological activities, 40 % of presented tests were conducted in vivo, 10% of them are performed in vivo and in vitro. Where extracts from all parts of the plant were used to determine these pharmacological proprieties. Encouraging findings can be considered as a scientific demonstration of the different historical uses of this plant as drug as specified in the chapter 3 of this review.

All previously cited researchers used the whole plant of E. helioscopia L. for their studies. However, there are no studies that use each organ (roots, stems, leaves or flowers) of the plant separately and compare their effects for example. The same remark is applicable for comparison of different methods of extraction or solvents that give the best yield extracts. Studies show that E. helioscopia L countless health benefits, such as antibacterial, antiviral, antioxidant, antifungal, anthelmintic, antitumor, anti-allergic, anti-asthmatic, cytotoxic, anticancer. Also, it is very promising as lipid- and Triglyceride-lowering activities. Thus, the pharmacological activities should be fully explored with in-depth in vitro and in vivo tests, and, ultimately, clinical trials to prove these activities in humans (Table 3).

Toxicity

Some herbal products are sold as non-toxic food supplements or popular drugs. However, this is not always true, especially if taken as over-the-counter medications, or used in combination with other herbs. In addition, they can have adverse effects, such as stimulation and hallucinogenic properties [102, 103]. Nevertheless, these products are readily available and have widespread use. A large variety of dietary supplements to lose weight are marketed with claims of effectiveness [104-105, 106]. The lack of data on toxicity and/or efficiency of many ingredients of these products, even the predominant ingredients, are worrying an alarming [107-108, 109].

Studies in vivo and in vitro were conducted to evaluate the potential toxicity of E. helioscopia L., their extracts or their association with other ingredients (Table 4). E. helioscopia L. caused several irritant contact dermatitis or allergic contact dermatitis, as a result of direct contact [25]. 12-dioxyphorbol-13-phenylacetate-20-acetate has been shown to be the major component of the toxic fraction and the most irritating substance [110, 111].

Molluscicidal activity is widespread in Euphorbiaceae family, although the activity varies considerably from one species to another and even between different parts of the same plant [4-23, 24]. Al-Zanbagi studied in 2000 E. helioscopia L. with two other plants from Euphorbiaceae family, from Saudi Arabia, to identify those parts of plants that had molluscicidal activity against the snail Biomphalaria pfeifferi. By 2005, she found that very low concentrations of fresh leaf extracts of methanol and acetone extracts of E. helioscopia L. were effective for killing the snail with LC50 =8.9 ppm. The same in other study results showed that acetone extract of E. helioscopia L. was the most toxic extract of both C. Pipiens larvae and B. Alexandrina snails. In addition pellets formulated from stems and leaves of E. helioscopia L. showed molluscicidal activity against molluscs, A. Hortensis and T. Pisana. E. helioscopia L. aqueous extract severely affected the germination of wheat (Triticum Aestivum L.) and pea (Pisum Sativum L.), by reduction of plumule and radicle length, as well as their fresh and dry masses.

Therefore, for toxicity testing, it is important to determine the dose of the drug, bearing in mind the form of pharmaceutical preparation of its extract and to specify the administered amount, particularly in vivo tests, where the weight of the animal is taken in to account. In addition to the numerous pharmacological benefits and useful therapeutic indications for humans, E. helioscopia L. has demonstrated toxicological potential, especially as skin irritant (Table 4).

CONCLUSION

Plus than one haundred references were used to prepare this work that gather as well recent and old conducted studies that aim to determine the different possible uses/proprieties of E. helioscopia L. These proprieties can be classified as chemical, pharmacological and toxic ones. A resume of objectives, used methodologies and main results is presented by type of propriety. Various biological and therapeutic activities of E. helioscopia L. have been reported in the literature. Effectiveness of the different classes of secondary metabolites isolated from this plant was confirmed by a wide range of experiments referred in this review. The use of this plant in certain biological and therapeutic applications requires determination of relevant concentrations and economic gains via biological reactor tests. Although a large number of studies were conducted on the determination of E. helioscopia L. different proprieties, series of assessments are needed to establish the limits of their environmental safety. Extracts from E. helioscopia L. have shown sufficient activity to warrant further investigation as possible biomolluscicides. The study of natural products of this plant could lead to the discovery of new structures that could serve as a basis for different future products.

Acknowledgements

We would like particularly to thank the Department of Plant Protection and Environment of the National School of Agriculture - Meknes, Morocco. This work was part of the Ph.D. thesis of Mrs. Anjoud HARMOUZI.