Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Contents lists available at ScienceDirect

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4 Journal of Ethnopharmacology
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journal homepage: www.elsevier.com/locate/jep
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Review
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A review of the medicinal uses, phytochemistry and pharmacology
13 of the genus Sapium
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15 L.M.R. Al Muqarrabun, N. Ahmat n, S. Ruzaina S. Aris
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17 Q1 Faculty of Applied Sciences, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor, Malaysia
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20 art ic l e i nf o a b s t r a c t
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22 Article history: Q5 Ethnopharmacological relevance: Several species from the genus Sapium possess a broad range of
Received 22 January 2014 medicinal properties and they have been used as traditional medicines by indigenous groups in several
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Received in revised form regions such as Malaysia, Africa, Southern China and Bolivia. Most of the species reported to possess
24 19 May 2014
therapeutic effects which are used for the treatment of skin-related diseases such as eczema and
25 Accepted 19 May 2014
dermatitis, but they may also be used for overstrain, lumbago, constipation and hernia. Species of this
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genus are also used to treat wounds and snake bites. In addition, the saps/latex of Sapium glandulosum,
27 Keywords: Sapium indicum and Sapium sebiferum have/has toxic effects and are used as bird and fish poisons. This
28 Sapium review discusses the current knowledge of the medicinal uses, phytochemistry, biological activities and
29 Phorbol ester
toxicities of species from the genus Sapium to reveal their therapeutic potentials and gaps offering
Skin diseases
30 opportunities for future research.
Digestive diseases
31 Antioxidant Materials and methods: This review is based on a literature study of scientific journals and books from
32 Cytotoxicity libraries and electronic sources, such as ScienceDirect, PubMed and ACS.
33 Results: As many as 65 compounds are included in this review. They belong to different classes of
34 compounds including flavonoids, terpenoids and several other types of compounds, such as alkaloids,
phenolic acids and amides. The pharmacological studies revealed that various types of preparations,
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extracts and single compounds of species from this genus exhibited a broad spectrum of biological
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activities including antioxidant, antimicrobial, anti-inflammatory and cytotoxic activities. However,
37 Sapium glandulosum, Sapium indicum and Sapium sebiferum were reported to possess toxic effects and
38 Sapium sebiferum was found to contain phorbol esters acting as a tumor-promoting agent.
39 Conclusion: The genus Sapium consists of 23 accepted (high confidence) species. However, only very few
40 of species have been phytochemically and pharmacologically studied. There is great potential to discover
41 new chemical constituents from this genus because only a few species have been phytochemically
42 investigated thus far. Only 27 compounds of 65 identified compounds have been studied for their
43 biological activities. Several extracts and single compounds from this genus were reported to exhibit
44 interesting biological activities such as antimicrobial, antioxidant and cytotoxic effects. Furthermore, the
45 toxicity studies of some phorbol esters suggested that the compounds acted as potential tumor-
promoting agents by stimulating protein kinase C. This is an interesting fact in which a plant with
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medicinal properties also possesses toxic effects as well. Therefore, more clinical studies on the toxicity
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of the extracts of the plants and the compounds isolated from this genus are also crucial to ensure their
48 safety and to assess their eligibility for use as sources for modern medicines.
49 & 2014 Published by Elsevier Ireland Ltd.
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53 Contents
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55 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
56 2. Medicinal uses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
3. Phytochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
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3.1. Flavonoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
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3.2. Terpenoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
59 3.3. Miscellaneous compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
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62 Corresponding author. Tel.: þ 60 355444643; fax: þ 60 355444562.
63 E-mail addresses: [email protected] (L.M.R. Al Muqarrabun), [email protected] (N. Ahmat), [email protected] (S.R.S. Aris).
64 http://dx.doi.org/10.1016/j.jep.2014.05.028
65 0378-8741/& 2014 Published by Elsevier Ireland Ltd.
66

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 2 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 4. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
2 4.1. Antimicrobial . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
3 4.2. Antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4 4.3. Anti-inflammatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
4.4. Cytotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
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4.5. Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
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5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
7 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
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12 1. Introduction
13 decoction of Sapium ellipticum is used for treating coughs in Kenya.
14 Sapium is a genus in the family Euphorbiaceae. Members of this In Tanzania, the dried stem is powdered and crushed with water
15 genus are distributed in India, Vietnam, China, throughout Malaysia, and applied on wounds, pain in the chest and head, among others.
16 parts of New Guinea and Africa (Esser and Welzen, 2005; Mwine and The leaves are used for abdominal swelling and eye diseases. The
17 Damme, 2011). In addition, some species of this genus are also root decoction is used for malaria. The traditional healers in
18 distributed in Mexico, Central America, Caribbean, tropical South Zambia and Burundi prescribe the stem bark decoction for anemia,
19 America, southern Brazil and temperate South America (Richter and fever, guinea worms, elephantiasis and rheumatic problems. The
20 Dallwitz, 2000-onwards). This genus consists of 23 accepted (high leaves of this plant are traditionally used for the treatment of
21 confidence) species with 254 names of synonym species according to mumps in Ethiopia by the Kaffa people of the Bonga zone
22 http://www.theplantlist.org. This review describes the medicinal (Neuwinger, 1994; Mwine and Damme, 2011). The diverse, impor-
23 uses and the phytochemical and pharmacological properties of tant ethnomedicinal properties possessed by this genus can be the
24 species from the genus Sapium. The phytochemical studies resulted basis for further research to investigate the phytochemical and
25 in the isolation of 65 compounds consisting of several classes of pharmacological aspects of this genus.
26 compounds dominated by flavonoids and terpenoids. The pharma-
27 cology of this genus has not been widely investigated. Although
28 3. Phytochemistry
many species of this genus have been discovered, only a handful of
29 species have been studied for their biological activities.
30 According to the authors' literature search, there is a great
This is an important review describing the current progress in
31 chance of discovering new chemical constituents from this genus,
research regarding the pharmacology and phytochemistry of the
32 as only six of 23 species of the genus Sapium have been phyto-
genus Sapium including the conducted studies and areas requiring
33 chemically investigated thus far. This genus has been reported
more research. If we consider the important medicinal uses of this
34 to contain several types of compounds from classes including
genus in the treatment of many types of ailments, it is clear that a
35 flavonoids, terpenoids and a few compounds from other classes.
broader range of biological activity studies are required to explore
36 However, within these compounds, diterpenoids are the most
their pharmacological properties. These gaps create an important
37 dominant constituent to be found in the currently studied species
research opportunity to study more about the phytochemistry
38 in this genus.
and pharmacology of genus Sapium considering the interesting
39 medicinal properties possessed by the species and the chemical
40 constituents of this genus. As a vast number of species in this 3.1. Flavonoids
41 genus have not yet been explored, significant opportunities are
42 available to find novel and bioactive compounds as well as Six flavonoid compounds have been reported from the genus
43 promising medicinal and pharmacological properties from various Sapium (Table 2). Devkota et al. (2009) isolated four known
44 extracts of the species. This research can also lead to possibilities flavones including rutin, quercetin, guaijaverin and nicotiflorin
45 of finding new sources of drugs for future applications, such as (1–4, respectively) from the water-soluble fraction of the metha-
46 drugs to treat cancer, hernia and acute skin diseases. nolic extract of Sapium insigne leaf. In 2004, Woldemichael et al.
47 reported a new highly oxygenated chalcone named α,β,3,4,5,
48 20 ,40 ,60 -octahydroxydihydrochalcone (5) from Sapium haematos-
49 2. Medicinal uses permum. In another study conducted three years later, a new
50 chalcone glycoside, chalcononaringenin 20 -O-β- -glucoside (6), was
51 Some species from this genus have been used traditionally in successfully obtained from the flower of Sapium sebiferum (Huang
52 several countries as therapeutic remedies (Table 1). In southern et al., 2007). All structures of the flavonoids are presented in Fig. 1.
53 China, skin-related diseases such as eczema, dermatitis, scabies
54 and herpes zoster can be treated using the leaf part of Sapium 3.2. Terpenoids
55 chihsianum, Sapium discolor, Sapium rotundifolium and Sapium
56 sebiferum. The root bark and leaf of Sapium japonicum were found Diterpenoid compounds of the genus Sapium are divided into
57 to be effective for treating overstrain, lumbago and pain in the three major types based on their basic skeletons, i.e. phorbol ester,
58 knees. Sapium sebiferum root bark and seed have been reported to labdane and kaurane (Table 3). All the diterpenes were isolated
59 have medicinal potential for digestive and excretory ailments, such from the aerial parts of the plants. No such compounds were
60 as constipation, ascites, dysuria and turbid urine (Lai et al., 2004; obtained from the stem or root parts. Chumkaew et al. (2003)
61 Shimizu et al., 2007). The resin of Sapium glandulosum has been successfully isolated nine methylaminobenzoate-containing phor-
62 used to treat hernia in Bolivia (Hajdu and Hohmann, 2012). The bol esters (10–14, 19–22) from the fruit of Sapium indicum.
63 bark juice of Sapium insigne is used traditionally in Nepal to help However, some of those compounds are also found in Sapium
64 with wound healing by dispelling worms and killing germs sebiferum (Brooks et al., 1987). Sapium insigne was also found to be
65 (Manandhar and Manandhar, 2002). Sapium ellipticum is widely rich in phorbol esters. Devkota et al. reported the occurrence of
66 used as an ethnomedicine in different parts of Africa. The root two phorbol esters (7 and 8) in the leaf part in 2009. Three years

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 3

1 Table 1
2 Medicinal uses of some Sapium species.
3
Species Part Medicinal Use Reference
4
5 Sapium glandulosum (L.) Resin Hernia Hajdu and Hohmann (2012)
6 Morong.
7 Sapium chihsinianum S.K. Leaf Eczema, dermatitis, snake bites Lai et al. (2004)
Lee
8 Sapium discolor (Champ. ex Root Constipation, dysuria, edema, wounds, snake bites Lai et al. (2004)
9 Benth.) Muell. Arg.
10 Leaf Dermatitis, herpes zoster, acute mastitis, eczema, wounds, snake bites Lai et al. (2004)
11 Sapium japonicum (Sieb. et Root bark, Overstrain, lumbago, pain in knees Lai et al. (2004)
Zucc.) Pax et Hoffm. leaf
12
Sapium rotundifolium Leaf Scabies, eczema, acute skin diseases, snake bites Lai et al. (2004)
13 Hemsl.
14 Sapium sebiferum (L.) Roxb. Root bark Constipation, dysuria, edema, ascites, whitish and turbid urine, acute skin diseases, Lai et al., 2004;
15 eczema, wounds, snake bites, dyspepsia, as a purgative and diuretic Duke and Ayensu, 1985; Hooper,
16 1905; Shimizu et al., 2007
Leaf Eczema, wounds, edema, snake bites, boils Duke and Ayensu, 1985; Lai et al.,
17 2004
18 Seed Eczema, allergic dermatitis, edema, constipation, antidote, emetic, hydragogue, purgative Lai et al., 2004; Duke and Ayensu,
19 1985
20 Seed oil Scabies, pustulosis, edema, constipation Lai et al. (2004)
Sapium cornutum Pax. Stem bark Bark decoction is used against hernia, scurvy and stomatitis, as a purgative and Mesia et al. (2008)
21
anthelmintic
22 Sapium insigne (Royle) Stem bark The bark juice is used for wound healing Manandhar and Manandhar (2002)
23 Benth. Ex Hook fil.
24 Sapium indicum Willd. Milky Wound healing Das and Alam (2001)
25 juice
Sapium ellipticum (Hochst.) Root Cough, malaria Mwine and Damme, 2011;
26 Pax Neuwinger, 1994
27 Stem Wound healing, chest pain, headache Mwine and Damme, 2011;
28 Neuwinger, 1994
29 Stem bark Anemia, fever, guinea worms, elephantiasis, rheumatic and burn treatment Mwine and Damme, 2011;
Neuwinger, 1994; Nyunja et al., 2009
30
Leaf Abdominal swelling, eye diseases, mumps Mwine and Damme, 2011;
31 Neuwinger, 1994
32 Sapium baccatum Roxb. Not Abscess Eswani et al. (2010)
33 mentioned
34
35
36 Table 2
37 Q6 Flavonoids from Sapium species.
38
No Compound Group Source Reference
39
40 1 Rutin Flavone Sapium insigne (Royle) Benth. Ex Hook fil. (leaf) Devkota et al. (2009)
41 2 Quercetin Flavone Sapium insigne (Royle) Benth. Ex Hook fil. (leaf) Devkota et al. (2009)
42 3 Guaijaverin Flavone Sapium insigne (Royle) Benth. Ex Hook fil. (leaf) Devkota et al. (2009)
4 Nicotiflorin Flavone Sapium insigne (Royle) Benth. Ex Hook fil. (leaf) Devkota et al. (2009)
43 5 α,β,3,4,5,20 ,40 ,60 -octahydroxydihydro chalcone Chalcone Sapium haematospermum Muell(whole plant) Woldemichael et al. (2004)
44 6 Chalcononaringenin 20 -O-β-&-glucoside Chalcone glycoside Sapium sebiferum L. Roxb. (flower) Huang et al. (2007)
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59 Fig. 1. Flavonoids from Sapium species.
60
61 later, four new phorbol esters, sapinsignoids A–D (15–18), were Sapium rigidifolium. Two other kaurane-type diterpenes (29–30),
62 isolated from the same species by Liu et al. (2012). They along with a new unusual diterpene called rigidol (34), were also
63 also managed to isolate three labdane diterpenes (23–25) and isolated from the aerial parts of Sapium rigidifolium (Siems et al.,
64 four kaurane diterpenes (26, 27, 28 and 31) from the twig and 1993). In 2004, Woldemichael et al. identified two pimaranes
65 leaf of Sapium insigne in the same study. In addition to being named lecheronols A and B (32 and 33, respectively) from Sapium
66 found in Sapium insigne, diterpene kauranes were also found in haematospermum.

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 4 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Table 3
2 Terpenoids from Sapium species.
3
No Compound Group Source Reference
4
5 7 16-hydroxyphorbol-16-acetate Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
6 phorbol ester (leaf)
7 8 4β-deoxy-16-hydroxyphorbol-16-acetate Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
phorbol ester (leaf)
8 9 12-deoxyphorbol 13-benzoate Diterpene Sapium sebiferum L. Roxb. (seed) Brooks et al. (1987)
9 phorbol ester
10 10 Sapintoxin A Diterpene Sapium sebiferum L. Roxb. (seed) Brooks et al. (1987); Chumkaew et al., 2003;
11 phorbol ester Taylor et al., 1981a
11 Sapintoxin B Diterpene Sapium indicum L. (fruit) Chumkaew et al., 2003; Taylor et al., 1981b
12
phorbol ester
13 12 Sapintoxin C Diterpene Sapium sebiferum L. Roxb. (seed) Brooks et al., 1987; Chumkaew et al., 2003;
14 phorbol ester Taylor et al., 1981b
15 13 12-(2-N-methylamino benzoyl)-4β,5,20- Diterpene Sapium indicum L. (fruit) Chumkaew et al. (2003)
16 trideoxyphorbol-13-acetate phorbol ester
14 12-(2-methylamino benzoyl)-4-deoxy phorbaldehyde- Diterpene Sapium indicum L. (fruit) Chumkaew et al., 2003; Taylor et al. 1981a
17 13-acetate phorbol ester
18 15 Sapinsignoid A Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
19 phorbol ester (twig and leaf)
20 16 Sapinsignoid B Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
phorbol ester (twig and leaf)
21
17 Sapinsignoid C Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
22 phorbol ester (twig and leaf)
23 18 Sapinsignoid D Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
24 phorbol ester (twig and leaf)
25 19 α-sapinine Diterpene Sapium indicum L. (fruit) Chumkaew et al., 2003; Taylor et al., 1981a
phorbol ester
26 20 12-(2-N-methylamino benzoyl)-4α,5,20-trideoxy Diterpene Sapium indicum L. (fruit) Chumkaew et al. (2003)
27 phorbol-13-acetate phorbol ester
28 21 12-(2-N-methylamino benzoyl)-4α,20-dideoxy-5- Diterpene Sapium indicum L. (fruit) Chumkaew et al. (2003)
29 hydroxyphorbol-13-acetate phorbol ester
22 12-(20 -N-methylamino benzoyl)-4α-deoxy-5,20- Diterpene Sapium indicum L. (fruit) Chumkaew et al., 2003; Edwards et al., 1983
30
dihydroxyphorbol-13-acetate phorbol ester
31 23 Sapinsignoid E Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
32 labdane (twig and leaf)
33 24 Sapinsignoid F Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
34 labdane (twig and leaf)
25 Ent-labda-8(17),13E-diene-3α,15-diol Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al., 2012; Konishi et al., 1996
35 labdane (twig and leaf)
36 26 Sapinsignoid G Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012)
37 kaurane (twig and leaf)
38 27 Ent-17-hydroxy-16α-kauran-3-one Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al. (2012); Borges-Argaez et al. (1997)
kaurane (twig and leaf)
39
28 Ent-16β,17-isopropylidene -dioxykauran-3-one Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al., 2012; Dawson et al., 1975
40 kaurane (twig and leaf)
41 29 17-nor-8β,13β-kauran-3-one, 13-(hydroxymethyl) Diterpene Sapium rigidifolium Huft (aerial parts) Siems et al. (1993)
42 kaurane
43 30 3-oxo-17-norkaurane-18-δ-13-carboxylic acid, Diterpene Sapium rigidifolium Huft (aerial parts) Siems et al. (1993)
kaurane
44
31 Kauranoic acid Diterpene Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al., 2012; Siems et al., 1993
45 kaurane
46 32 Lecheronol A Diterpene Sapium haematospermum Muell (whole Woldemichael et al. (2004)
47 pimarane plant)
33 Lecheronol B Diterpene Sapium haematospermum Muell (whole Woldemichael et al. (2004)
48
pimarane plant)
49 34 Rigidol Diterpene Sapium rigidifolium Huft (whole plants) Siems et al. (1993)
50 35 Lupeol Triterpene Sapium baccatum (leaf) Ahmed et al. (2010)
51 36 Epi-lupeol Triterpene Sapium haematospermum Muell (whole Woldemichael et al. (2004); Ahmad and Atta-
52 plant) ur-Rahman (1994)
37 Betulin Triterpene Sapium baccatum Roxb. (leaf) Ahmed et al. (2010)
53
38 Taraxerol Triterpene Sapium baccatum Roxb. (leaf) Ahmed et al. (2010)
54 39 Taraxerone Triterpene Sapium baccatum Roxb. (leaf) Ahmed et al. (2010)
55 40 Aleuritolic acid Triterpene Sapium baccatum Roxb. (leaf) Khastigir et al., 1969; Ray et al., 1975
56 41 3-acetoxy-aleuritolic acid Triterpene Sapium baccatum Roxb. (leaf) Khastigir et al., 1969; Ray et al., 1975
42 3α-hydroxyolean-12-ene Triterpene Sapium haematospermum Muell (whole Woldemichael et al., 2004; Ahmad and Atta-
57
plant) ur-Rahman, 1994
58 43 3β-hydroxyolean-12-ene Triterpene Sapium haematospermum Muell (whole Woldemichael et al., 2004; Ahmad and Atta-
59 plant) ur-Rahman, 1994
60 44 2α,3β,23-trihydroxyolean-12-E-28-oic acid Triterpene Sapium haematospermum Muell (whole Woldemichael et al., 2004; Ahmad and Atta-
61 plant) ur-Rahman, 1994
45 3α-hydroxyurs-12-ene Triterpene Sapium haematospermum Muell (whole Woldemichael et al., 2004; Ahmad and Atta-
62
plant) ur-Rahman, 1994
63 46 Cycloartanol Triterpene Sapium haematospermum Muell (whole Woldemichael et al. (2004)
64 plant)
65 47 3-O-acetylcycloart-23-en-25-ol Triterpene Sapium insigne (Royle) Benth. Ex Hook fil. Srivastava and Agnihotri (1985)
(twig and leaf)
66

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
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1 Table 3 (continued )
2
No Compound Group Source Reference
3
4 48 3-O-β-lauroyl-cycloart-(23E)-en-25-ol Triterpene Sapium haematospermum Muell (whole Woldemichael et al. (2004)
5 plant)
6 49 β-sitosterol Steroid Sapium baccatum Roxb. (leaf) Ahmed et al., 2010; Khastigir et al., 1969
7 50 Stigmasterol Steroid Sapium baccatum Roxb. (leaf) Ahmed et al. (2010)

8
9
10 Lupeol (35), epi-lupeol (36) and betulin (37) are the only lupane important to obtain information about the eligibility of certain
11 triterpenes to be isolated from this genus until now. They were extracts or compounds of the species to be applied as drugs.
12 found in Sapium baccatum (Ahmed et al., 2010) and Sapium
13 haematospermum (Woldemichael et al., 2004). Woldemichael 4.1. Antimicrobial
14 et al. (2004) also reported three oleananes (42–44), one ursane
15 (45) and two cycloartane triterpenes (46 and 48) in the species, A species from this genus, Sapium cornutum, was reported to
16 while Srivastava and Agnihotri (1985) identified 3-O-acetylcy- demonstrate anti-protozoic activity. Mesia et al. (2008) investi-
17 cloart-23-en-25-ol (47) from Sapium insigne. The structures of gated the anti-plasmodial activity of the stem bark methanolic
18 the triterpenes reported in this genus are presented in Fig. 2. extract against three different protozoas. The extract displayed
19 pronounced anti-plasmodial activity against Plasmodium falci-
20 parum with IC50 of 2.0 mg/mL. However, the extract was found to
21 3.3. Miscellaneous compounds have low activity against Trypanosoma brucei brucei and Trypano-
22 soma cruzi.
23 Table 4 shows the other classes of compounds found in some Woldemichael et al. (2004) studied the anti-mycobacterium
24 species from the genus Sapium. (─)-Bukittinggine (51) is the only activity of several compounds they isolated from Sapium haema-
25 alkaloid ever isolated from this genus (Arbain et al., 1990). Gallic tospermum. They found that only four compounds including a
26 acid (52) was reported from Sapium insigne by Devkota et al. pimarane diterpene (208) and three triterpenes (211, 212 and 216)
27 (2009, 2010), along with its derivatives (53–60). In addition, they showed significant antibacterial activity against Mycobacterium
28 also successfully identified two other phenolic esters, fraxin (61) tuberculosis H37Rv. Sapintoxins A and C (186 and 187, respectively)
29 and 3-O-caffeoyl quinic acid (62). Siems et al. (1993) managed to exhibited significant activity against Mycobacterium tuberculosis
30 isolate two amide compounds, phenylalanine-N-benzoyl-2-(ben- H37Ra, while the other two phorbol esters, 195 and 197, did not
31 zoylamino)-3-phenyl propyl ester and benzenepropanamide-N-[1- show antibacterial activity against the bacteria strain (Chumkaew
32 [(acetyloxy) methyl]-2-phenylethyl]-α-(benzoyl amino) (64 and et al., 2003).
33 65, respectively) from Sapium rigidifolium aerial parts (Fig. 3).
34 4.2. Antioxidant
35
36 4. Pharmacology The crude ethanolic extract of Sapium glandulosum bark
37 showed low antioxidant activities in both DPPH (1,1-diphenyl-2-
38 Based on other searches, the pharmacological aspects of the picrylhydrazyl) and FIC (ferrous ion chelating) assays. However, its
39 extracts from species from the genus Sapium have not been leaf extract exhibited good and moderate activities in both tests,
40 studied thoroughly, as shown in Table 5. Only a few reports respectively (Silva et al., 2011). In another study, Kim et al. (2010)
41 regarding the antioxidant and cytotoxic properties of some species found that the leaf and branch extracts of Sapium japonicum
42 from this genus were reported. However, the biological activities exhibited an outstanding integral antioxidative capacity (IAC) of
43 of the isolated compounds including antibacterial, antiviral and water-soluble substances and significantly inhibited the produc-
44 anti-inflammatory have been reported in some works (Table 6). tion of NO in a dose-dependent manner. Recently, several fractions
45 Until recently, as recording to the literature search completed of the leaf extract of Sapium sebiferum have been investigated (Fu
46 by the authors, only a few biological activities have been investi- et al., 2013). The antioxidant activity (DPPH assay) of an ethyl
47 gated from this genus including antimicrobial, antioxidant, anti- acetate fraction of the new leaf (NL) was lower than that of the
48 inflammatory and cytotoxicity. In fact, the traditional uses of fallen leaf (FL). In ABTS assay, both leaf extracts showed signifi-
49 species of the genus Sapium revealed a broad range of medicinal cantly higher activities compared to the standard (ascorbic acid).
50 properties possessed by Sapium species. For example, Sapium However, they showed low antioxidant activity in a nitrite-
51 glandulosum has been used to treat hernia and Sapium sebiferum scavenging assay.
52 is used to cure constipation, dysuria, edema, ascites, whitish and
53 turbid urine, acute skin diseases, eczema, wounds, snake bites, and 4.3. Anti-inflammatory
54 as a purgative and diuretic. However, researchers have only
55 studied the antioxidant activity of Sapium glandulosum extract, The anti-inflammatory activity of both the plant extracts and
56 while Sapium sebiferum extracts have only been studied for single compounds of this genus has not been studied extensively.
57 antioxidant and cytotoxic properties. There have been no reports Panthong et al. (1998) reported anti-inflammatory activity dis-
58 regarding the pharmacological properties of these species related played by the major alkaloid isolated from this species, (─)-bukit-
59 to their medicinal uses. In addition, several species that have been tinggine (51), which was isolated for the first time by Arbain et al.
60 used traditionally to treat some types of ailments have not been (1990).
61 investigated for their biological activities at all. Of course, this is an
62 opportunity to find new pharmacological properties from this 4.4. Cytotoxicity
63 genus, not to mention promising sources for drugs, such as for
64 cancer, hernia, skin and digestive diseases. Furthermore, the The Sapium cornutum stem bark extract was reported to show
65 toxicity of the genus members has not been studied except for no cytotoxicity against MRC-5 cell lines (Mesia et al., 2008). The
66 in Sapium baccatum and Sapium sebiferum. This aspect is very growth of B16 melanoma cells was ideally inhibited by the

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 6 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Fig. 2. Terpenoids from Sapium species.
63
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66

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 7

1 Table 4
2 Miscellaneous compounds from Sapium species.
3
No Compound Group Source Reference
4
5 51 (─)-bukittinggine Alkaloid Sapium baccatum (Roxb.) (leaf) Arbain et al. (1990)
6 52 Gallic acid Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2010)
7 acid (leaf)
53 Methyl gallate Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
8 ester (leaf)
9 54 1-O-galloyl-β-&-glucoside Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
10 ester (leaf)
11 55 1,3-di-O-galloyl-β-&-glucoside Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
ester (leaf)
12
56 1,3,6-tri-O-galloyl-β-&-glucoside Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
13 ester (leaf)
14 57 1,3,4,6-tetra-O-galloyl-β-&-glucoside Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
15 ester (leaf)
16 58 Brevifolin carboxylic acid Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2010)
ester (leaf)
17 59 4-dehydrochebulic acid-1,6-dimethyl ester Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2010)
18 ester (leaf)
19 60 Corilagin Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
20 ester (leaf)
61 Fraxin Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2010)
21
ester (leaf)
22 62 3-O-caffeoyl quinic acid Phenolic Sapium insigne (Royle) Benth. Ex Hook fil. Devkota et al. (2009)
23 ester (leaf)
24 63 1-naphtalenepentanoic acid Carboxylic Sapium insigne (Royle) Benth. Ex Hook fil. Liu et al., 2012; Escamilla and
25 acid (leaf, twig) Ortega, 1991
64 Phenylalanine-N-benzoyl-2-(benzoylamino)-3-phenyl propyl ester Amide Sapium rigidifolium Huft (aerial parts) Siems et al. (1993)
26 65 Benzenepropanamide, N-[1-[(acetyloxy)methyl]-2-phenylethyl]-α- Amide Sapium rigidifolium Huft (aerial parts) Siems et al. (1993)
27 (benzoyl amino)
28
29
30
31
32 methanolic extract of Sapium sebiferum stem bark (Shimizu et al., 100 mg/kg dose of the extract. In addition, they found that the
33 2007). Sowemimo et al. investigated the cytotoxicity of Sapium extract caused an increase in the distortion of hepatocytes, the
34 ellipticum leaf and stem bark extracts in 2009. They found that the presence of massive cytoplasm and necrosis of hepatocytes for rats
35 leaf extract displayed good cytotoxicity against HeLa cell line by treated with 250 and 500 mg/kg doses of the extract. From these
36 causing over 50% inhibition, which is better than the inhibition by results, it was suggested that the non-polar extract of the stem
37 the stem bark extract (causing only 40% inhibition). One year later, bark of Sapium baccatum may promote toxic effects in the animals.
38 Kim et al. (2010) reported that Sapium japonicum leaf extract A number of Sapium species were denoted to have toxic effects.
39 showed no activity against RAW 264.7 and HS-68 cell lines using Sapium glandulosum was noted to produce poisonous latex which
40 MTT assay. is effective against warts. It is also used by Indians to catch birds
41 Woldemichael et al. (2004) deemed that the compounds they (Burkill, 1935), while Sapium indicum is used in fish poisoning (Das
42 tested for antimycobacterial activity (32, 36, 37 and 41) were also and Alam, 2001). Sapium sebiferum (Chinese Tallow) has been
43 active against Vero cells (ATCC CCL-81). Recently, sapinsignoids A– reported to contain phorbol esters, which are well known for both
44 D (15–18, respectively), four phorbol ester diterpenes, were their pro-inflammatory and tumor-promoting activities in vivo
45 reported to demonstrate moderate activity against human lung (Evans, 1986). However, phorbol esters were also reported to
46 cancer (A-549) and leukemia cell lines (HL-60) (Liu et al., 2012). inhibit HIV-1 (El-Mekkawy et al., 2000). Chinese tallow is known
47 to possess several toxic effects. Ingestion of the fruits has also been
48 4.5. Toxicity associated with a number of human poisonings (Ellis, 1978) and
49 was suspected to be a causative agent in human cancers (Ohigashi
50 The toxicity of the extracts (methanol, petroleum ether, carbon- et al., 1983). In a study conducted in 1987, Brooks et al. investi-
51 tetrachloride and dichloromethane extracts) and three compounds gated the toxicity of Sapium sebiferum covering the pro-
52 from Sapium baccatum 35, 39 and 49 were determined by using a inflammatory activity and the ability of three isolated phorbol
53 brine shrimp lethality bioassay. In comparison with the positive esters from the seed, i.e. 12-deoxyphorbol 13-benzoate (9), sapin-
54 control (vincristine sulfate), it was evident that all the test samples toxin A (10) and sapintoxin C (12), to stimulate protein kinase C.
55 were lethal to brine shrimp nauplii. However, petroleum ether, Those compounds were examined for their pro-inflammatory
56 carbon-tetrachloride extracts, some column fractions of petroleum activity on mouse skin using an established assay. Compounds 9
57 ether extract and pure compound 49 exhibited quite potent and 10 elicited inflammation of mouse skin with ID50 values of
58 activity in the brine shrimp lethality bioassay. These positive 0.042 and 2.60 nmol/5 ml per ear, respectively, while compound 12
59 results suggested that they may contain antitumor or pesticidal was inactive in doses up to 20 nmol/5 ml. The protein kinase C
60 activity (Ahmed et al., 2010). Recently, Taher et al. (2012) inves- activation assays were carried out on samples of enzyme purified
61 tigated the toxicity effects of hexane extract of Sapium baccatum from mammalian brains. Both of the phorbol esters demonstrating
62 stem bark towards rats through observation of physiological pro-inflammatory activity in vivo (9 and 10) significantly activated
63 changes of the rats as well as through gross and histological protein kinase C with the activity (Ka) values of 76 and 176 nM,
64 examinations of their livers over 14 days of observation. The respectively, while compound 12 was inactive.
65 results indicated the presence of abnormal hepatocytes with a More than a decade later, Lai et al. (2004) reported in his book
66 distorted shape and undefined cell linings for rats treated with a that Sapium sebiferum possesses numerous medicinal properties

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 8 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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47 Fig. 3. Miscellaneous compounds from Sapium species.
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49
50
51 and has been used as a traditional medicine in China. This fact pharmacologically studied, some of them are actually the syno-
52 appears contradictory to the results obtained by Brooks et al. nyms of the other recently-accepted names (http://www.theplant
53 (1987). In addition to Sapium sebiferum, diterpene phorbol esters list.org). However, most studies regarding this genus were under-
54 also occur in Sapium indicum and Sapium insigne. The bark and taken under the names used in this manuscript which are the
55 leaves of Sapium insigne are traditionally used in Nepal as fish popular names of the species. Therefore, to avoid confusion over
56 poisons, which may be associated with the phorbol esters it the species names, in this review authors used the names used by
57 contains. These facts inform researchers that the species of Sapium the authors in their original publications. Table 7 displays the list
58 containing phorbol esters possess both toxic effects and medicinal of some Sapium species names and their synonyms.
59 properties. Therefore, further toxicological studies on the extracts
60 and purified compounds, especially phorbol esters, are crucial to
61 validate the application of phorbol ester-containing Sapium spe-
62 cies to treat various ailments. Therefore, the information about the 5. Conclusion
63 safety and eligibility of the plants as traditional medicine as well as
64 modern drugs can be ensured with valid data. Species from genus Sapium have been widely used as tradi-
65 Even though the species were mentioned under the genus tional medicine by indigenous groups in several countries. The
66 Sapium in the reports when they were phytochemically and roots, stem bark, leaves and seeds of several species in the genus

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 9

1 Table 5
2 Biological Activities of Some Sapium Species.
3
Biological Species Extract Description Reference
4 Activity
5
6 Antioxidant Sapium glandulosum (L.) Bark Crude ethanol extract (CEE) showed low antioxidant activity (DPPH assay) with IC50 and AEAC Silva et al.
7 Morong. Burra-leiteira values of 183.45 77.60 mg/mL and 8.80 7 0.37 mg AA/100 mg, respectively. The standard used was (2011)
rutin with IC50 and AEAC values of 22.96 7 1.99 mg/mL and 70.6576.09 mg AA/100 mg,
8 respectively.
9 Crude ethanol extract (CEE) exhibited low antioxidant activity (FIC assay) with IC50 of Silva et al.
10 2152.98 7490.38 mg/mL. The standard used was EDTA with IC50 of 15.26 7 0.58 mg/mL. (2011)
11 Leaves Crude ethanol extract (CEE) showed good antioxidant activity (DPPH assay) with IC50 and AEAC Silva et al.
values of 58.55 7 6.35 mg/mL and 34.117 2.39 mg AA/100 mg, respectively. The standard used was (2011)
12
rutin with IC50 and AEAC values of 22.96 7 1.99 mg/mL and 70.6576.09 mg AA/100 mg,
13 respectively.
14 Crude ethanol extract (CEE) exhibited moderate antioxidant activity (FIC assay) with IC50 of Silva et al.
15 127.107 9.44 mg/mL. The standard used was EDTA with IC50 of 15.26 7 0.58 mg/mL. (2011)
16 Sapium sebiferum (L.) Roxb. Leaves Ethyl acetate fraction of the new leaves (NL) with IC50 of 4.91 70.08 μg/mL showed no significant Fu et al.
difference antioxidant activity (DPPH assay) compared to the standard. The standard used was (2013)
17 ascorbic acid (Vc) with IC50 of 4.79 7 0.01 μg/mL. Ethyl acetate fraction of the fallen leaves (FL)
18 with IC50 of 4.40 7 0.06 μg/mL showed significantly higher antioxidant activity (DPPH assay) than
19 the control.
20 NL and FL with IC50 1.19 70.19 μg/mL and 1.55 7 0.13 μg/mL exhibited significant antioxidant Fu et al.
activity (ABTS assay) compared to the standard (Po 0.05). The standard used was ascorbic acid (2013)
21
(Vc) with IC50 of 2.167 0.11 μg/mL.
22 NL and FL with IC50 128.37 79.79 μg/mL and 240.097 29.18 μg/mL displayed significantly lower Fu et al.
23 antioxidant activity (nitrite scavenging assay) compared to the standard (P o 0.05). The standard (2013)
24 used was ascorbic acid (Vc) with IC50 of 13.017 2.53 μg/mL.
25 NL and FL with IC50 6.26 μg/mL and 6.28 μg/mL showed significantly higher antioxidant activity Fu et al.
(β-carotene bleaching assay) compared to the standard (P o0.05). 2,6-di-tert-butyl-4- (2013)
26 methylphenol (BHT) was used as the standard, with IC50 of 21.90 μg/mL.
27 Sapium japonicum (Siebold & Leaves, Exhibited outstanding integral antioxidative capacity (IAC) values of water-soluble substances Kim et al.
28 Zucc.) Pax & K.Hoffm. branch (4 2.50 mmol ascorbic acid equivalents/g). (2010)
29 Leaves, Significantly inhibited the nO production in a dose-dependent manner with IC50 of 109 mg/mL. Kim et al.
branch (2010)
30
Anti- Sapium cornutum Pax. Stem Crude methanolic extract displayed a pronounced antiplasmodial activity against Plasmodium Mesia et al.
31 protozoa bark falciparum (Pf) with IC50 of 2.0 7 0.3 mg/mL. The control used was chloroquine 2H3PO4 with IC50 of (2008)
32 0.08 70.01 mg/mL.
33 Stem Crude methanolic extract displayed low antiplasmodial activity against Trypanosoma brucei brucei Mesia et al.
34 bark (Tbb) and Trypanosoma cruzi (Tc) with IC50 of 34.0 7 2.6 and 35.07 1.5 mg/mL, respectively. The (2008)
control used was Suramin with IC50 of 0.08 7 0.02 and 0.05 70.01 mg/mL against Tbb and Tc,
35 respectively.
36 Cytotoxicity Sapium cornutum Pax. Stem Crude methanolic extract did not display cytotoxicity against MRC-5 cell lines with IC50 of Mesia et al.
37 bark 464 mg/mL. The control used was tamoxifen with IC50 of o 0.25 mg/mL. (2008)
38 Sapium sebiferum (L.) Roxb. Stem Methanolic extract (10 mg/mL) showed ideal cytotoxicity by inhibiting the growth of B16 Shimizu
bark, melanoma cells by 30% versus the control. Kojic acid (500 mg/mL) and arbutin (100 mg/mL) were et al. (2007)
39
wood used as positive controls.
40 Sapium ellipticum (Krauss.) Leaves Ethanolic extract (500 mg/mL) exhibited good cytotoxicity against HeLa cell lines causing over 50% Sowemimo
41 Pax. inhibiton. The standards used were cisplatin at 10 and 100 mM causing 49.257 3.33% and et al. (2009)
42 88.197 0.60% inhibition, respectively.
43 Stem Ethanolic extract (500 mg/mL) exhibited low cytotoxicity against HeLa cell lines causing less than Sowemimo
bark 40% inhibition. The standards used were cisplatin at 10 and 100 mM causing 49.25 73.33% and et al. (2009)
44
88.197 0.60% inhibition, respectively.
45 Sapium japonicum (Siebold & Leaves, Showed no cytotoxicity against RAW 264.7 and HS-68 cells (MTT assay), with TC50 of 4500 mg/ Kim et al.
46 Zucc.) Pax & K.Hoffm. branch mL. (2010)
47
48
49
50 were reported to possess medicinal properties and are used to 42, respectively) showed strong antibacterial activity against
51 treat a broad range of ailments, such as skin-related diseases, Mycobacterium tuberculosis H37Rv.
52 hernia, constipation, and have also been applied for healing Because only six out of 23 species of the genus Sapium have
53 wounds and snake bites. The phytochemical investigation of this been phytochemically studied thus far, there is significant oppor-
54 genus revealed the presence of various types of compounds tunity to find new chemical constituents from this genus. The
55 including flavonoids, terpenoids and other classes of compounds traditional uses of species of the genus Sapium revealed a broad
56 such as alkaloid and phenolic esters. The terpenoid compounds in range of medicinal properties possessed by Sapium species. How-
57 this genus are dominated by diterpenes from several skeleton ever, there have been no reports regarding the pharmacological
58 types such as diterpene phorbol esters, labdanes and kauranes. properties of the species based on their medicinal uses. In
59 Several types of extracts and single compounds from this genus addition, several species that have been used traditionally to treat
60 have been reported to exhibit biological activities including anti- many types of ailments have not been investigated for their
61 microbial, anti-inflammatory, antioxidant and cytotoxic activities. biological activities at all. These facts open up a great opportunity
62 Compound 9 (12-deoxyphorbol-13-benzoate) isolated from the to discover new pharmacological properties from this genus, as
63 seed of Sapium sebiferum displayed significant anti-inflammatory well as promising sources for drugs, such as for cancer, hernia,
64 activity. Sapintoxins A and B (10 and 11, respectively) significantly skin and digestive diseases. Furthermore, the toxicity studies of
65 inhibited the growth of Mycobacterium tuberculosis H37Ra, while some phorbol esters suggested that the compounds are potential
66 lecheronol A, epi-lupeol and 3α-hydroxyolean-12-ene (32, 36 and tumor-promoting agents via the stimulation of protein kinase C.

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 10 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Table 6
2 Biological activities of some compounds from Sapium species.
3
Biological
4 No Compound name
activity
Description Reference
5
6 1 Rutin Antibacterial Selectively promoted Escherichia coli topoisomerase IV-dependent DNA cleavage, Bernard et al. (1997)
7 inhibited topoisomerase IV-dependent decatenation activity and induced the SOS
response of the Escherichia coli strain.
8 Antiviral Showed acitivity against HSV, respiratory syncytial virus, poliovirus and Sindbis virus Middleton and
9 Chithan (1993),
10 Selway (1986)
11 2 Quercetin Antibacterial Oral administration of either 142.9 mg/kg quercetin or 214.3 mg/kg quercetin Vijaya and Ananthan
protected guinea pigs against an induced Shigella infection that killed untreated (1996)
12
control animals.
13 Antibacterial Inhibited Escherichia coli DNA gyrase's ATPase activity by binding to its GyrB subunit. Plaper et al. (2003)
14 Antibacterial Increased the permeability of the inner bacterial membrane and a dissipation of the Mirzoeva et al. (1997)
15 membrane potential, decreasing the resistance of cells to other antibacterial agents.
16 Antiviral Inhibited HIV-1 integrase Ono et al. (1990)
Antiviral Showed activity against HSV, respiratory syncytial virus, poliovirus and Sindbis virus Middleton and
17 Chithan, 1993;
18 Selway, 1986
19 Antiviral Potentiated the effects of 5-ethyl-2–dioxyuridine against HSV and pseudorabies Middleton and
20 infection Chithan (1993)
Antiviral Potentiated the effects of acyclovir against HSV and pseudorabies infection Mucsi et al. (1992)
21
5 α,β,3,4,5,20 ,40 ,60 - Antibacterial Exhibited insignificant antibacterial activity against Mycobacterium tuberculosis Woldemichael et al.
22 octahydroxydihydrochalcone H37Rv (ATCC 27294) with MIC of 4128 mg/mL. The control used was rifampin with (2004)
23 MIC of 0.06 mg/mL.
24 10 Sapintoxin A Antibacterial Displayed significant antibacterial activity against Mycobacterium tuberculosis H37Ra Chumkaew et al.
25 with MIC of 3.12 mg/mL. The controls used were isoniazide and kanamycin sulfate (2003)
with MICs of 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
26 11 Sapintoxin B Antibacterial Showed significant antibacterial activity against Mycobacterium. tuberculosis H37Ra Chumkaew et al.
27 with MIC of 12.5 mg/mL. The controls used were isoniazide and kanamycin sulfate (2003)
28 with MICs of 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
29 12 Sapintoxin C Antibacterial Inhibited the growth of Mycobacterium tuberculosis H37Ra with MIC of 25 mg/mL. The Chumkaew et al.
controls used were isoniazide and kanamycin sulfate with MICs of 0.04–0.09 mg/mL (2003)
30
and 2.0–5.0 mg/mL, respectively.
31 13 12-(2-N-methyl aminobenzoyl)- Antibacterial Showed antibacterial activity against Mycobacterium. tuberculosis H37Ra with MIC of Chumkaew et al.
32 4β,5,20-trideoxyphorbol-13-acetate 50 mg/mL. The controls used were isoniazide and kanamycin sulfate with MIC of (2003)
33 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
34 14 12-(2-methylamino benzoyl)-4-deoxy Antibacterial Exhibited antibacterial activity against Mycobacterium tuberculosis H37Ra with MIC of Chumkaew et al.
phorbaldehyde-13-acetate 25 mg/mL. The controls used were isoniazide and kanamycin sulfate with MICs of (2003)
35 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
36 15 Sapinsignoid A Cytotoxicity Showed moderate activity against human lung cancer cell line (A-549) with IC50 of Liu et al. (2012)
37 1.8 mM and against leukimia cell line (HL-60) with IC50 of 3.4 mM.
38 16 Sapinsignoid B Cytotoxicity Showed moderate activity against human lung cancer cell lines (A-549) with IC50 of Liu et al. (2012)
0.2 mM and against leukimia cell lines (HL-60) with IC50 of 6.5 mM.
39
17 Sapinsignoid C Cytotoxicity Showed moderate activity against human lung cancer cell line (A-549) with IC50 of Liu et al. (2012)
40 0.4 mM and against leukimia cell line (HL-60) with IC50 of 2.7 mM.
41 18 Sapinsignoid D Cytotoxicity Showed moderate activity against human lung cancer cell line (A-549) with IC50 of Liu et al. (2012)
42 0.9 mM.
43 19 α-sapinine Antibacterial Displayed no antibacterial activity against Mycobacterium tuberculosis H37Ra with Chumkaew et al.
MIC of 4200 mg/mL. The controls used were isoniazide and kanamycin sulfate with (2003)
44
MICs of 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
45 20 12-(2-N-methyl aminobenzoyl)- Antibacterial Insignificantly inhibited the growth of Mycobacterium tuberculosis H37Ra with MIC of Chumkaew et al.
46 4α,5,20-trideoxy phorbol-13-acetate 200 mg/mL. The controls used were isoniazide and kanamycin sulfate with MICs of (2003)
47 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
21 12-(2-N-methyl aminobenzoyl)- Antibacterial Demonstrated no antibacterial activity against Mycobacterium tuberculosis H37Ra Chumkaew et al.
48
4α,20-dideoxy-5-hydroxyphorbol-13- with MIC of 4200 mg/mL. The controls used were isoniazide and kanamycin sulfate (2003)
49 acetate with MICs of 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
50 22 12-(20 -N-methyl aminobenzoyl)-4α- Antibacterial Exhibited antibacterial activity against Mycobacterium tuberculosis H37Ra with MIC of Chumkaew et al.
51 deoxy-5,20-dihydroxyphorbol-13- 25 mg/mL. The controls used were isoniazide and kanamycin sulfate with MICs of (2003)
52 acetate 0.04–0.09 mg/mL and 2.0–5.0 mg/mL, respectively.
32 Lecheronol A Antibacterial Showed significant antibacterial activity against Mycobacterium tuberculosis H37Rv Woldemichael et al.
53
(ATCC 27294) with MIC of 4 mg/mL. The control used was rifampin with MIC of (2004)
54 0.06 mg/mL.
55 Cytotoxicity Deemed active against Vero cells (ATCC CCL-81) with IC50 of 104.8 mg/mL. Woldemichael et al.
56 (2004)
33 Lecheronol B Antibacterial Displayed insignificant antibacterial activity against Mycobacterium tuberculosis Woldemichael et al.
57
H37Rv (ATCC 27294) with MIC of 128 mg/mL. The control used was rifampin with MIC (2004)
58 of 0.06 mg/mL.
59 36 Epi-lupeol Antibacterial Exhibited significant antibacterial activity against Mycobacterium tuberculosis H37Rv Woldemichael et al.
60 (ATCC 27294) with MIC of 13.4 mg/mL. The control used was rifampin with MIC of (2004)
61 0.06 mg/mL.
Cytotoxicity Deemed active against Vero cells (ATCC CCL-81) with IC50 of 127.2 mg/mL. Woldemichael et al.
62
(2004)
63 42 3α-hydroxyolean-12-ene Antibacterial Showed significant antibacterial activity against Mycobacterium tuberculosis H37Rv Woldemichael et al.
64 (ATCC 27294) with MIC of 12.2 mg/mL. The control used was rifampin with MIC of (2004)
65 0.06 mg/mL.
Cytotoxicity Deemed active against Vero cells (ATCC CCL-81) with IC50 of 127.2 mg/mL. Woldemichael et al.
66
(2004)

Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎ 11

1 Table 6 (continued )
2
3 Biological
No Compound name Description Reference
activity
4
5 43 3β-hydroxyolean-12-ene Antibacterial Insignificantly inhibited the growth of Mycobacterium tuberculosis H37Rv (ATCC Woldemichael et al.
6 27294) with MIC of 64 mg/mL. The control used was rifampin with MIC of 0.06 mg/mL. (2004)
7 44 2α,3β,23-trihydroxyolean-12-E-28-oic Antibacterial Exhibited insignificant activity against Mycobacterium tuberculosis H37Rv (ATCC Woldemichael et al.
acid 27294) with MIC of 4128 mg/mL. The control used was rifampin with MIC of 0.06 mg/ (2004)
8 mL.
9 45 3α-hydroxyurs-12-ene Antibacterial Displayed insignificant activity against Mycobacterium tuberculosis H37Rv (ATCC Woldemichael et al.
10 27294) with MIC of 4128 mg/mL. The control used was rifampin (MIC of 0.06 mg/mL).(2004)
11 46 Cycloartanol Antibacterial Showed significant activity against Mycobacterium tuberculosis H37Rv (ATCC 27294) Woldemichael et al.
with MIC of 8 mg/mL. The control used was rifampin (MIC of 0.06 mg/mL). (2004)
12
Cytotoxicity Deemed active against Vero cells (ATCC CCL-81) with IC50 of 102.4 mg/mL. Woldemichael et al.
13 (2004)
14 48 3-O-β-lauroyl-cycloart-(23E)-en-25-ol Antibacterial Exhibited insignificant antibacterial activity against Mycobacterium tuberculosis Woldemichael et al.
15 H37Rv (ATCC 27294) with MIC of 4128 mg/mL. The control used was rifampin (MIC (2004)
16 of 0.06 mg/mL).
51 (─)-bukittinggine Anti- Exhibited anti-inflammatory activity Panthong et al. (1998)
17 inflammatory
18
19
20
21
22 Table 7 aggregation and erythema of skin. Acta Pharmacology and Toxicology 53,
23 Accepted names of some Sapium species. 177–187.
El-Mekkawy, S., Meselhy, M.R., Nakamura, N., Hatori, M., Kawahata, T., Otake, T.,
24
Species name (Synonym) Accepted namea 2000. Anti-HIV-1 phorbol esters from the seeds of Croton tiglium. Phytochem-
25 istry 53, 457–464.
26 Sapium indicum Willd. Shirakiopsis indica (Willd.) Esser Ellis, M.D., 1978. Dangerous plants, snakes, arthropods and marine life. In: Ellis, M.
27 Sapium ellipticum (Hochst.) Pax Shirakiopsis elliptica (Hochst.) Esser D. (Ed.), Toxicity and Treatment. Drug Intelligence Publications Inc., Hamilton,
Sapium insigne (Royle) Benth. & Hook. f. Falconeria insignis Royle IL, p. 39.
28 Escamilla, E.M., Ortega, A., 1991. Labdane diterpenoids from Stevia seleriana.
29 a
http://www.theplantlist.org Phytochemistry 30, 599–602.
30 Esser, H.J., Welzen, P.C.V., 2005, Flora of Thailand. 10. Balakata. Q4
Eswani, N., Kudus, K.A., Nazre, M., Noor, A.G.A., 2010. Medicinal plant diversity and
31 Therefore, more clinical studies on the toxicity of the extracts of vegetation analysis of logged over hill forest of Tekai Tembeling Forest Reserve,
32 the plants and the compounds isolated from this genus are also Jerantut, Pahang. Journal of Agricultural Science 2, 189–210.
33 crucial to ensure their safety and to assess their eligibility to be Evans, F.J., 1986. Environmental hazards of diterpene esters from plants. In: Evans, F.J.
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34 used as sources of modern medicines.
Fu, R., Zhang, Y.T., Guo, Y.R., Huang, Q.L., Peng, T., Xu, Y., Tang, L, Chen, F., 2013.
35 Antioxidant and anti-inflammatory activities of the phenolic extracts of Sapium
36 sebiferum (L.) Roxb. leaves. Journal of Ethnopharmacology 147, 517–524.
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Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i
 12 L.M.R. Al Muqarrabun et al. / Journal of Ethnopharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

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Please cite this article as: Al Muqarrabun, L.M.R., et al., A review of the medicinal uses, phytochemistry and pharmacology of the genus
Sapium. Journal of Ethnopharmacology (2014), http://dx.doi.org/10.1016/j.jep.2014.05.028i