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4
Biological Activities and
Phytochemicals of the Fruits of Vitex Plants
J.F. Pío-León1, J. Montes-Avila1, S.P. Díaz-Camacho1
and F. Delgado-Vargas1*
ABSTRACT
The Vitex genus (Lamiaceae) is composed of 270 species, trees or shrubs; that are distributed
in tropics worldwide. Vitex has been the source of a large number of compounds with
pharmacological activities, many of them associated with their fruits. In spite of the high
number of Vitex spp., fruit studies have been mainly focused in a reduced group; Vitex agnuscastus is the best studied, and several fruit-derived drugs, used to treat premenstrual syndrome,
are commercialized in the United States of America and Europe. Other species with a good
number of studies are V. rotundifolia, V. trifolia, V. negundo and V. doniana. Interesting
activities associated with Vitex fruits are antitumoral (e.g., against breast, gastric, colon,
leukemia and cervix cells), antioxidant, antimicrobial and anti-diarrhea. Identified fruit
compounds belong to different phytochemical families such as flavonoids (e.g., casticin,
orientin, and isoorientin), terpenes (e.g., rotundifaran, ferruginol), iridoids (e.g., agnoside,
aucubin) and essential oils (e.g., 1,8-cineolene, sabinene). Interestingly, these fruits showed
dark colors that have been poorly studied; these pigments could be associated with important
biological activities based on the actual knowledge about natural pigments. In this review, we
are showing the main studies about the chemicals and biological activities of Vitex spp. fruits,
and it will be a reference material for future studies.
Keywords: Vitex fruits, Biological activities, Chemical composition, Nutritional and
nutraceutical properties, Essential oils, Chocolate berries, Gynecologic disorders,
Anti-diarrheal.
———————
1
Facultad de Ciencias Químico Biológicas de la Universidad Autónoma de Sinaloa. Ciudad
Universitaria s/n, Culiacán, Sinaloa, México, CP 80010
*
Corresponding author: E-mail: fdelgado@uas.edu.mx
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Introduction
Linnaeus described the genus Vitex (Lamiaceae before Verbenaceae) in 1753
and four species were registered (V. agnus-castus, V. negundo, V. pinnata and V. trifolia);
nowadays, this genus includes between 250 and 300 species of trees and bushes
(rarely lianas). These plants are mainly distributed in tropical or sub-tropical areas
over the world (Chantaranothai, 2011; de Kok, 2008; Munir, 1987). Vitex agnus-castus
shows a wide distribution in Mediterranean Europe and Central Asia and it is the
best known and studied plant of this genus (Padmalatha et al., 2009).
The leaves of Vitex spp. are opposite, decussate with three to five folioles, rarely
two or one as in V. rotundifolia; flowers are zygomorphic, calyx with five fused sepals,
persistent, tubular-like or bell-shaped like, sometimes dentate; corolla with five fused
petals, deciduous of tubular-like form with internal villous and sometimes pubescent
(Munir, 1987). Historically, Vitex spp. have been widely used in traditional medicine;
and up to date, they have a large number of ethnopharmacological applications such
as: treatment of premenstrual and gynecologic affections, bacterial infections,
gastrointestinal problems and inflammation; as well as insect repellent and against
stings of venomous animals (Padmalatha et al., 2009).
A large number of the medicinal properties of Vitex spp. are associated with
their fruits; some of them are important as foods in highly marginated and low income
areas. Vitex spp. fruits are small succulent drupes, globular or ovoid of 0.2-2 cm size
(usually smaller than 2 cm); they possess a hardened endocarp that is divided in four
pyrenes, each one with a seed (Chantaranothai, 2011; de Kok, 2008; Munir, 1987).
Fruits of different Vitex spp. have similar morphology and sometimes they are difficult
to differentiate. The ripe pulp of these fruits is characterized by dark-purple to brown
colors (Figure 4.1) (Chantaranothai, 2011; Munir, 1987; NRC, 2008; Webster, 2008).
In this review, we are showing the main characteristics of the Vitex spp. fruits,
emphasizing their phytochemicals (more than 100 identified compounds) and
biological activities. The current knowledge of these fruits is discussed as well as the
future research trends.
Nutritional Characteristics of Vitex Fruits
Fruits are important foods in human diet; they mainly provide vitamins, minerals
and fiber. Recently, functional and nutraceutical foods, which provide benefits for
the prevention/treatment of diseases in addition to their nutritional components,
have acquired an increased relevance; within these food groups, fruits are highly
represented (e.g. grapes, cranberries, blueberries, pomegranate) and their consumption
have been associated with a healthy condition and longevity (Kaliora and Dedoussis,
2007; Kalra, 2003; Kaur and Kapoor, 2001; Rissanen et al., 2003).
Many of the Vitex fruits are edible; about 70 species have been registered just in
Africa, where they are known as “chocolate berries”. These wild berries have a
significant contribution to food security and sustainable rural development for some
African communities and many of them are valuable commercial products in those
regions (NRC, 2008). The most representative chocolate berries are V. doniana, V.
payos, V. fischeri, V. grandifolia, V. simplicifolia, V. madiensis, V. mombassae, V. ferruginea
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and V. pooara (Maundu, 1999; NRC, 2008). Vitex fruits are consumed fresh, dried or in
boiled preparations with sugar (e.g. jelly, marmalade) (NRC, 2008). Research groups
have developed new products based on the properties of chocolate berries, for example,
the V. doniana pulp was used to prepare a syrup with sensorial characteristics and
acceptability similar to those of honey (Egbekun et al., 1996); a pasteurized juice of V.
mombassae showed good acceptability and its physicochemical characteristics were
preserved up to 3 months of storage (Ndabikunze et al., 2010). In Mexico, V. mollis is
used for sweet preparations that can be consumed alone or mixed with milk; however,
the properties of such products have not been established (Montiel-Herrera et al.,
2004).
Table 4.1: Physico-chemical and nutritional parameters of Vitex spp. fruits.
V. mollis1
V. doniana2
V. keniensis3
V. fischerii3
87
39.42
40.56
37.74
Protein
0.60
0.85
0.87
0.98
–
Lipids
0.38
2.44
2.35
2.66
–
Ash
0.66
3.41
3.40
3.66
–
Fiber
1.92
11.48
10.42
12.38
–
9.48
43.12
42.49
42.67
–
Ca
45
320
–
–
55
Mg
–
72
–
–
156
Na
300
100
–
–
43
K
1610
880
–
–
1757
P
–
200
–
–
309
Fe
4
–
–
–
2.69
Zn
4.4
–
–
–
1.53
Cu
0.38
–
–
–
0.27
Ascorbic acid (mg/100g f.w.)
5.8
81.6-100
–
–
40.4
pH
4.86
4.38
–
–
3.56
Acidity (per cent)
0.13
0.36
–
–
0.14
14
5.2
–
–
12.3
Parameter
V. mombassae5
Proximate (per cent f.w.)
Moisture
Carbohydrates
Minerals (mg/100 g d.w.)
Soluble solids (°Brix)
–: Non reported.
Cited papers–1: Montiel-Herrera et al. (2004); 2: Egbekum et al. (1996); and 2,3: Ochieng and Nanwa
(2010).
In spite of the use of chocolate berries as foods, their physicochemical,
phytochemical and nutritional/nutraceutical characteristics have been poorly studied
(NRC, 2008). Nevertheless, it has been clearly demonstrated that Vitex fruits are good
sources of fiber, vitamin C and some minerals; they showed an uncommon low content
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of water (40 per cent) (Table 4.1). After moisture and carbohydrates, the most important
component of Vitex spp. is the fiber. Vitex doniana fruits are rich in calcium and
vitamin C; V. mombassae in potassium; and V. mollis in copper and zinc (Table 4.1).
Consumption of 100 g fresh weight (f.w.) of V. doniana provides 100 and 19.4 per cent
of the recommended daily intakes for vitamin C and calcium (90 and 1000 mg,
respectively) (FNB/FNIC, 2010).
Vitex fruits show characteristic odor and color. Odor is influenced by the
composition of fruit essential oils which will be discussed in section 7 of this review.
With respect to color, the dark hue of Vitex fruits has not been associated with specific
components. The dark intense colorations of common fruits such as blackberry,
chokeberry or elderberry, are produced by anthocyanins, soluble pigments of low to
intermediate molecular weight which are characterized for color changes induced by
pH variation, property used to quantitate anthocyanins (Delgado-Vargas and ParedesLópez, 2003; Wrolstad, 2002). Our research group is studying the dark pigment of V.
mollis. This pigment is very stable to pH and thermal treatment; it presents high
antioxidant activity and a relative high molecular weight (personal communication).
Thus, V. mollis pigment is not an anthocyanin and we have hypothesized that melanin
pigments are responsible of the dark colors of Vitex fruits. Melanins are amorphous
polymers, of dark colors, low solubility in common solvents and high molecular
weight; in plants, these pigments are produced by the oxidation-polymerization of
phenolic compounds, as it has been demonstrated for the black tea (Sava et al., 2001).
On the other hand, some fungi have edible melanins which are associated with
sugars and they are water soluble (Seniuk et al., 2010). The chemical and biological
characterization of the Vitex pigments is an unexplored and promising research
area.
Characterized Phytochemicals of Vitex Fruits
Vitex fruits have been the source of many new compounds; considering the most
studied fruits (i.e. V. agnus-castus, V. rotundifolia, V. trifolia, V. negundo and V.
cannabifolia), 100 chemicals are presented in Table 4.1 and Figure 4.2. The main
components of Vitex spp. are terpenoids, mainly diterpenes, and flavonoids. Casticin
(also known as vitexicarpin) is the Vitex spp. compound with the highest number of
demonstrated biological activities (e.g., estrogenic, opioid, antitumoral, antioxidant,
anti-inflammatory) (Lee et al., 2011; Xu et al., 2012; Ye et al., 2010). The properties of
other interesting Vitex compounds, such as agnoside and rotundifaran, are discussed
in following sections.
Gynecologic Properties of Vitex Fruits
The main traditional uses of Vitex fruits have been for gynecologic and hormonal
problems such as premenstrual syndrome (PMS), post-menopause disorders, and
libido modulation. As a matter of fact, V. agnus-castus has been used since before
Christ by Greek and Roman cultures; fruit preparations have been applied as antiinflammatory; to diminish the libido, the dysmenorrhoea and menopause symptoms,
PMS and acne; to treat infertility and to stop lactation (AMR, 2009; Halaska et al.,
1999; Webster, 2008). Nowadays, many of the traditional uses of V. agnus-castus have
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Figure 4.2: Chemical structures of compounds obtained from Vitex spp. fruits.
Terpenoids
HO
NH
OH
H
O
H
HO
O
O
O
O
OAc
(1)
(2)
(3)
O
O
O
HO
HO
O
HO
OH
OH
H
H
R1
R2
O
H
(4)
O
(5)
OCH3
(6)
H
(7); R1 = OH, R2 = CH3
O
O
O
O
OH
O
OH
O
H
O
O
(8)
OAc
(9)
(10)
Contd...
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Figure 4.2–Terpenoids–Contd...
R1
R2
O
OH
OH
HO
O
H
O
HO
HO
H
OH
(11) R1 = Me, R 2 = H
(12) R1 = H, R2 = Me
OH
HO
(13)
(14)
OH
O
O
O
OH
O
H
H
OCOCH3
O
(15)
OCOCH3
(16)
O
OH
OCOCH3
O
H
O
O
HO
(18)
HO
(17)
H
H
H
H
HO
H
( 44)
(19)
O
HO
OH
OH
OCOCH 3
OCOCH3
( 45)
OH
OCOCH3
( 46)
OCOCH 3
OH
( 47)
AcO
H
(48)
Contd...
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Figure 4.2–Terpenoids–Contd...
O
O
OH
O
OH
OH
OH
HO
O
OH
( 49)
H
(51)
(50)
(52)
HO
HO
O
OCOCH3
H
O
O
HO
O
H
H
(75)
HO
HO
(89)
H
(90)
(91)
O
O
O
O
O
O
O
O
H
O
H
H
OAc
O
(92)
H
OAc
(93)
O
(94)
(95)
O
OH
OH
OH
OO
OH
H
OCOCH 3
HO
H
OH
(96)
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(97)
Contd...
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Bioactive Phytochemicals: Perspectives for Modern Medicine Vol. 2
Figure 4.2–Contd...
Flavonoids
R4
OR5
R3 O
O
R2
R1
OH
OH
O
RO
(20) R 1 = R2 OMe, R3 = R5 Me, R4 = OH
(21) R1 = R2 = OMe, R3 = Me, R 4 = R5 = H
(22) R1 = R 2 = R 3 = R4 = R5 = H
(23) R1 = OMe, R2 = R3 = R4 = R5 = H
(24) R1 = R2 = R3 = R5 = H, R4 = OH
(25) R1 = OH, R 2 = R3 = R4 = R5 = H
(26) R1 = OMe, R2 = R3 = R5 = H, R4 = OH
(27) R 1 = OMe, R2 = R5 = H, R3 = Me, R4 = OH
OH
OH
O
R
OH
H3 CO
OH
OH
O
GlU
HO
O
OH
(28) R = H
(29) R = Me
OCH3
H3 CO
O
O
O
(31) H
(32) OH
(30)
R4
Glu
HO
OH
R3
OH
HO
O
O
R2
Rha
OH
OH
OH
O
OH
O
O
(33)
HO
R1
O
(61) R1 = R3 = H, R2 = Glc, R4 = OH
(62) R1 = R2 = H, R3 = Glc, R4 = OH
HO
O
OH
(78)
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O
(79)
OH
Contd...
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Figure 4.2–Flavonoids–Contd...
OH
OH
HO
O
OH
HO
O
OH
OH
O
OH
OCH3
(80)
(81)
OR1
OCH3
O
H3 CO
OR2
H3 CO
O
H3 CO
OH
OCH3
OH
H3 CO
O
OCH3
OH
O
(98) R1 = R2 = CH 3
(99) R1 = R2 = H
(100)
Simple phenolics
O
O
OR2
OH
O
HO
R1
OH
OH
OH
HO
(34) R1 = OMe, R2 = H
(35) R1 = H, R2 = p-hydroxyphenylenanol
(36) R1 = R2 = H
HO
(37)
(82)
HO CO2 H
O
HO
O
OH
OH
OH
(83)
Contd...
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Figure 4.2–Contd...
Iridoids
OH
OH
OH
H
O
OH
HO
O
O
H
H
O
H
HO
HO
O
GlcO
OH
OH
OH
H
O
(42)
HO
(60)
(43)
HO
HO
H
O
H 3CO
O
HO
H
H
OCH3
O
O
OH
OGlc HO
O
H
O
(71)
H
OGlc
COOCH 3
O
H
HO
OGlc
(73)
(72)
Lignan derivatives
O
R2
OMe
OMe
O
O
H
OR3
HO
O
H 3CO
R1
O
OH
HO
OCH 3
R
OH
HO
(38) R = -CHO
(39) R = -CH 2CH2CH2OH
(40) R = -(E)-CH=CH-CHO
(63) R1 = OCH 3 , R2 = H, R3 = Glc
(64) R1 = H, R 2 = OCH3 , R3 = Glc
(65) R1 = H, R 2 = OCH3 , R3 = H
(66) R1 = H, R 2 = OCH3 , R3 = OH
OCH 3
OH
(67)
Contd...
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Figure 4.2–Lignan derivatives–Contd...
O
H 3CO
H
R
HO
OCH3
O
H 3CO
OH
H
OCH 3
H
HO
OH
O
(68) R = H
(69) R = OH
(70)
Catechins
OH
OH
OH
HO
OH
OH
O
HO
O
OH
OH
OH
OH
(84)
(85)
Anthraquinones
O
OH
OH
O
OH
OH
O
O
O
(86)
OH
(87)
Others
OGlc
OH
H3C
OH
HO
O
7
O
O
4
O
(41)
(74)
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O
CH3
N
N
N
N
CH 3
(88)
Vitex spp.
Vitex agnus-castus
Vitex trifolia
Family of Compounds: Identified Compounds
References
Terpenoids: Vitexlactam A (1)
Li et al. (2002)
Viteagnusin A (2), viteagnusin B (3), viteagnusin C (4), viteagnusin D (5), viteagnusin E (6),
8-epi-sclareol (7), (rel 5S,6R,8R,9R,10S,13R)-6-acetoxy-9,13-epoxy-15-methoxy-labdan-16,
15-olide (8)
Ono et al. (2008)
Viteagnusin I (9), 8-epi-manoyl oxide (10), 3-epi-maslinic acid (11), 3-epi-corosolic acid (12),
aromadendrane-4a,10a-diol (13), ilelatifol D (14)
Chen et al. (2011)
Vitetrifolin B (15), vitetrifolin C (16), rotundifaran (17), vitexilactone (18), spathulenol (19)
Hajdu et al. (2007), Webster
et al. (2011)
Flavonoids: Casticin (20), penduletin (21), apigenin (22), 3-methylquercetin (23), luteolin (24),
Kaempferol (25), 3,7-dimethylquercetin (26), 3-O-methylkaempferol (27), 5,7,32,52tetrahydroxyflavanon (28), 5,32,52-trihydroxymethoxylflavanone (29), eupatorin (30), vitexin (31),
orientin (32), apigenin 3, 8-di-C-glycosides (33)
Chen et al. (2011), Hajdu et
al. (2007), Webster et al.
(2011), Ibrahim et al. (2008)
Phenolics: Ferulic acid (34), phydroxyphenylethanol-p-coumarate (35), p-Coumaric acid (36),
4-hydroxybenzoic acid (37). Neolignans: Ficusal (38), vladirol F (39), balanophonin (40),
Glycerides: Glyceryl linoleate (41).
Chen et al. (2011)
Iridoids: Agnuside (42)
Webster et al. (2011)
Aucubin (43)
Ibrahim et al. (2008)
Terpenoids: Vitetrifolin A (44), vitetrifolin B (15), vitetrifolin C (16), vitetrofilin D (45), vitetrofolin E (46), Ono et al. (2000), Li et al.
vitetrifolin F (47), vitetrifolin H (48), vitetrifolin I (49), rotundifaran (17), Dihydrosolidagenone (50),
(2005), Wu et al. (2009)
abietatriene 3b-ol (51), vitexilactone (18), (rel 5S,6R,8R,9R,10S)-6-acetoxy-9-hydroxy-13(14)labden-16,15-olide (52).
Gu et al. (2008)
Vitexoid (56), 6-acetoxy-9-hydroxy-13(14)-labdane-16,15-olide (57), previtexilactone (58),
6-acetoxy-9,13;15,16-diepoxy-15-methoxylabdane (59)
Wu et al. (2009)
Flavonoids: Casticin (20)
Xu et al. (2012)
Iridoids: Eucommiol (60)
Gu et al. (2008)
Contd...
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Vitrifol A (53), dihydrodehydrodiconifenyl alcohol (54), stigmast-4-en-6b-ol-3-one (55)
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Table 4.2: Characterized phytochemicals obtained from Vitex spp. fruits.*
Vitex spp.
Vitex cannabifolia
Family of Compounds: Identified Compounds
References
106 |
Flavonoids: 5,4’-dihydroxy-3,6,7,8,3’-pentamethoxyflavone (61), isoorientin (62), orientin (32)
Lignans: vitecannaside A (63), vitecannaside B (64), vitedoin A (65), 6-hydroxy-4-(4-hydroxy-3methoxyphenyl)-3-hydroxymethyl-7-methoxy-3,4-dihydro-2-naphthaldehyde (66), detetrahydroconidendrin (67), vitrofolal E (68), vitrofolal F (69), pinoresinol (70).
Yamasaki et al. (2008)
Iridoids: agnuside (42), 10-O-vanilloyl aucubin (71), nisindaside (72), geniposide (73).
Phenylbutanone glucoside: 4-(3,4-dihydroxyphenyl)-butan-2-one-4 O b D-glucoside (74).
Vitex negundo
Terpenoids: vitedoin B (75). Lignans: Vitedoin A (65), vitedoamine A (76), 6-hydroxy-4-(4-hydroxy- Ono et al. (2004)Guha et al.
3-methoxyphenyl)-3-hydroxymethyl-7-methoxy-3,4-dihydro-2-naphthaldehyde (66), detetrahydro(2010)
conidendrin (67), vitrofolal E (68), vitrofolal F (69), 2a,3b-7-O-methylcedrusin (77).
Flavonoids: naringenin (78), genistein (79), biochanin A (80), delphinidin (81). Phenolics:
4-Hydroxybenzoic acid (37), gallic acid (82), chlorogenic acid (83). Catechins: (-)-gallocatechin (84),
epicatechin (85). Anthraquinones: alizarin (86), rhein (87). Others: Caffeine (88).
Vitex rotundifolia
Diterpenoids: Vitexifolin A (89), vitexifolin B (90), vitexifolin C (91), vitexifolin D (92), vitexifolin E (93), Ono et al. (1998; 1999; 2002)
vitetrifolin D (45), trisnor-g-lactone (94), iso-ambreinolide (95), ferruginol (96), abietatrien-3b-ol (51),
viteoside A (97)
Rotundifaran (17)
Hu et al. (2007)
Flavonoids: Casticin (20), luteolin (26), artemetin (98), quercetagetin (99), 5,3’-dihydroxy-6,7,4’–
trimethoxyflavanone (100).
Kobayakawa et al. (2004), Ko
et al. (2000), Ono et al.
(2002), Hu et al. (2007)
Iridoid: agnuside (42)
Hu et al. (2007)
* Bold type numbers within parenthesis correspond to the structure presented in Figure 4.2.
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Table 4.2–Contd...
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been demonstrated and in particular its use for PMS (Roemheld-Hamm, 2005; Webster,
2008; Wuttke et al., 2003). In herbal medicine, a tincture was employed for PMS and
prepared by mixing 1/5 of dried V. agnus-castus fruits with alcohol (50 per cent or 70
per cent), with a recommended dose of 20 drops/day (about 1 mL/day); alternatively,
the German Commission E has suggested the consumption of 30-40 mg of dried
fruit/day to treat not only PMS but also mastalgia and irregular menstruation (Webster,
2008). Now, diverse standardized extracts are commercialized: Agnolyt (caps and
solution), Agnucaston (tablets), Mastonynon (tablets and solution), Femarpim and
Ze 440 (tablets). These preparations were obtained by extraction with ethanol (50-70
per cent) and standardized for the content of casticin or agnoside (0.3-0.6 per cent).
To date, the effect of these extracts in libido modulation has not been demonstrated
(Roemheld-Hamm, 2005; Webster, 2008). In general, the commercial preparations of
V. agnus-castus are well tolerated and secondary effects (i.e., headache, seasickness,
tiredness or thirst) are non-frequent or slight (Daniele et al., 2005; Roemheld-Hamm,
2005). It has been proposed that V. agnus-castus extracts are good for the symptoms
but not for curing, since symptoms return within some days of leaving the treatment
(Berger et al., 2000).
The mechanism of action of the V. agnus-castus on PMS has not been established
but multiple targets have been proposed; one of them involves the inhibition of
hyperprolactinemy during the premenstrual stage. High prolactin in serum stimulates
breast milk production and induces mastalgia. The V. agnus-castus compounds bind
dopamine receptors and inhibit the pituitary liberation of prolactin; the proposed
chemicals involved are diterpenes (Wuttke, et al., 2003) and the flavonoid casticin
(Ye, et al., 2010); remarkably, these compounds have also been isolated from other
Vitex spp. (Table 4.2). Other proposed mechanisms are the estrogenic (Hu et al., 2007;
Ibrahim et al., 2008; Liu et al., 2001), contributing to the hormonal homeostasis, and
opioid activities (Webster et al., 2011; Webster et al., 2006) of Vitex fruits. Extracts and
flavonoids of V. agnus-castus (e.g. casticin, apigenin, 3-methylkaempferol, and luteolin)
show affinity for the µ and d opioid receptors, acting analogously to b-endorphin, but
not for the ê receptor. During PMS, opioid activity decrease and the appearance of
pain and mood changes are facilitated; thus, V. agnus-castus is acting in PMS by
reactivation of opioid activity (Webster, et al., 2011; Webster, et al., 2006). Among the
evaluated flavonoids, casticin shows the highest affinity for the opioid receptors
(Chen et al., 2011). Similar effects have been obtained with other opiaceous such as
morphine; the advantage of the Vitex extracts over morphine is that after hundred
years of use, they do not induce secondary effects (Webster et al., 2011).
In some places, V. agnus-castus is not available and people use the fruits of V.
rotundifolia or V. trifolia. These fruits share similar ethnopharmacological applications.
Some commercial preparations of V. agnus-castus are adulterated with V. rotundifolia
or V. trifolia and up to date, the use of these mixtures have not induced secondary
effects but it is suggested that the desirable pharmacological effect is reduced (Webster,
2008).
Essential oils of V. agnus-castus have been used for treatment of post-menopausal
symptoms. The oils obtained from fruits or leaves diminished the hot flashes, night
sweets, dry vagina with pain during sex and insomnia. Moreover, treatment with the
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oil of leaves reduces depression symptoms, changes in personality, prolonged
bleedings, loss of memory, confusion and libido. Within the adverse effects of essential
oil application are queasiness, headache, depression and nightmares. It has been
suggested that these preparations must not be used in combination with
anticonceptives, progesterone or anti-neuroleptics (Lucks, 2003; Lucks et al., 2002).
Studies with chimpanzees of the Gombe National Park, Tanzania, showed that
consumption of V. fischeri fruits by females increased the urinary progesterone in
contrast with seasons of non-consumption or the levels of estrogens or male
testosterone; these last two parameters did not change (Emery-Thompson et al., 2008).
Antitumoral Properties of Vitex Fruits
Vitex fruits have shown antitumoral activity (Table 4.3). Vitex agnus-castus, V.
trifolia and V. rotundifolia preparations induce apoptosis in tumoral cell lines; some
of the identified compounds do not affect the growth of normal cells. The mechanism
of action is still unknown but it has been proposed that apoptosis induction is
mediated by inhibition of the cell cycle (G0/G1, G2-M), of the dynamics microtubule
formation/degradation or by inducing cell oxidative stress. Amongst the Vitex
compounds, casticin has shown the highest antitumoral activity. It has been suggested
that substituent hydroxyls (3’ and 5) and methoxyls (3 and 4’) are important structural
characteristics associated with its activity. Ono et al. (2002) showed higher activity of
casticin against tumoral colon cells (HCT116) (IC50 = 119 ng/mL) than cisplatin (IC50
= 794 ng/mL). On the other hand, rotundifaran was also better against leukemia
cells K562 and tsFT210 than cisplatin (IC50, 33.3 and higher than 100 µg/mL,
respectively) (Table 4.3). In rats, the availability of oral casticin was good (45.5 per
cent) with a half life of 36.48 min; it was suggested that casticin has high potential for
future clinical applications (Xu, et al., 2012).
Antioxidant Properties of Vitex Fruits
A large body of evidence has established a correlation between fruit and vegetable
consumption and a decreased risk of chronic degenerative diseases (Liu et al., 2000;
Rissanen, et al., 2003). Nevertheless, the main causes of morbidity and mortality over
the world are associated with an inadequate alimentation (WHO, 2008). Fruits and
vegetables not only provide essential nutrients (e.g., vitamins and minerals) but also
useful compounds for prevention/treatment of different diseases and those materials
are catalogued as “functional foods” or “nutraceuticals” (Kaur and Kapoor, 2001).
Oxidative stress is common to a large number of diseases (e.g., atherosclerosis,
hypertension, cardiac failure, Alzheimer, diabetes); thus, antioxidant activity is one
of the most evaluated properties of plant foods to designate them as nutraceutical
(Kaliora and Dedoussis, 2007; Mladµnka et al., 2010).
Some Vitex fruits are characterized by their high antioxidant capacity. The
antioxidant activity of methanol-acetone-water (6: 3: 1 v/v) extracts of three Vitex
spp. (V. doniana, V. keniensis and V. fischeri) from Kenya were analyzed by three methods
(DPPH, FRAP y NO scavenging) (Ochieng and Nanwa, 2010); ripe fruits showed
higher activity than green-ripe fruits and similar to that of the standards used (i.e.,
vitamin C, rutin and gallic acid). Moreover, total phenolics contents of the three Vitex
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Fruit
Vitex rotundifolia
Cell Line Evaluated
Responsible Compounds
Vitex agnuscastus
References
HL-60 (myeloid leukemia) (99) IC50 = 4.03 µM; (20) IC50 = 0.12 µM; Apoptosis induction (DNA fragmentation
(98) IC50 = 30.98 µM; (17) IC50 = 22.5 µM. and releasing of nucleosomes to cytoplasm
Ko et al. (2000;
2001)
PC-12 (lung cáncer),
HCT116 (colon cancer).
Inhibition of tubulin polymerization.
Substituent groups are important for activity:
3’,5-hydroxyl and 3,4’ methoxyl
Ono
et
(2002)
Casticin stop the cell cycle at G2/M by
inhibition of the processing of microtubules.
Groups 3’,5-hydroxyl and 3,4’ methoxyl
are important for the activity
Kobayakawa et
al. (2004)
(20) IC50 PC-12 = 114 ng/mL, IC50 =
HCT116 = 119 ng/mL; (98) IC50 PC-12=
2270 ng/mL, IC50 HCT116 = 2200 ng/mL.
KB (nasopharynx cancer) (20) IC50 = 0.23 µM; (98) IC50 = 16 µM;
(99) IC50 = 15.3 µM; (100) IC50 = 18.6 µM
Vitex trifolia
Proposed Mechanism of Action
al.
tsFT210 y K562 (myeloid (17) IC50 tsFT210 = 36.2 µg/mL, IC50 K562 Apoptosis and inhibition of the cell cycle
leukemia)
= 26.5 µg/mL; (45) IC50 tsFT210 = 41.3
progression in the G0/G1 phase
µg/mL, IC50 K562 = 35.2 µg/mL; (18, 52,
46) IC50 tsFT210 >80 µg/mL, IC50 K562
>50 µg/mL.
Li et al. (2005)
HeLa (cervical cancer)
Wu et al. (2009)
(49) IC50 = 4.9 µMol/L; (18) IC50 = 9.5
µMol/L; (45, 46, 48) IC50 = 15 µMol/L
KATO-III (gastricsignetEthanolic extract
ring carcinoma), SKOV-3
(breast cancer), COLO
201 (colon cancer),
Lu-134-A-H (small cell
lung carcinoma), MCF-7
(ovarian cancer),
SKG-3ª (cervical cancer)
Inhibition of the cell cycle in the stage G0/G1
Apoptosis in the cell lines: KATO-III, SCOV-3, Ohyama et al.
COLO 201 and Lu-134-A-H. In the KATO-III (2003; 2005)
is induced by cell oxidative stress
Bioactive Phytochemicals: Perspectives for Modern Medicine Vol. 2
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Table 4.3: Cytotoxic activity and suggested action mechanism of compounds isolated of Vitex spp. fruits.*
*IC50 = Half maximal (50 per cent) inhibitory concentration. Bold type numbers within parenthesis corresponds with structures of Figure 4.2.
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Bioactive Phytochemicals: Perspectives for Modern Medicine Vol. 2
fruits were high and similar among them; phenolics were also higher in ripe fruit
(572-719 mg of gallic acid equivalents/100 g f.w.) than green-ripe fruit (290-371 mg of
gallic acid equivalents/100g f.w.). Fruit ripening of Vitex fruits is accompanied by
color changes from green to dark intense hue, which could be correlated with the
phenolics content.
Aqueous extracts of V. agnus-castus show higher antioxidant activity than low
polarity preparations; the activities of aqueous extracts from fruits and leaves (2.27
and 2.50 mM Trolox equivalents, respectively) were better than those of ethanolic
and hexanic extracts (0.097-1.57 mM Trolox equivalents) evaluated by the ABTS
method (Saglam et al., 2007). Similar results were reported by Sirikurkcy et al. (2009),
who found that the aqueous extract of V. agnus-castus fruits was more active than the
low polarity extracts and essential oils by using the methods of DPPH, b-carotene
bleaching and iron reducing power; in addition, the antioxidant results by the bcarotene bleaching method with the aqueous extract were similar to those registered
for the food approved antioxidants butylated hydroxytoluene (BHT) and butylated
hydroxyanisole (BHA) (93 – 99 per cent). Total phenolics of the aqueous extracts
(112.5 mg of gallic acid equivalents/g of extract) were higher than those of the other
preparations (21.7 – 46.6 mg/g of extract); however, dichloromethane extract had a
higher concentration of flavonoids (43.5 mg of quercetin equivalents/g of extract).
Hajdu et al. (2007) identified casticin as the antioxidant molecule in an ethyl acetate
fraction obtained from a methanolic extract of V. agnus-castus; they also demonstrated
that casticin shows higher inhibition of lipid peroxidation (IC50 = 0.049 mM) than
vitamin C (IC50 = 0.703 mM) in a rat brain homogenate.
The Masateru Ono group from Japan analyzed the antioxidant activity of
phytochemicals obtained from the methanolic extracts of different Vitex spp. fruits;
they identified ferruginol (abietane-type diterpene) from V. rotundifolia which showed
higher antioxidant activity than BHT by the ferric thiocyanate method, but lower by
the DPPH method (Ono et al., 1999); isoorientin and orientin were obtained from V.
cannabifolia and identified as better antioxidants than L-cysteine and a-tocopherol by
the DPPH method (Yamasaki et al., 2008); this group also characterized the two new
lignans viteodin A and vitedoamine A (structures 65 and 76, Figure 4.2) from V.
negundo seeds, which were more potent than L-cysteine by the DPPH method (Ono et
al., 2004).
Essential Oils of Vitex spp. Fruits
Vitex fruits are an interesting source of essential oils and the best studied species
is Vitex agnus-castus (Table 4.4). The main components of the Vitex agnus-castus essential
oil are 1,8-cineole, sabinene and a-pinene and its composition is almost the same at
different maturity stages (Novak et al., 2005; Stojkovic et al., 2011). However, a clear
variation between species has been registered and essential oil composition can be
used for species identification; based on this consideration, pharmacological
applications associated with essential oil composition must change with the Vitex
sp. On the other hand, contrasting the essential oil composition of fruits and leaves
from Vitex agnus-castus, they were similar (Novak, et al., 2005; Stojkovic, et al., 2011). It
has been registered that secondary effects of treatment with V. agnus-castus essential
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Bioactive Phytochemicals: Perspectives for Modern Medicine Vol. 2
oil depends on the source (leaf or fruit), but both have reduced the symptoms associated
with gynecologic problems (see section 4) (Lucks, 2003; Lucks, et al., 2002).
Table 4.4: Composition (per cent) of essential oils of Vitex spp. fruits.
Compound
1,8 Cineole
V. agnus-castus V. agnus-castus
(Ripe fruit)
(Unripe fruits)
V. negundo
V. pseudonegundo
14-30.2
13.7-28.2
Sabinene
11.6-48.2
11.8-48.2
2.9
a-Pinene
1.1-25.5
1.1-19.4
31.7
Limonene
tr-6.8
tr-5.3
11.5
trans-b-Farnesene
0-9.3
0-7.5
a-Terpinyl acetate
0-6.6
0-6.5
Caryophyllene oxide
0-4.6
0-3.8
3
0.6-6.7
1-6.4
5
3
0.7
Terpinen-4-ol
0.3-3.6
0.4-3
a-Terpineol
0.6-3.6
0.6-4.5
0-2
0-1.7
Geranyl linalool
2.25-2.3
0.7
Myrcene
1.4-2.9
1.1-3
1.2
1
trans-Sabinene hydrate
0-0.9
0-0.9
b-Pinene
0-2.2
1.0-1.8
cis-b-Farnesene
0-0.7
0-0.5
Ledol
0-1.8
0.3-1.6
b-Selinene
–
–
22
a-Cedrene
–
–
14
0-2.1
0-1.4
8
trans-b-Caryophyllene
ô-Cadinol
Sclarene
Abietatriene
Germacrene D
1.2
1.7
4.6
Germacrene B
4.3
2.0
Aristolene
8
Hexadecanoic acid
8
a-Copaene
5.4
a-Humulene
4
Guaia-3,7-diene
2
Bicyclogermacrene
1.8
1.9-9.9
1.2-9.4
14.5
Citronellyl acetate
1.4
allo-Aromadendrene
2.7
a-Phellandrene
1.2
b-Sesquiphellandrene
1.2
a-Gurjunene
1.1
trans-a-Bergamotene
1.1
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The essential oil of V. agnus-castus showed low antioxidant activity when
evaluated in aqueous media (DPPH and ferric ion reducing power), but high activity
was obtained in an emulsion system (b-carotene bleaching) (Sarikurkcu, et al., 2009).
The essential oils of V. agnus-castus and V. doniana were potent antimicrobials (Khokra
et al., 2008; Stojkovic, et al., 2011; Suleiman and Yusuf, 2008). The V. agnus-castus oil
was effective against Staphylococcus aureus ATCC 6538, Micrococcus flavus ATCC 9341,
Bacillus subtilis ATCC 10907, Salmonella typhimurium ATCC 13311 and Escherichia
coli ATCC 35210 (minimal inhibitory concentration, MIC = 44.5 X“p”X“ 445 µg/
mL), and also against the fungi Alternaria alternata DSM 2006, Aspergillus flavus ATCC
9643, Aspergillus niger ATCC 6275, Aspergillus ochraceus ATCC 12066, Fusarium
tricinctum CBS 514478, Penicillium ochrochloron ATCC 9112, Penicillium funiculosum
ATCC 36839 and Trichoderma viride JCM 22452 (MIC = 44.5 X“p”X“ 219 µg/mL).
The active constituents of this essential oil were 1,8-cineole and a-pinene and their
MIC values for bacteria and fungi (4-8 µg/mL) were better than those of streptomycin
(MIC = 50-100 µg/mL) and bifonazole (MIC = 100-150 µg/mL). The V. doniana essential
oil inhibited the growth of S. aureus, B. subtilis and E. coli, in the disc diffusion assay;
diameters were slightly smaller than those obtained with ciprofloxacin (Khokra, et
al., 2008; Stojkovic, et al., 2011; Suleiman and Yusuf, 2008).
Other Biological Activities of Vitex spp. Fruits
Vitex mollis and V. doniana are commonly employed for diarrhea and
gastrointestinal disorders. Fractions of the methanolic extract of V. mollis were active
against enteropathogenic bacteria; the ethyl acetate fraction was enriched in phenolics
(tannins and flavonoids) and showed the highest activity, being specially effective
vs. Shigella dysenteriae (causal agent of dysentery) (MIC = 2 mg/mL) (Delgado-Vargas
et al., 2010). On the other hand, the aqueous extract of V. doniana (0.3 – 2.4 mg/mL)
inhibited the pig intestine contractions induced by treatment with acetylcholine; in
addition, it showed a dose-response effect (150 – 650 mg/kg) in the reduction of the
gastrointestinal transit time and in the diarrhea index produced by treating mice
with castor oil (Suleiman and Yusuf, 2008). As it happened with other Vitex spp., V.
doniana was also rich in flavonoids and tannins. It has been proposed that phenolics
are useful for diarrhea treatment because of their antibacterial activity and effect in
the reduction of the gastrointestinal transit time (Palombo, 2006; Ríos and Recio,
2005), supporting the observations registered for the Vitex spp. fruits and their use as
antidiarrheic agents.
A flavonoid rich extract obtained from V. negundo seeds induced infertility in
rats (15 and 30 mg/rat/day/15 days). The treated rats showed reduced weight of
sexual organs and lower density, motility and morphological abnormalities of
spermatozoids (double headed and separation of head and tail); in addition, they
had reduced the a-glucosidase activity in the epididymis, the citric acid in prostate
and the fructose in the seminal vesicles.
Some arthropods bite humans and animals and can be vectors of a range of
diseases such as borreliosis, malaria, yellow fever and dengue; natural repellents
have been used to prevent the attack of these insects. At this respect, a supercritical
CO2 extract of V. agnus-castus seeds was repellent, up to 8 h, against ticks (Ixodes
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ricinus and Rhipicephalus sanguineus), fleas (Ctenocephalides felis), mosquitoes (Culex
quinquefasciatus, Anopheles stephensi and Aedes aegypti) and flies (Stomoxys calcitrans),
evaluated in human and animal models. Remarkably, the extract (1-3 per cent) did
not produce allergic responses (Mehlhorn et al., 2005).
The aqueous extract of V. rotundifolia shows antiallergenic effects. The polymer
48/80 is produced by condensation of N-methyl-p-methoxyphenethylamine with
formaldehyde and induces mast cells to release histamine; then, an anaphylactic
allergic reaction is produced that can end with the death of the affected animal. All
rats injected (i.p., 8 mg/kg) with the 48/80 compound died; but mortality was avoided
when rats were treated with 1 g/kg of the aqueous extract of V. rotundifolia, 1 h before
or 5 to 10 min after the injection of 48/80. The analysis of the rat plasma showed that
the aqueous extract decreased by 70 per cent the histamine release, related with the
peak of histamine produced when only the allergen was applied (Shin et al., 2000).
These results support the traditional use in Korea of V. rotundifolia for treatment of
diverse allergenic diseases.
Concluding Remarks
Vitex spp. fruits show a variety of biological properties that can be used for
humanity benefits. These species are widely distributed around the world and people
could benefit from those available in every region. Many species share
ethnopharmacological uses and compounds, suggesting that Vitex spp. share
biological activities, but this needs to be scientifically tested. For example, some of the
Vitex spp. are used to treat pre-menstrual syndrome but it has been validated only for
V. agnus-castus. Other research area involves the chemical and biological
characterization of the less studied Vitex fruits; casticin, agnoside and rotundifaran
are markers for these species and they are associated with specific biological activities.
Moreover, essential oils of the Vitex fruits share components and some of them have
shown high antibacterial and antifungal activity. It is particularly interesting that
Vitex pigments have not been studied and preliminary results have showed their
high antioxidant activity. Outstandingly, aqueous extracts of V. agnus-castus showed
higher antioxidant activity than low polarity extracts, while those of V. doniana and
V. rotundifolia were effective against diarrhea in mice and as antiallergenic,
respectively. It is possible that such biological properties could be related to the dark
soluble pigments. This hypothesis remains to be tested as most of the chemicalbiological studies of Vitex fruits have been carried out with low to intermediate polarity
extracts without analyzing the aqueous extract.
Briefly, we are pointing out the following research areas with the Vitex spp.
fruits:
✰ Scientific validation of the ethnopharmacological properties of Vitex spp.
with similar uses.
✰ Isolation and characterization of representative compounds of the genus
Vitex and their association with pharmacological relevant activities (e.g.
casticin and agnoside).
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Bioactive Phytochemicals: Perspectives for Modern Medicine Vol. 2
✰ New product development of foods and standardized extracts based on
Vitex spp. and demonstration of their nutritional and nutraceutical
properties.
✰ Chemical and biological characterization of the dark pigments of Vitex
fruits.
Acknowledgments
Authors acknowledge to López-Valenzuela J.A. by the critical reading of
manuscript.
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Figure 4.1: Fruits of different Vitex spp.: V. mollis (A), V. agnus-castus (B), V. rotundifolia (C), V. vestita (D), V. cymosa (E), V. schliebenii (F),
V. polygama (G), V. payos (H), V. doniana (I), V. fischeri (J) and V. cochinchinensis (K)Sources of the images: (A) Authors of this work, (B)
http: //www.biodiversidadvirtual.org/herbarium/Vitex-agnus-castus-L-img57586.html, (C) http: //eol.org/data_objects/1990800, (D)
Chantaranothai (2011) (E) http: //eol.org/data_objects/13508823, (F) http: //eol.org/data_objects/19246219, (G) http: //www.bananasraras.org/
frutasrarasingles/vitex2.htm, (H) Mandu (1999), (I) http: //www.prota4u.org/searchresults.asp, (J) Emery-Thompson et al. (2008), (K)
Chantaranothai (2011).
Francisco Delgado-Vargas