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Review
Medicinal properties of mangosteen (Garcinia mangostana)
José Pedraza-Chaverri
*
, Noemí Cárdenas-Rodríguez, Marisol Orozco-Ibarra, Jazmin M. Pérez-Rojas
Facultad de Química, Departamento de Biología, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, 04510 Mexico, DF, Mexico
article info
Article history:
Received 14 May 2008
Accepted 25 July 2008
Keywords:
Garcinia mangostana
Mangosteen
Xanthones
Medicinal properties
abstract
Many tropical plants have interesting biological activities with potential therapeutic applications. Garci-
nia mangostana Linn. (GML) belongs to the family of Guttiferae and is named ‘‘the queen of fruits”. It is
cultivated in the tropical rainforest of some Southeast Asian nations like Indonesia, Malaysia, Sri Lanka,
Philippines, and Thailand. People in these countries have used the pericarp (peel, rind, hull or ripe) of
GML as a traditional medicine for the treatment of abdominal pain, diarrhea, dysentery, infected wound,
suppuration, and chronic ulcer.
Experimental studies have demonstrated that extracts of GML have antioxidant, antitumoral, antialler-
gic, anti-inflammatory, antibacterial, and antiviral activities. The pericarp of GML is a source of xanthones
and other bioactive substances. Prenylated xanthones isolated from GML have been extensively studied;
some members of these compounds possess antioxidant, antitumoral, antiallergic, anti-inflammatory,
antibacterial, antifungal and antiviral properties. Xanthones have been isolated from pericarp, whole
fruit, heartwood, and leaves. The most studied xanthones are
a
-, b-, and
c
-mangostins, garcinone E, 8-
deoxygartanin, and gartanin. The aim of this review is to summarize findings of beneficial properties
of GML’s extracts and xanthones isolated from this plant so far.
Ó2008 Elsevier Ltd. All rights reserved.
Contents
1. Introduction . . . ..................................................................................................... 3228
2. Xanthones isolated from the pericarp of mangosteen-fruit. . . . ............................................................... 3228
3. Xanthones from whole fruit, trunk, branches, and leaves of GML . . . . . . . . . . . . . . . . . ............................................ 3232
4. Main biological and medicinal properties of GML . . . . . . . . . . . ............................................................... 3232
4.1. Antioxidant properties . . ...................................................... .................................. 3232
4.2. Antitumoral properties . . ................................................................ ........................ 3233
4.3. Anti-inflammatory and antiallergy properties.......................................... .............................. 3234
4.4. Antibacterial, antifungal and antiviral properties . . . . . . . . . . . . . . . . ....................... .............................. 3236
4.5. Antimalarial properties . . ................................................... ..................................... 3237
5. Medicinal properties of xanthones isolated from sources other than G. Mangostana .............................................. 3237
6. Conclusions. . . . ..................................................................................................... 3237
Conflict of interest statement . . . . . . . . .................................................................................. 3237
Acknowledgements . . . . . . . . . . . . . . . . .................................................................................. 3237
References ......................................................................................................... 3237
0278-6915/$ - see front matter Ó2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.fct.2008.07.024
Abbreviations: ABTS, 2,20-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid); BHA, butylated hydroxyanisole; BHT, butylated hydroxytoluene; CAT, catalase; CD,
concentration required to double QR induction activity; CNS, central nervous system; COX, cyclooxygenase; CPK, creatine phosphokinase; DHR-123, dihydrorhodamine 123;
LD
50
, lethal dose 50%; DMH, 1,2-dimethylhydrazine; DMBA, 7,12-dimethylbenz[a]anthracene; DPPH, 2,2-diphenyl-1-picrylhydrazyl; ED
50
, effective dose in 50% of the test
organisms; 5-FMT, 5-fluoro-
a
-methyltryptamine; 5-FU, 5-fluorouracil; GOT, glutamate oxoloacetate transaminase; GSH, reduced glutathione; GML, Garcinia mangostana
Linn.;H
2
O
2
, hydrogen peroxide; GPx, glutathione peroxidase; GPT, glutamate pyruvate transaminase; GST, glutathione-S-transferase; 5-HT, 5-hydroxytryptamine; HIV-1,
human immunodeficience virus; HO
, hydroxyl radical; IC
50
, inhibitory concentration at 50%; LDH, lactate dehydrogenase; LDL, low density lipoprotein; LOX, lipoxygenase;
LPS, lypopolisaccharide; M,
a
-mangostin; 1M, 1-isomangostin; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; MT, mangostin
triacetate; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide; NO
, nitric oxide; iNOS, inducible nitric oxide sintase; ONOO
, peroxynitrite; O
2
,
superoxide anion; PGE
2
, prostaglandin-E
2
, PML, polymorphonuclear leucocyte; QR, quinone reductase; ROS, reactive oxygen species; SOD, superoxide dismutase; TBARS,
thiobarbituric reactive substances; VRE, vancomycin resistant Enterococci.
*Corresponding author. Tel./fax: +52 55 5622 3878.
E-mail address: pedraza@servidor.unam.mx (J. Pedraza-Chaverri).
Food and Chemical Toxicology 46 (2008) 3227–3239
Contents lists available at ScienceDirect
Food and Chemical Toxicology
journal homepage: www.elsevier.com/locate/foodchemtox
1. Introduction
Mangosteen (Garcinia mangostana Linn.) (GML) is a tropical tree
from India, Myanmar, Malaysia, Philippines, Sri Lanka, and Thai-
land. This tree can reach 6–25 m and it has leathery, glabrous
leaves and is slow to grow (Morton, 1987).
The mangosteen-fruit is dark purple or reddish, with white, soft
and juicy edible pulp with a slightly acid and sweet flavor and a
pleasant aroma (Jung et al., 2006). Mangosteen is known as ‘‘the
queen of fruits” because it is one of the best tasting tropical fruits.
The pericarp of mangosteen-fruit has been used as a medicinal
agent by Southeast Asians for centuries in the treatment of skin
infections and wounds (Mahabusarakam et al., 1987; Pierce,
2003), amoebic dysentery (Garnett and Sturton, 1932; Chopra
et al., 1956), etc. (see Table 1). In Ayurvedic medicine the pericarp
of mangosteen-fruit has wide use against inflammation and diar-
rhea (Balasubramanian and Rajagopalan, 1988), and cholera and
dysentery (Sen et al., 1980b).
GML has been shown to contain a variety of secondary metab-
olites such as prenylated and oxygenated xanthones (Govindachari
and Muthukumaraswamy, 1971; Sultanbawa, 1980; Peres et al.,
2000).
Xanthones or xanthen-9H-ones are secondary metabolites
found in some higher plant families, fungi and lichens (Peres
et al., 2000; Vieira and Kijjoa, 2005), and they comprise an impor-
tant class of oxygenated heterocycles. The xanthone nucleus is
known as 9-xanthenone or dibenzo-
c
-pyrone and it is symmetric
(Fig. 1)(Vieira and Kijjoa, 2005; Pinto et al., 2005; Souza and Pinto,
2005; Gales and Damas, 2005). Xanthones have been classified in
five groups: (a) simple oxygenated xanthones, (b) xanthone glyco-
sides, (c) prenylated xanthones, (d) xanthonolignoids and (e) mis-
cellaneous xanthones (Sultanbawa, 1980; Jiang et al., 2004).
From 20 higher plant families (122 species in 44 genus), 19 fun-
gi species and 3 lichens species, 278 new xanthones were identi-
fied between 2000 and 2004 (Vieira and Kijjoa, 2005). Currently,
approximately 1000 different xanthones have been described (Sou-
za and Pinto, 2005). The biological activities of this class of com-
pounds are associated with their tricyclic scaffold but vary
depending on the nature and/or position of the different substitu-
ents (Souza and Pinto, 2005; Jiang et al., 2004; Bennett and Lee,
1989; Mandal et al., 1992; Peres and Nagem, 1996).
Xanthones have been isolated from pericarp, whole fruit, bark,
and leaves of GML. Several studies have shown that xanthones ob-
tained from mangosteen-fruit have remarkable biological activities
(Suksamrarn et al., 2006).
a
-, b- and
c
-mangostins, garcinone E, 8-
deoxygartanin and gartanin are the most studied xanthones. In
addition, synthetic xanthones have been used in several studies.
Antioxidant, antitumoral, anti-inflammatory, antiallergy, antibac-
terial, antifungal and antiviral are some of the reported activities
of xanthones isolated from GML which are discussed in the present
review.
2. Xanthones isolated from the pericarp of mangosteen-fruit
Fifty xanthones have been isolated from pericarp mangosteen-
fruit (Table 2). The first of them was named mangostin (after it
was named
a
-mangostin) when it was isolated in 1855 (Fig. 1)
(Schmid, 1855). It is a yellow coloring matter that can also be ob-
tained from bark and dried sap of GML (Dragendorff, 1930).
Later, Dragendorff (1930) and Murakami (1932) elucidated the
mangostin structure. Yates and Stout (1958) established the
molecular formula, and type and position of substituents of
a
-
mangostin. Furthermore, Dragendorff (1930) isolated b-mangostin,
the structure of which was not elucidated until 1968 (Yates and
Bhat, 1968). Jefferson (1970) and Govindachari and Muthukumar-
aswamy (1971) also isolated
a
- and b-mangostins.
Recently, mangosharin was isolated from the bark of GML (Ee
et al., 2006) and
a
- and b-mangostins were isolated from the root
of Cratoxylum cochinchinense, which is a shrub tree belonging to the
Guttiferae family (Laphookhieo et al., 2006).
Other xanthones that have been isolated from the pericarp of
mangosteen-fruit are
c
-mangostin (Jefferson et al., 1970),
gartanin and 8-deoxygartanin (Govindachari and Muthukumar-
aswamy, 1971), 5,9-dihydroxy-8-methoxy-2,2-dimethyl-7-isopre-
Table 1
Traditional medicinal properties of Garcinia mangostana
Illness References
Dysentery Garnett and Sturton (1932), Chopra et al. (1956), Morton (1987) and Yates and Stout (1958)
Diarrhea and chronic diarrhea in adults and children Garnett and Sturton (1932), Chopra et al. (1956), Morton (1987) and Wan et al. (1973)
Haemorrhoids Pierce (2003)
Food allergies Pierce (2003)
Arthritis
a
Pierce (2003)
Wounds
a
Mahabusarakam et al. (1986, 1987), Wan (1973) and Pierce (2003)
Skin infections Mahabusarakam et al. (1987), Pierce (2003) and Jinsart et al. (1992)
Tuberculosis Harbone et al. (1999) and Suksamrarn et al. (2006)
Inflammation Saralamp et al. (1996), Chairungsrilerd et al. (1996a,b) and Harbone et al. (1999)
Ulcers Harbone et al. (1999) and Hasegawa et al. (1996)
Micosis Saralamp et al. (1996) and Harbone et al. (1999)
Affections of the genito-urinary tracts Caius (2003)
Gonorrhea, cystitis and urethra suppuration Garnett and Sturton (1932), Morton (1987) and Moongkarndi et al. (2004a)
Mouth aphthae Caius (2003)
Fever Caius (2003), Morton (1987) and Yates and Stout (1958)
Amoebic dysentery Caius (2003) and Morton (1987)
Eczema
b
Morton (1987)
Acne
c
Saralamp et al. (1996) and Chomnawang et al. (2005)
Thrush Morton (1987)
Abdominal pain Moongkarndi et al. (2004a)
Suppuration Moongkarndi et al. (2004a)
Leucorrhoea Moongkarndi et al. (2004a)
Cholera Sen et al. (1980a)
Convulsants Malawska (2005)
a
Pericarp poultice.
b
Local use as ointment.
c
Cosmetic cream.
3228 J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239
nyl-2H,6H-pyrano [3,2-b] xanthen-6-one (Sen et al., 1980a), garci-
none A, B and C (Sen et al., 1980a, 1982), garcinone D (Sen et al.,
1986), garcinone E (Dutta et al., 1987), BR-xanthone A and BR-xan-
thone B (Balasubramanian and Rajagopalan, 1988), 1,5-dihydroxy-
2-isoprenyl-3-methoxyxanthone, 1,7-dihydroxy-2-isoprenyl-
3-methoxy xanthone and mangostinone (Asai et al., 1995),
2,7-di-isoprenyl-1,3,8-trihydroxy-4-methyl xanthone and 2,8-di-
isoprenyl-7-carboxy-1,3,-trihydroxy-4-methyl xanthone (Gopala-
krishnan and Balaganesan, 2000), mangostanol (Chairungsrilerd,
1996a), euxanthone (Gopalakrishnan et al., 1997), garcimango-
sones A, B, C and D, tovophyllin A and B and 1,3,6,7-tetrahydr-
oxy-8-isoprenyl-9H-xanthen-9-one (Huang et al., 2001),
mangostenol, mangostenone A and B (Suksamrarn et al.,
2002), 2-isoprenyl-1,7-dihydroxy-3-methoxyxanthone (Matsum-
oto et al., 2003), compound 7 and mangostanine (Suksamrarn
et al., 2003), 8-hydroxycudraxanthone G, mangostinone and
esmeatxanthone A (Jung et al., 2006), caloxanthone A, maclurax-
anthone and 1,7-dihydroxyxanthone (Iinuma et al., 1996). Sme-
athxanthone A has also been isolated from Garcinia smeathmannii
(Komguem et al., 2005).
Calabaxanthone was isolated from the bark of Calophyllum cala-
ba and Calophyllum bracteautum in 1972 (Somanathan and Sul-
tanbawa, 1972), it was studied by
13
C MNR (Westerman et al.,
1977) and later was also isolated from the pericarp of mango-
steen-fruit (Mahabusarakam et al., 1987; Sen et al., 1980a).
Seven new xanthones were isolated from the pericarp of man-
gosteen-fruit in 1987: 1-isomangostin, 1-isomangostin hydrate,
3-isomangostin and 3-isomangostin hydrate (Mahabusarakam
Fig. 1. Xanthone nucleus with IUPAC numbers of carbons and chemical structure of the most studied xanthones.
J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239 3229
Table 2
Xanthones isolated from G. mangostana pericarp
Xanthone References
a
-Mangostin Schmid (1855), Yates and Stout (1958) and Stout and Krahn (1968)
b-Mangostin Dragendorff (1930), Yates and Bhat (1968) and Mahabusarakam et al.
(1987)
c
-Mangostin Jefferson et al. (1970), Mahabusarakam et al. (1987) and Jinsart et al.
(1992)
Mangostanol Chairungsrilerd (1996a), Suksamrarn et al. (2002, 2003) and Huang et al.
(2001)
Mangostenol Suksamrarn et al. (2002, 2003)
1-Isomangostin Mahabusarakam et al. (1987) and Jung et al. (2006)
1-Isomangostin hydrate Mahabusarakam et al. (1987)
3-Isomangostin Huang et al. (2001) and Mahabusarakam et al. (1987)
3-Isomangostin hydrate Mahabusarakam et al. (1987)
1,6-Dihydroxy-7-methoxy-8-isoprenyl-6
0
,6
0
-dimethylpyrano(2
0
,3
0
:3,2)xanthone (compound 7) Suksamrarn et al. (2003)
Toxyloxanthone A (trapezifolixanthone) Suksamrarn et al. (2002, 2003)
Calabaxanthone
a
Mahabusarakam et al. (1987) and Sen et al. (1980a)
Demethylcalabaxanthone Mahabusarakam et al. (1987) and Suksamrarn et al. (2003)
Caloxanthone A Iinuma et al. (1996)
Macluraxanthone Iinuma et al. (1996)
1,7-dihydroxyxanthone Iinuma et al. (1996)
Euxanthone Gopalakrishnan et al. (1997)
Cudraxanthone Jung et al. (2006)
8-hydroxycudraxanthone G Jung et al. (2006)
Esmeatxanthone A Jung et al. (2006)
BR-xanthone A Balasubramanian and Rajagopalan (1988)
BR-xanthone B Balasubramanian and Rajagopalan (1988)
Mangostanin Suksamrarn et al. (2003)
Mangostenone A Suksamrarn et al. (2002, 2003)
Mangostenone B Suksamrarn et al. (2002)
Mangostinone Asai et al. (1995), Suksamrarn et al. (2002, 2003) and Matsumoto et al.
(2003)
Gartanin Govindachari et al. (1971), Mahabusarakam et al. (1987) and Asai et al.
(1995)
8-Deoxygartanin Gopalakrishnan et al. (1997), Govindachari et al. (1971) and Huang et al.
(2001)
Garcinone A Sen et al. (1980b, 1982).
Garcinone B Sen et al. (1980b, 1982), Huang et al. (2001) and Suksamrarn et al. (2002,
2003)
Garcinone C Sen et al. (1980b, 1982)
Garcinone D Sen et al. (1986), Gopalakrishnan et al. (1997) and Huang et al. (2001)
Garcinone E Dutta et al. (1987), Sakai et al. (1993) and Asai et al. (1995)
Garcimangosone A Huang et al. (2001)
Garcimangosone B Jung et al. (2006) and Huang et al. (2001)
Garcimangosone C Huang et al. (2001)
Garcimangosone D Huang et al. (2001)
Tovophyllin A Huang et al. (2001), Ho et al. (2002) and Jung et al. (2006)
Tovophyllin B Huang et al. (2001) and Suksamrarn et al. (2002, 2003)
1,5-dihydroxy-2-isoprenyl-3-methoxyxanthone Asai et al. (1995), Iinuma et al. (1996) and Huang et al. (2001)
Mangostingone [7-methoxy-2-(3- isoprenyl)-8-(3-methyl-2-oxo-3-buthenyl)-1,3,6-
trihydroxyxanthone
Jung et al. (2006)
5,9-Dihydroxy-2,2-dimethyl-8-methoxy-7-isoprenyl-2H,6H-pyrano [3,2-b] xanthen-6-one Sen et al. (1980b), Huang et al. (2001) and Chairungsrilerd (1996a)
2-(
c
,
c
-Dimethylallyl)-1,7-dihydroxy-3-methoxyxanthone Mahabusarakam et al. (1987)
2,8-Bis(
c
,
c
-dimethylallyl)-1,3,7-trihydroxyxanthone Mahabusarakam et al. (1987)
1,3,7-Trihydroxy-2,8-di-(3-methylbut-2-enyl) xanthone Mahabusarakam et al. (1987)
1,7-Dihydroxy-2-isoprenyl-3-methoxyxanthone Asai et al. (1995), Iinuma et al. (1996) and Huang et al. (2001)
2,7-Diisoprenyl-1,3,8-trihydroxy 4-methylxanthone Gopalakrishnan and Balaganesan (2000)
2,8-Diisoprenyl-7-carboxy-1,3 dihydroxyxanthone Gopalakrishnan and Balaganesan (2000)
2-Isoprenyl-1,7-dihydroxy-3 methoxyxanthone Matsumoto et al. (2003)
1,3,6,7-Tetrahydroxy-8-(3 methyl-2-buthenyl)-9H-xanthon-9-one Huang et al. (2001)
a
This xanthone was originally isolated from bark of Calophyllum calaba and Calophyllum bracteautum (Somanathan and Sultanbawa, 1972).
Table 3
Xanthones isolated from Garcinia mangostana fruit
Xanthone References
Thwaitesixanthone
a
, mangostinone
b
, mangostenone E, mangostenone D, mangostenone C, mangostanol
b
, mangostanin
b
, gartanin
b
, garcinone E
b
,
garcinone D
b
, garcinone C
b
, garcinone B
b
, demethylcalabaxanthone
b
, compound 7
b
, 11-hydroxy-1-isomangostin,
Suksamrarn et al.
(2006)
1-Isomangostin
b
Sundaram et al. (1983)
1,2-Dihydro-1,8,10-trihydroxy-2-(2-hydroxypropan-2-yl) Chin et al. (2008)
-9-(3-Methylbut-2-enyl)furo[3,2-a]xanthen-11-one; 6-deoxy-7-demethylmangostanin
a
It was previously isolated from Calophylum macrocarpum and Calophylum walkeri by Ampofo and Waterman (1986).
b
It was was also isolated from mangosteen-fruit pericarp (see Table 2). It was previously isolated from Cratoxylum cochinchinense by Sia et al. (1995).
3230 J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239
et al., 1987). 2-(
c
,
c
-dimethylallyl)-1,7-dihydroxy-3-methoxy-
xanthone, demethylcalabaxanthone, 1,3,7-trihydroxy-2,8-di-
(3-methylbut-2-enyl)xanthone and 2,8 bis (
c
,
c
-dimethylallyl)-1,
3,7-trihydroxyxanthone were isolated of the arils (seed coats).
They also obtained several xanthones already isolated (mangostin,
gartanin, b-mangostin,
c
-mangostin, and calabaxanthone).
Recently,
a
- and b-mangostin, 9-hydroxycalabaxanthone, 3-
isomangostin, gartanin, and 8-desoxygartanin have been extracted
of the fruit rind of mangosteen, identified and quantitatively deter-
mined used high performance liquid chromatograpy (HPLC) (Walk-
er, 2007). The xanthones 3-isomangostin, 8-desoxygartanin,
gartanin,
a
- and b-mangostins and 9-hydroxycalabaxanthone also
have been identified by UV spectra and quantified by HPLC with
photodiode array detector and HPLC with time-of-flight mass spec-
trometry system coupled with electrosplay ionization interface (Ji
et al., 2007).
Table 4
Xanthones isolated from bark of G. mangostana
Xanthone References
1,3,6,7-Tetrahydroxyxanthone (Norathyriol) Holloway and Scheinmann (1975)
1,3,6,7-Tetrahydroxy-O-glucosylxanthone
Mangoxanthone, dulxanthone D, 1,3,7-trihydroxy-2-methoxyxanthone Nilar et al. (2005)
1,3,5-Trihydroxy-13,13-dimethyl-2H-piran[7,6-b]xanthen-9-one
2,6-Dihydroxy-8-methoxy-5-(3-methylbut-2-enyl)-xanthone (mangosharin) Ee et al. (2006)
Garciniafuran, 6-O-Methylmangostanin, mangostanin
a
,Nilar and Harrison (2002)
1,6-Dihydroxy-3,7-dimethoxy-2-isoprenylxanthone
1,6-Dihydroxy-2-(2-hydroxy-3-methylbut-3-enyl)-3,7-dimethoxy-8-isoprenyl xanthone
1,6-Dihydroxy-8-(2-hydroxy-3-methylbut-3-enyl)-3,7-dimethoxy-2-isoprenyl-xanthone
1,6-Dihydroxy-3,7-dimethoxy-2-isoprenyl-8-(2-oxo-3-methylbut-3-enyl)-xanthone
(16E)-1,6-dihydroxy-8-(3-hydroxy-3-methylbut-1-enyl)-3,7-dimethoxy-2-isoprenyl-xanthone
1-Hydroxy-2-(2-hydroxy-3-methylbut-3-enyl)-3,6,7-trimethoxy-8-isoprenyl-xanthone
1-Hydroxy-8-(2-hydroxy-3-methylbut-3-enyl)-3,6,7-trimethoxy-2-isoprenyl-xanthone
(16E)-1-hydroxy-8-(3-hydroxy-3-methylbut-1-enyl)-3,6,7-trimethoxy-2-isoprenyl-xanthone
1,3-Dihydroxy-2-(2-hydroxy-3-methylbut-3-enyl)-6,7-dimethoxy-8-isoprenyl-xanthone
1-Hydroxy-3,6,7-trimethoxy-2-(2-hydroxy-3-methylbut-3-enyl)-8-isoprenyl-xanthone
1-Hydroxy-3,6,7-trimethoxy-2-isoprenyl-8-(2-oxo-3-methylbut-3-enyl)-xanthone
1-Hydroxy-3,6,7-trimethoxy-2-isoprenyl-xanthone
a
It was also isolated from mangostan-fruit and pericarp (see Tables 2 and 3).
Table 5
Xanthones isolated from mangosteen leaves (Parveen and Khan, 1988)
1,6-Dihydroxy-3-methoxy-2-isoprenyl xanthone
Gartanin
a
1,5,8-Trihydroxy-3-methoxy-2-isoprenyl-xanthone
a
It was also isolated from mangosteen-fruit and pericarp (see Tables 2 and 3).
Table 6
Synthetic derivatives of
a
-mangostin
Derivative References
3-O-methylmangostin Sundaram et al. (1983)
3,6-di-O-methylmangostin
Mangostin triacetate
Mangostin 3,6-d-O-tetraacetylglucoside Shankaranarayan et al. (1979)
Mangostin 3,6 di-O-glucoside
1-Hydroxy-3,6,7-trimethoxy-2,8-bis-(isoprenyl)-9H-xanthen-9-one Mahabusarakam et al. (2000)
1,3-Dihydroxy-6-acetoxy-7-ethoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1,6-Dihydroxy-3-(2,3-dihydroxypropoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1-Hydroxy-3,6-di(2,3-dihydroxypropoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1-Hydroxy-3,6-di(4-cianopropoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1,3-Dihydroxy-6-(4-cianopropoxi)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1,3-Dihydroxy-6-(N,N-diethylaminoethoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1-Hydroxy-3,6-di(N,N-diethylaminoetoxi)-7-methoxy-2,8-bis(isoprenyl)- 9H-xanton-9-one
1,3-Dihydroxy-6-(N,N-dimethylaminoethoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1,3-Dihydroxy-6-(N,N-dimethylaminopropoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1,3-Dihydroxy-6-(2-hydroxy-3-N,N-dimethylaminopropoxy)- 7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1,3-Dihydroxy-6(2-hydroxy-3-N-isopropylaminopropoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
1-Hydroxy-3,6-di(2-hydroxy-3-N-isopropylaminopropoxy)-7-methoxy-2,8-bis(isoprenyl)-9H-xanthen-9-one
5-Hydroxy-8-methoxy-9-(N,N-dimethylaminoethoxy)-7-(isoprenyl)-2,2-dimethyl-pyrano[3,2-b]xanthen-6-one
5-Hydroxy-8-methoxy-9-(3-N,N-dimethylaminopropoxy)-7-(isoprenyl)-2,2-dimethyl-pyrano[3,2-b]xanthen-6-one
5-Hydroxy-8-methoxy-9-(2-hydroxy-3-N,N-dimethylaminopropoxy)-7-(isoprenyl)-2,2-dimethyl-pirano[3,2-b]xanton-6-one
5-Hydroxy-8-methoxy-9-(2-hydroxy-3-N-isopropilaminopropoxi)-7-(isoprenyl)-2,2-dimethyl-pyrano[3,2-b]xanthen-6-one
5-Hydroxy-8-methyl-(3-cyanobutoxy)-7-(isoprenyl)-2,2-dimethyl-pyranol[3,2-b]xanthen-6-one
Bicyclomangostin
Di-O-methylamangostin Gopalakrishnan et al. (1997)
Di-O-ethylmangostin
Di-O-butylmangostin
Di-O-isopropylmangostin
Di-O-all Di-O-methallylmangostin ylmangostin
Di-O-acethylmangostin
3-Isomangostin
J. Pedraza-Chaverri et al./ Food and Chemical Toxicology 46 (2008) 3227–3239 3231
3. Xanthones from whole fruit, trunk, branches, and leaves of
GML
Three new xanthones were isolated from the whole mango-
steen-fruit: mangostenone C, D and E (Suksamrarn et al., 2006)
(Table 3). In total, 18 xanthones have been isolated from the whole
mangosteen-fruit. In addition, 21 xanthones have been isolated
from trunk and branches of GML (Holloway and Scheinmann,
1975; Nilar et al., 2005; Nilar and Harrison, 2002; Ee et al., 2006)
(Table 4). On the other hand, 1,6-dihydroxy-3-methoxy-2-isopre-
nyl-xanthone, 1-hydroxy-6-acetoxy-3-methoxy-2-isoprenylxanth-
one and gartanin were isolated from mangosteen leaves
(Parveen and Khan, 1988)(Table 5). Chin et al. (2008) isolated
and identificated two new compounds of mangosteen powder
fruit 1,2-dihydro-1,8,10-trihydroxy-2-(2-hydroxypropan-2-yl)-9-
(3-methylbut-2-enyl)furo[3,2-a]xanthen-11-one and 6-deoxy-7-
demethylmangostanin.
Also, 31 synthetic derivatives have been obtained from
a
-
mangostin, and they have been used to perform several studies
(Table 6).
4. Main biological and medicinal properties of GML
4.1. Antioxidant properties
In the Table 7 the antioxidant properties of mangosteen-fruit
extracts and some xanthones that have been studied are
summarized.
The antioxidant activity of extracts and xanthones isolated from
GML has been shown using the following methods: 2,2-diphenyl-
1-picrylhydrazyl (DPPH) radical scavenging activity (Yoshikawa
et al., 1994; Leong and Shui, 2002; Weecharangsan et al., 2006;
Chomnawang et al., 2007; Haruenkit et al., 2007), the ferric thiocy-
anate method (Yoshikawa et al., 1994; Fan and Su, 1997), and the
2,20-azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assay
(Leong and Shui, 2002; Haruenkit et al., 2007).
Yoshikawa et al. (1994) found that the methanolic extracts of
GML hulls showed DPPH radical scavenging activity.
a
and
c
-
mangostins showed antioxidant activity using the ferric thiocya-
nate method (Yoshikawa et al., 1994; Fan and Su, 1997). Williams
et al. (1995) found that
a
-mangostins decreases the human low
density lipoproteins (LDL) oxidation induced by copper or peroxyl
radical. They found that
a
-mangostin (i) prolonged lag time of con-
jugated dienes at 234 nm in a dose-dependent manner, (ii) dimin-
ishes thiobarbituric reactive substances (TBARS) production, and
(iii) decreases the
a
-tocopherol consumption induced by LDL oxi-
dation. Consistently, Mahabusarakam et al. (2000) also found that
a
-mangostin and their synthetic derivatives prevent the decrease
of the
a
-tocopherol consumption induced by LDL oxidation. These
authors found that the structural modifications of
a
-mangostin
modify the antioxidant activity. For example, substitution of C-3
and C-6 with aminoethyl derivatives enhanced the activity;
whereas substitution with methyl, acetate, propanediol or nitrile
reduced the antioxidant activity (Mahabusarakam et al., 2000).
On the other hand, Leong and Shui (2002) compared the total
antioxidant capacity of twenty-seven fruits available in the Singa-
pore market, including mangostan, using the ABTS and DPPH as-
says. They showed that the GML extract had the eighth place in
antioxidant efficiency.
Weecharangsan et al. (2006) studied the antioxidant and neuro-
protective properties of four extracts obtained from mangosteen-
fruit pericarp (water, 50% ethanol, 95% ethanol and ethyl acetate).
The antioxidant capacity was evaluated by the DPPH method using
1, 10, 50 and 100
l
g/mL of each extract. Water and ethanolic (50%)
extracts showed high antioxidant capacity (inhibitory concentra-
tion at 50% (IC
50
) = 34.98 ± 2.24 and 30.76 ± 1.66
l
g/mL, respec-
tively). The antioxidant capacity of these extracts was tested on a
neuroblastoma cell line (NG108-15) exposed to hydrogen peroxide
(H
2
O
2
); both extracts exhibited neuroprotective activity when they
used concentration of 50
l
g/mL. The 50% ethanolic extract had
higher neuroprotective activity than the water extract. More re-
cently, Chomnawang et al. (2007) showed that GML ethanolic ex-
tract possesses a significant antioxidant activity, as measured by
the inhibition of the formation of DPPH radicals by 50%. This ex-
tract displayed an IC
50
of 6.13
l
g/mL in comparison with ethanolic
extracts of Houttuynia cordata,Eupatorium odoratum and Senna ala-
ta (IC
50
of 32.53, 67.55 and 112.46
l
g/mL, respectively). In addi-
tion, the extract of G. mangostana significantly reduced the
reactive oxygen species (ROS) production of polymorphonuclear
leucocytes (PML) with 77.8% of superoxide anion (O
2
) inhibition
ratio (62.6%, 44.9% and 35.18% for H. cordata,E. odoratum, and S.
alata, respectively). Haruenkit et al. (2007) showed the antioxidant
activity of mangosteen measured with DPPH and ABTS assays.
They found values of 79.1 and 1268.6
l
M trolox equivalents/
100 g of fresh weight for DPPH and ABTS assays, respectively. In
addition, in rats fed with basal diet supplemented with 1% of cho-
lesterol plus 5% of mangosteen the increase in plasma lipids and
decrease in antioxidant activity seen with cholesterol alone was
prevented.
Moongkarndi et al. (2004a) showed that a GML extract signifi-
cantly diminished intracellular ROS production, which was mea-
sured using 2,7-dichlorofluorescein diacetate (DCFH-DA) in
SKBR3 cell line. In a similar study, Garcia et al. (2005) studied
the antioxidant capacity of several fruits and vegetables from the
Table 7
Antioxidant properties of G. mangostana
G. mangostana extracts and/or xanthone References
The methanol extract of the fruit hulls of GML showed DPPH scavenging activity Yoshikawa et al. (1994)
a
-Mangostin inhibited copper-induced LDL oxidation in vitro Williams et al. (1995)
a
and
c
-Mangostin showed antioxidant activity using the ferric thiocyanate method Fan and Su (1997)
The copper-induced LDL oxidation in vitro was inhibited by
a
-mangostin and by prenylated xanthones derived from this xanthone Mahabusarakam et al. (2000)
Methanolic extract of the edible portion of GML exhibited antioxidant activity using DPPH and ABTS assays Leong and Shui (2002)
The crude methanol extract of pericarp from GML ameliorated the intracellular production of ROS in SKBR3 cells Moongkarndi et al. (2004a)
The pericarp extract of GML was able to scavenge HO
and effective to inhibit lipid peroxidation Garcia et al. (2005)
Several xanthones showed scavenging ONOO
ability in vitro Jung et al. (2006)
The aqueous and ethanolic extracts of the pericarp of GML present DPPH scavenging activity and protects neuroblastoma cell line
NG108-15 from H
2
O
2
citotoxicity
Weecharangsan et al. (2006)
The ethanolic extract of GM showed antioxidant activity against DPPH radicals and reduced the ROS production of PML Chomnawang et al. (2007)
Mangosteen-fruit showed antioxidant activity against DPPH and ABTS radicals and prevents the decrease in antioxidant activity
induced by a cholesterol supplemented diet in rats
Haruenkit et al. (2007)
a
-Mangostin showed protective effect against isoproterenol-induced oxidative damage and myocardial injury in rats Devi Sampath and Vijayaraghavan
(2007)
c
-Mangostin showed HO
-scavenging activity Chin et al. (2008)
3232 J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239
Philippines by measurement of lipoperoxidation (linoleic acid sys-
tem) and hydroxyl radical (HO
) scavenging (deoxyribose method).
They found that the extract obtained from the mangosteen-fruit
pericarp had one of the highest antioxidant activities. On the other
hand, Jung et al. (2006) measured the peroxynitrite (ONOO
) scav-
enging capacity of 13 xanthones by monitoring the oxidation of
dihydrorhodamine 123 (DHR-123). ONOO
is the oxidant specie
produced by the reaction between nitric oxide (NO
) and O
2
(Chi-
rino et al., 2006). The IC
50
(
l
M) value for ONOO
scavenging was
determined for several compounds. Xanthones with the highest
capacity to scavenge ONOO
were smeathxanthone A (2.2), 8-
hydroxycudraxanthone G (4.6),
c
-mangostin (8), gartanin (9.1),
a
-mangostin (12.2), garcinone E (14.1), garcimangosone B (15.9),
1-isomangostin (19.2) and garcinone D (26). They also studied
the ONOO
scavenging capacity of cudraxanthone G, 8-deoxygart-
anin, mangostinone and tovophyllin A, but it was lower
(IC
50
>30
l
M). DL-penicillamine was used as a positive control
and its IC
50
was 3.1
l
M. Devi Sampath and Vijayaraghavan
(2007) evaluated the effect of
a
-mangostin on the antioxidant de-
fense system and on lipid peroxidation during isoproterenol-in-
duced myocardial infarction in rats. Treatments of rats with
isoproterenol (150 mg/kg for 2 days) showed a significant decrease
of the antioxidant enzymes glutathione-S-transferase (GST), gluta-
thione peroxidase (GPx), superoxide dismutase (SOD), catalase
(CAT) and reduced glutathione (GSH); as well as marked elevation
in serum enzymes such as lactate dehydrogenase (LDH), creatine
phosphokinase (CPK), glutamate oxaloacetate transaminase
(GOT), glutamate pyruvate transaminase (GPT) and lipid peroxides.
The histological examination of rats treated with isoproterenol
showed necrotic changes in the tissue with intense infiltration of
neutrophils. Pretreatment with
a
-mangostin (200 mg/kg) for 6
days prior and 2 days concurrently with isoproterenol administra-
tion significantly attenuated these changes. This xanthone showed
a protective effect against lipid peroxidation and antioxidant de-
fense system during injury-induced myocardial infarction in rats.
Chin et al. (2008) studied the HO
-scavenging activity of several
xanthones isolated from the fruit powder of GML. Only
c
-mango-
stin from the 16 xanthones tested showed HO
-scavenging activity
(IC
50
= 0.2
l
g/mL). In addition, Chin et al. (2008) tested the same
xanthones for the induction of quinone reductase (QR, phase II
drug-metabolizing enzyme), using murine hepatoma cells (Hepa
1c1c7) in vivo. All the xanthones, with the exception of
a
-mango-
stin, were found to induce QR activity. The concentration required
to double QR induction activity (CD) values of compounds were
1.3, 2.2, 0.68 and 0.95
l
g/mL for 1,2-dihydro-1,8,10-trihydroxy-
2-(2-hydroxypropan-2-yl)-9-(3-methylbut-2-enyl)furo[3,2-a]xan-
then-11-one, 6-deoxy-7-demethylmangostanin, 1,3,7-trihydroxy-
2,8-di-(3-methylbut-2-enyl)xanthone and mangostanin, respec-
tively.
In our laboratory, we found that
a
-mangostin (pericarp iso-
lated), mangosteen extract and commercial mangosteen juice, are
able to scavenge directly ROS and prevent neurotoxicity and ROS
production induced by 3-nitropropionic acid in cultured neurons
(unpublished observations and Guzman-Beltran et al., submitted
to publication).
The above data indicate that the antioxidant properties of ex-
tracts and some xanthones isolated from GML warrant additional
studies to further examine their antioxidant properties in supple-
mentary experimental models.
4.2. Antitumoral properties
Several studies have been designed to examine the anticancer
activities of xanthones isolated from mangosteen-fruit pericarp
(Table 8). Hepatocellular carcinoma (Ho et al., 2002), SKBR3 human
breast cancer (Moongkarndi et al., 2004a) and human leukemia
(Matsumoto et al., 2003) cell lines have been used.
Ho et al. (2002) found that garcinone E has a potent cytotoxic
effect on hepatocellular carcinoma cell lines. They studied the
cytotoxic effect of 6 xanthones isolated from mangosteen-fruit
pericarp and found that garcinone E was the most toxic. Therefore,
garcinone E was tested against HCC36, TONG, HA22T, Hep3B,
HEpG2 and SK-Hep-1 hepatocellular carcinoma cell lines; NCI-
Hut 125, CH27 LC-1, H2891 and Calu-1 lung carcinoma cell lines;
and AZ521, NUGC-3, KATO-III and AGS gastric carcinoma cell lines.
Garcinone E exhibited a very broad spectrum of dose- and time-
dependent cytotoxic effects against various cancer cell lines; with
the exception of lung carcinoma cell line CH27 LC-1, all cell lines
tested were killed. The values for garcinone lethal dose 50%
(LD
50
) against the cell lines studied were between 0.1 and
5.4
l
M. Garcinone E had an antitumoral effect in the following or-
der: SK-Hep-1 > HA22T > HEpG2 > Hep3B > HCC36.
Matsumoto et al. (2003) studied the effect of 6 xanthones (
a
,b
and
c
-mangostins, mangostinone, garcinone E and 2-isoprenyl-
1,7-dihydroxy-3-methoxy xanthone) isolated from mangosteen-
fruit pericarp on the cell growth inhibition of human leukemia cell
line HL60. They examined cytotoxic effects 72 h after cell incuba-
tion with xanthone at 5 or 40
l
M. All xanthones showed a signifi-
cant inhibition effect, but
a
,band
c
-mangostins were particularly
effective from 10
l
M. The most abundant compound in the extract
was
a
-mangostin, and it showed the highest inhibitory activity
(IC
50
10
l
M). Later, the
a
-mangostin effect was shown in other leu-
kemia cell lines: K562, NB4 and U937. Cell growth of all these leu-
kemia cell lines was inhibited by
a
-mangostin at 5–10
l
M.
Nabandith et al. (2004) investigated whether the administra-
tion of
a
-mangostin in the diet had short-term chemopreventive
effects on putative preneoplastic lesions involved in rat colon
carcinogenesis, induced by a subcutaneous injection of
Table 8
Antitumoral properties of xanthones isolated from Garcinia mangostana
Effect References
Garcinone E has a cytotoxic effect on hepatoma cells lines as well as on the gastric and lung cancer cell lines Ho et al. (2002)
Six xanthones from the pericarp of GML showed antiproliferative activity against human leukemia HL60 cells. In addition,
a
-mangostin induced
caspase 3-dependent apoptosis in HL60
Matsumoto et al. (2003)
The treatment with dietary
a
-mangostin inhibits cells proliferation in the colon lesions in rats injected with DMH Nabandith et al. (2004)
Aqueous extract of the fruit rind GML showed antileukemic activity in four cells lines Chiang et al. (2004)
a
-Mangostin induced apoptosis in human leukemia cell lines Matsumoto et al. (2004)
Ethanolic and methanolic extracts of GML showed antiproliferative effect on human breast cancer SKBR3 cells Moongkarndi (2004a,
2004b)
The antiproliferative effect of
a
- and
c
-mangostins, was associated with apoptosis in human colon cancer DLD-1 cells Matsumoto et al. (2005)
a
-Mangostin inhibited DMBA-induced preneoplastic lesions in a mouse mammary organ culture Jung et al. (2006)
Mangostenone C, mangostenone D, demethylcalabaxanthone, b-mangostin, gartanin, garcinone E,
a
-mangostin, mangostinone,
c
-mangostin,
garcinone D, and garcinone C showed cytotoxic effect on the three human cancer cell lines
Suksamrarn et al. (2006)
a
-Mangostin showed antitumoral activity against DLD-1 cells Nakagawa et al. (2007)
J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239 3233
1,2-dimethylhydrazine, DMH (40 mg/kg body weight once a week
for 2 weeks). They found that dietary administration of
a
-mango-
stin significantly inhibited the occurrence of biomarkers for short-
term colon carcinogenesis (aberrant crypt foci, dysplastic foci and
b-catenin accumulated crypt) induced by DMH.
In another study, Chiang et al. (2004) investigated the antileu-
kemic activity of hot water and juice extracts of 17 most used fruits
in Taiwan in K562, P3HR1, Raji and U937 leukemia cells. Only the
hot water extract of mangosteen-fruit pericarp exhibited a potent
antileukemic activity, with an IC
50
of 61 ± 9.9 and 159 ± 12
l
g/mL
against K562 and Raji cells, respectively. This extract also had a
moderate activity against U937 cells, but it was less effective
against P3HR1 cells.
Matsumoto et al. (2004) studied the mechanism of cell death in-
duced by
a
-mangostin treatment in human leukemia cell line
HL60. They found that this xanthone induces apotosis in HL60
cells, which was mediated by mitochondrial dysfunctions in the
early phase. They found that
a
-mangostin induces caspases 9
and 3 activation, loss of mitochondrial membrane potential, and,
release of ROS and cytochrome C. They also showed that neither
bcl-2 family proteins nor activation of mitogen-activated protein
kinases are involved in
a
-mangostin-induced cell death.These re-
sults indicated that mitochondria play a pivotal role in induction
of apoptosis by
a
-mangostin.
Moongkarndi et al. (2004b) tested the antiproliferative activity
of 9 Thai medicinal plants against SKBR3 human breast adenocar-
cinoma cell line. The extract obtained from GML had the most po-
tent activity with an IC
50
value of 15.45 ± 0.5
l
g/mL.
In another study performed by the same authors (Moongkarndi
et al., 2004a), the antiproliferation, apoptosis and antioxidant
activity of crude methanolic extract from mangosten-fruit pericarp
was evaluated using SKBR3 human breast cancer cell line as a mod-
el. This methanolic extract had a significant antiproliferation activ-
ity (ED
50
= 9.25 ± 0.64
l
g/mL) by inducing apoptotic cell death.
Also, the methanolic extract showed antioxidant activity by inhib-
iting the intracellular ROS production.
Matsumoto et al. (2005) studied the antiproliferative effect of 4
prenylated xanthones (
a
,b, and
c
-mangostins and methoxy-b-
mangostin) in human colon cancer DLD-1 cells. Except for meth-
oxy-b-mangostin, the other three xanthones strongly inhibited cell
growth at 20
l
M at 72 h and their antitumor efficacy was corre-
lated with the number of hydroxyl groups. Apoptosis was associ-
ated with antiproliferative effect of
a
and
c
-mangostins, but not
of b-mangostin. The affected expression of cyclins cdc2 and p27
shown that cell-cycle arrest was related with the antiproliferative
effect of
a
,b(G1 arrest) and
c
-mangostin (S arrest).
Recently, the following authors have investigated the antitu-
moral properties of GML:
Jung et al. (2006) isolated from mangosteen-fruit pericarp two
new xanthones (8-hydroxycudraxanthone G and mangostinone)
as well as 12 known xanthones. They determined their antitumoral
properties in preneoplastic lesions induced by 7,12-dimethyl-
benz[a]anthracene (DMBA) in a mouse mammary organ culture.
a
-mangostin inhibited DMBA-induced preneoplastic lesions with
an IC
50
of 1.0
l
g/mL (2.44
l
M).
Suksamrarn et al. (2006) isolated from mangosteen-fruit peri-
carp three new prenylated xanthones (mangostenones C, D and
E) as well as 16 known xanthones. The cytotoxic properties of
these xanthones were determined against three different human
cancer cell lines: epidermoid carcinoma of mouth (KB), breast can-
cer (BC-1), and small cell lung cancer (NCI-H187). Mangostenone C
exhibited a cytotoxic effect against the three cell lines proved, with
IC
50
values of 2.8, 3.53, and 3.72
l
g/mL, respectively. However,
a
-
mangostin exhibited the most potent effect against BC-1 cells with
an IC
50
value of 0.92
l
g/mL, an activity that was greater than the
standard drug ellipticine (IC
50
= 1.46
l
g/mL);
a
-mangostin also
had a cytotoxic effect against KB cells (IC
50
= 2.08
l
g/mL); and
gartanin was able to inhibit the NCI-H187 growth (IC
50
= 1.08
l
g/
mL). Laphookhieo et al. (2006) found that
a
- and
c
-mangostins
have a cytotoxic effect against NCI-H187.
Nakagawa et al. (2007) evaluated
a
-mangostin for in vitro cyto-
toxicity against DLD-1 cells. They demonstrated that the number of
viable cells was decreased by the treatment with mangostin
20
l
M. They also showed the synergistic growth suppression in
the cells by the combination treatment with 2.5
l
M of mangostin
and 2.5
l
M of 5-fluorouracil (5-FU), a chemotherapeutic agent
for colorectal adenocarcinoma.
In summary, the results suggest that
a
-mangostin and its ana-
logs would be candidates for preventive and therapeutic applica-
tion for cancer treatment.
4.3. Anti-inflammatory and antiallergy properties
There is evidence about antiallergy and anti-inflammatory
properties of GML in differerent in vitro models, such as RBL-2H3
cells (Nakatani et al., 2002b) and C6 rat glioma cells (Nakatani
et al., 2002a,b, 2004; Yamakuni et al., 2006), rabbit thoracic aorta
and guinea-pig trachea (Chairungsrilerd et al., 1996b,c) and several
models in vivo in rats (Shankaranarayan et al., 1979; Nakatani
et al., 2004)(Table 9).
Shankaranarayan et al. (1979) made up xanthone synthetic
derivatives (3-O-methyl mangostin, 3,6-di-O-methyl mangostin,
mangostin triacetate, 1-isomangostin, mangostin-3,6-di-O-(tetra
acethyl)-glucoside and mangostin-3,6-di-O-glucoside) from
a
-
mangostin to be used in pharmacologic studies as well as
a
-
mangostin. Oral and intraperitoneal administration (50 mg/kg) of
a
-mangostin, 1-isomangostin and mangostin triacetate exhibited
anti-inflammatory activity in rats tested by the carrageenan-in-
duced hind paw edema (M, 1M and MT showed 66.6%, 63.19%
and 59.03% of reduction, respectively), cotton pellet granuloma
(M, 1M and MT showed 56.99%, 52.81% and 52.63% of reduction,
respectively) and granuloma pouch techniques (M, 1M and MT
showed 65.6%, 63.3% and 58.3% of reduction, respectively). As po-
sitive control, dexamethazone treated rats (1 mg/kg) were used;
and as negative control, acacia-gum treated rats (2 mL/kg) were
used. The anti-inflammatory activity of these compounds was also
shown in adrenalectomised rats. In addition, Gopalakrishnan
(1980) showed that
a
-mangostin isolated from the rinds of the
mangosteen inhibited systemic anaphylaxis, immunocytoadher-
ence in guinea pigs and rats, and inhibited the primary and second-
ary responses of adjuvant-induced arthritis in rats.
Chairungsrilerd et al. (1996c) demonstrated that methanolic ex-
tract of mangosteen-fruit pericarp inhibits the contractions of iso-
lated thoracic rabbit aorta induced by histamine and serotonin.
They suggested that
a
- and
c
-mangostins are histaminergic and
serotonergic receptor blocking agents, respectively. This same re-
search group studied the effect of
a
-mangostin on histamine-in-
duced contractions in rabbit thoracic aorta and guinea-pig
trachea (Chairungsrilerd et al., 1996a).
a
-mangostin inhibited his-
tamine-induced contractions in a dose-dependent manner with or
without cimetidine, an antagonist of the H
2
-histamine receptor.
Also,
a
-mangostin inhibited contractions mediated by the hista-
mine H
1
receptor. Furthermore,
a
-mangostin competitively inhib-
its [
3
H]mepyramine (specific antagonist of histamine H
1
receptor)
binding to rat aortic smooth muscle cells. Chairungsrilerd et al.
(1998b) also showed that 0.03–5
l
Mof
c
-mangostin purified from
the GML caused a parallel rightwards shift of the concentration/re-
sponse curve for the contraction elicited by 0.5 mM of 5-hydroxy-
tryptamine (5-HT) in the rabbit aorta without affecting the
contractile responses to 30 mM of KCl, 3
l
M of phenylephrine or
histamine. The perfusion pressure response of rat coronary artery
to 5-HT
2A
was reduced concentration dependently by
c
-mangostin
3234 J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239
(IC
50
= 0.32
l
M). 5-HT amplified, ADP-induced aggregation of rab-
bit platelets was inhibited by
c
-mangostin (IC
50
= 0.29
l
M). This
xanthone (5
l
M) also affected 5-HT-induced contraction of the
guinea-pig ileum (3
l
M of 5-HT
3
) in the presence of 5-HT
1
, 5-HT
2
and 5-HT
4
receptor antagonists and inhibited [
3
H]spiperone bind-
ing to cultured rat aortic myocytes (IC
50
= 3.5 nM). Chairungsrilerd
et al. (1998a) showed that
c
-mangostin (10–40 nmol/mouse)
inhibited 5-fluoro-
a
-methyltryptamine (5-FMT, 45 mg/kg i.p.) in-
duced head-twitch response in mice by blocking 5-HT
2A
receptors,
not by blocking the release of 5-HT from the central neurone.
c
-
mangostin is a promising 5-HT
2A
receptor antagonist in vascular
smooth muscle, platelets and the central nervous system (Chair-
ungsrilerd et al., 1998a,b).
Nakatani et al. (2002b) examined the effect of extracts from
mangosteen-fruit (water and ethanol 40%, 70% and 100%) on hista-
mine release and prostaglandin-E
2
(PGE
2
) synthesis. They found
that 40% ethanol extract (100 and 300
l
g/mL) inhibits the hista-
mine release induced by IgE in RBL-2H3 cells. This effect was high-
er than aqueous extract of Rubus suavissimus, which has been used
in Japan as antiallergic drug; whereas 70% and 100% extracts
showed only weak inhibition. A 40% ethanol extract of GML ex-
tracts (3, 10, 30 and 100
l
g/mL) potently inhibited A23187 (a cal-
cium ionophore)-induced PGE
2
release in C6 rat glioma cells, while
the water extract of R. suavissimus had no effect. In addition, pas-
sive cutaneous anaphylaxis reactions in rats were significantly
inhibited by this ethanol extract.
This same group examined the effect of
c
-mangostin isolated
from mangosteen-fruit pericarp on arachidonic acid cascade in
C6 rat glioma cells. They found that
c
-mangostin has a potent
inhibitory activity on A23187-induced PGE
2
release. This inhibition
was concentration-dependent, with an IC
50
of about 5
l
M. Conver-
sion of arachidonic acid to PGE
2
was inhibited by
c
-mangostin,
which also inhibited the activities of both constitutive cyclooxy-
genase-1 and inducible cyclooxygenase-2 (COX-1 and COX-2,
respectively) in a concentration-dependent manner (IC
50
of about
0.8 and 2
l
M, respectively) (Nakatani et al., 2002a).
Nakatani et al. (2004) studied the effect of
c
-mangostin on
spontaneous release of prostaglandin E
2
and COX-2 gene
expression using C6 rat glioma cells. After 18 h of
c
-mangostin
treatment, spontaneous release of PGE
2
was inhibited in a concen-
tration-dependent manner (IC
50
of about 2
l
M). Furthermore,
c
-
mangostin prevents (in a concentration-dependent manner) the
lipopolysaccharide-induced expression of COX-2 protein and its
mRNA, but not those of constitutive COX-1. In this work, the effect
of
c
-mangostin on nuclear factor
j
B activation was also examined.
It was found that
c
-mangostin suppressed the inhibitor
j
B kinase
activity to inhibit lypopolisaccharide-induced nuclear factor
j
B
activation and thereby decreases COX-2 induction.
Yamakuni et al. (2006) found that garcinone B (10
l
M) reduced
by 30% the increase of PGE
2
release induced by A23187 in C6 rat
glioma cells. Garcinone B (20
l
M) also diminished approximately
30% of lypopolisaccharide-induced nuclear factor
j
B activation.
These results suggest that garcinone B may be a pharmacological
tool to investigate intracellular signaling pathways involved in
inflammation.
Recently, Chen et al. (2008) demonstrated that
a
- and
c
-man-
gostins significantly inhibited lipopolysaccharide-stimulated NO
production and cytotoxicity to RAW 264.7 cells. The amount of
NO
production at 3 to 25
l
M was continously measured, and the
IC
50
values were 12.4 and 10.1
l
M for
a
- and
c
-mangostins. The
a
- and
c
-mangostins also significantly reduced PGE
2
production
in lipopolysaccharide-activated RAW 264.7 cells with IC
50
values
of 11.08 and 4.5
l
M, respectively. The effects of these xanthones
were probed by measuring the induction of inducible nitric oxide
synthase (iNOS) and COX enzyme expressions. The two xanthones
concentration-dependently reduced the induction of iNOS. The
RAW 264.7 cells were activated with lipopolysaccharide (1
l
g/
mL) for 12 h and the treatment with
a
-or
c
-mangostins (5
l
g/
mL) for 24 h weakly inhibited iNOS activity in activated RAW
264.7 macrophages.
The anti-inflammatory effects of
a
- and
c
-mangostins were
evaluated by carrageenan-induced paw edema in mice. The
a
-
mangostin and sulindac (reference compound) treatment showed
a potent inhibition of paw edema at 3 h and 5 h, respectively.
The action of
a
-mangostin was more rapid than that of sulindac.
However,
c
-mangostin did not significant inhibit the paw oedema
in mice. This demonstrated that in vivo
a
-mangostin has more
anti-inflammatory activity than
c
-mangostin. In addition, Des-
champs et al. (2007) demonstrated that
a
-mangostin inhibited
12-human lipoxygenase (12-LOX) with an IC
50
of 0.58
l
M.
The IgE receptor activates intracellular signal transductions
resulting in the release of inflammatory signal mediators such as
histamine and this is the primary event in several allergic re-
sponses. Based on this information, Itoh et al. (2008) demonstrated
that xanthones isolated from mangosteen (
a
,band
c
-mangostins)
suppressed the degranulation in Ag-mediated activation of IgE
Table 9
Anti-inflammatory and antiallergy properties of G. mangostana
Effect References
a
-Mangostin, 1-isomangostin, and mangostin triacetate showed antiiflamatory activity in several experimental models in rats Shankaranarayan et al.
(1979)
a
-Mangostin, i.p. has anti-inflammatory effects in several experimental models of inflammation in rats and guinea pigs Gopalakrishnan et al.
(1980)
a
-Mangostin ameliorates the histamine-induced contraction of aorta and trachea from male guinea pigs Chairungsrilerd et al.
(1996a)
The crude methanol extract of GM hulls blocked the histaminergic and serotonergic response in isolated rabbit aorta strips.
a
-mangostin
blocked the histaminergic response and
c
-mangostin blocked the serotonergic response
Chairungsilerd et al.
(1996b)
c
-Mangostin is 5HT
2A
receptor antagonist in vascular smooth muscles and platelets Chairungsrilerd et al.
(1998a)
c
-Mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-HT
2A
receptors Chairungsrilerd et al.
(1998b)
Extracts of mangosteen hulls inhibited histamine release in RBL-2H3 cells and decreased A23187 induced PGE
2
synthesis in C6 rat glioma cells Nakatani et al. (2002b)
c
-Mangostin inhibited A2318 induced PGE
2
release in C6 cells and arachidonic acid conversion to PGE
2
in isolated microsomes as well as the
activities of both constitutive COX-1 and inducible COX-2
Nakatani et al. (2002b)
c
-Mangostin (a) inhibited COX-1 and -2 activity and PGE
2
synthesis in C
6
rat glioma cells, (b) inhibited LPS-induced expression of COX-2
protein and its mRNA, (c) reduced the LPS-inducible activation of NF-kB, and (d) inhibited rat carrageenan-induced paw edema
Nakatani et al. (2004)
Garcinone B reduced A23187-induced PGE
2
release and LPS-induced transcription of NF-kB-mediated in C6 rat glioma cells Yamakuni et al. (2006)
a
- and
c
-mangostins inhibited LPS-stimulated citotoxicity, NO
and PGE
2
production, and iNOs induction in RAW 264.7 cells.
a
-Mangostin
showed a potent inhibition on paw oedema in mice
Chen et al. (2008)
a
-Mangostin inhibits human 12-LOX Deschamps et al. (2007)
J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239 3235
receptors in rat basophilic leukemia RBL-2H3 cells. These authors
suggest that the inhibitory mechanism of degranulation by xant-
hones was mainly due to suppression of the SYK/PLC
c
s/PKC
pathway.
All the data above indicate that xanthones isolated from man-
gosteen could be a novel target of anti-inflammatory and antialler-
gic compounds.
4.4. Antibacterial, antifungal and antiviral properties
Several studies have demonstrated antibacterial, antifungal and
antiviral properties of xanthones and extracts obtained from GML
(Tables 10 and 11).
Sundaram et al. (1983) studied the antibacterial and antifungal
properties of
a
-mangostin and four of its derivatives. They found
that bacteria S. aureus,P. aeruginosa,Salmonella typhimurium and
Bacillus subtilis were highly susceptible to xanthones, whereas Pro-
teus sp., Klebsiella sp. and Escherichia coli were only moderately sus-
ceptible to them. About fungi, Epidermophyton floccosum,Alternaria
solani,Mucor sp., Rhizupus sp. and Cunninghamella echinulata were
also highly susceptible to xanthones, whereas Trichophyton ment-
agrophytes,Microsporum canis,Aspergillus niger,Aspergillus flavus,
Penicillium sp., Fusarium roseum and Curvularia lunata were only
moderately susceptible to them. The minimum inhibitory concen-
tration (MIC, the lowest concentration of an antimicrobial that will
inhibit the visible growth of a microorganism after overnight incu-
bation) of
a
-mangostin was between 12.5 and 50
l
g/mL for bacte-
ria and between 1 and 5
l
g/mL for fungi. The order of the
antibacterial and antifungal efficiency was as follows:
a
-mango-
stin > isomangostin > 3-O-methyl mangostin > 3,6-di-O-methyl
mangostin. Mangostin triacetate had no activity.
Mahabusarakam et al. (1986) investigated the antimicrobial
activities of mangostin, gartanin,
c
-mangostin, 1-isomangostin
and 3-isomangostin isolated from GML against S. aureus, both nor-
mal and penicillin-resistant strains. The order of the efficacy deter-
mined by the MIC (
l
g/mL) was found to be methicillin (3.9) >
a
-
mangostin (15.6) >
c
-mangostin (31.2) > 1-isomangostin (62.5) >
3-isomangostin (125) > gartanin (250) against normal strain, and
for penicillin-resistant strains
a
-mangostin (1.56–12.5) > methicil-
lin (1.56–12.5) > 1-isomangostin (125) > 3-isomangostin (250),
c
-
mangostin (250) and gartanin (250). In addition, the activities of
mangostin, gartanin and
c
-mangostin against Candida albicans,
Cryptococcus neoformans,T. mentagrophytes and Microsporum gyp-
seum were tested. All of the components showed moderate activi-
ties against T. mentagrophytes and M. gypseum but exhibited no
activity against C. albicans and C. neoformans.
Iinuma et al. (1996) studied the inhibitory effect of several xant-
hones, isolated from mangosteen-fruit pericarp, against the growth
of methicillin-resistant S. aureus (MRSA).
a
-mangostin exhibited
high efficacy, with MIC values of 1.57–12.5
l
g/mL.
Chanarat et al. (1997) found that polysaccharides obtained from
mangosteen-fruit pericarp can stimulate activity of polymorpho-
nuclear phagocytic cells against Salmonella enteritidis.
Suksamrarn et al. (2003) studied the antituberculosis potential
of prenylated xanthones obtained from mangosteen-fruit pericarp.
Among them
a
-, and b-mangostins and garcinone B exhibited the
most potent inhibitory effect against Mycobacterium tuberculosis,
with an MIC of 6.25
l
g/mL; whereas demethylcalabaxanthone
and trapezifolixanthone had an MIC value of 12.5
l
g/mL and
c
-
mangostin, garcinone D, mangostanin, mangostenone A and tovo-
phyllin B had an MIC value of 25
l
g/mL. The xanthones with low
antituberculosis potential were mangostenol and mangostanol
with MIC values of 100
l
g/mL and 200
l
g/mL, respectively.
Chomnawang et al. (2005) evaluated the antibacterial activity
of 19 medicinal plants from Thailand against Staphylococcus epide-
rmidis and Propionibacterium acnes, which have been recognized as
pus-forming bacteria triggering an inflammation in acne. Only 13
Thai medicinal plants were able to inhibit the growth of both bac-
teria. Among these, GML exhibited the most potent inhibitory ef-
fect, with an MIC value of 0.039
l
g/mL for both bacteria.
Table 10
Antibacterial properties of G. mangostana
Effect References
a
-Mangostin strongly inhibited S. aureus,P. aeruginosa,S. thypimurium,B. Subillis Sundaram et al. (1983)
It was showed the antibacterial activity of the
a
- and
c
-mangostins in 49 species of methicillin-resistant Staphylococcus aureus (MRSA)
and the antibacterial activity of
a
-mangostin in 50 species of MRSA and 13 species of Enterococcus spp.
Phongpaichit et al. (1994)
Six xanthones including
a
-mangostin, garcinone E, gartanin, and
c
-mangostin showed antibacterial activity against MRSA Iinuma et al. (1996)
Polysaccharides form the pericarp of GML enhanced the ability of phagocytic cells to kill Salmonella enteritidis in vitro Chanarat et al. (1997)
a
and
c
-mangostins and garcinone B exhibited strong inhibitory effect against Mycobacterium tuberculosis Suksamrarn et al. (2003)
Extract of GML ihibited the growth of Propionibacterium acnes and Staphylococcus epidermidis Chomnawang et al. (2005)
a
-Mangostin is active against vancomycin resistant Enterococci (VRE) and MRSA Sakagami et al. (2005)
Ethanolic extracts of GML inhibited MRSA and S. aureus ATCC25923 Voravuthikunchai and Kitpipit
(2005)
The herbal mouthwash containing the pericarp extract of GML may be used as an adjunct in treating oral malodor Rassameemasmaung et al.
(2007)
Table 11
Antifungal and antiviral properties of G. mangostana
Effect References
a
-Mangostin showed antifungal activity against Epidermdophyton floccosum.Alternaria solani,Mucor sp., Rhizopus sp., Cunninghamella
echinulata
Sundaram et al. (1983)
a
-Mangostin, gartanin,
c
-mangostin, 1-isomangostin and 3-isomangostin showed activity against Staphylococcus aureus both normal
and penicilline-resistan strains. Mangostin,
c
-mangostin and gartanin showed moderate activities against Trichophyton
mentagrophytes and Microsporum gypseum
Mahabusarakam et al. (1986)
Ethanolic extract of GM, and
a
and b-mangostins have a potent inhibitory activity against HIV-1 protease (proteolytic cleavage) Chen et al. (1996) and Vlietinck et al.
(1998)
a
-mangostin, BR-xanthone A, gartanin, 8-deoxygartanin, garcinone D,
c
-mangostin, and euxanthone showed antifungal activity
against F. oxysprum vasinfectum,A. tenuis, and D. oryzae
Gopalakrishnan et al. (1997)
Gopalakrishnan et al. (1997) demonstrated that A and B rings of xanthones are important to antifungal activity.
3236 J. Pedraza-Chaverri et al. / Food and Chemical Toxicology 46 (2008) 3227–3239
Furthermore, the GML minimal bactericidal concentration, that is
the lowest concentration to kill bacteria, was 0.039 and 0.156
l
g/
mL against P. acnes and S. epidermidis, respectively. In addition,
the same author showed that G. mangostana ethanolic extract
could significantly reduce TNF-
a
production generated from
peripheral blood mononuclear cells by stimulating with P. acnes
(Chomnawang et al., 2007).
Sakagami et al. (2005) found that
a
-mangostin had inhibitory
activity against vancomycin resistant Enterococci (VRE) and MRSA
with MIC values of 6.25 and 12.5
l
g/mL, respectively. Synergy be-
tween
a
-mangostin and gentamicin against VRE; and
a
-mangostin
and vancomycin hydrochloride against MRSA was shown. Further-
more, partial synergy between
a
-mangostin and ampicillin or min-
ocycline was also shown.
Voravuthikunchai and Kitpipit (2005) studied aqueous an etha-
nolic extracts obtained from 10 traditional Thai medicinal plants
for their ability to inhibit MRSA from 35 hospitals. Nine Thai plants
had activity against these bacteria. Ethanolic extracts from GML,
Punica granatum and Quercus infectoria were highly efficient at
inhibiting bacterial growth, with MIC values of 0.05, 0.2 to 0.4
and 0.1 to 1.6
l
g/mL, respectively.
Phongpaichit et al. (1994) studied the antibacterial activity of
a
-
and
c
-mangostins and a mangostin mixture on 49 strains of MRSA
isolated from patients in Songklanagarind Hospital. They also stud-
ied the antibacterial activity of
a
-mangostin on 50 strains of MRSA
and 13 strains of Enterococcus spp. isolated from patients in Maha-
raj Nakorn Chiang Mai Hospital. Mangostin mixture had the most
potent effect against MRSA, with an MIC value of 1.48
l
g/mL,
which was the same value as vancomycin, an antimicrobial agent
used as a positive control. Penicillin G was also used as control
and its MIC was >50
l
g/mL. Furthermore,
a
- and
c
-mangostins
also had an effect against MRSA, with MIC values of 3.12 and
2.26
l
g/mL, respectively. The MIC value of
a
-mangostin against
MRSA was 8
l
g/mL. Mangostin inhibited the growth of all Entero-
coccus spp. with an MIC value of 1
l
g/mL.
Gopalakrishnan et al. (1997) demonstrated the antifungal activ-
ity of several xanthones isolated from mangosteen-fruit pericarp
and some
a
-mangostin-derivatives against three phytopathogenic
fungi (Fusarium oxysporum vasinfectum,Alternaria tenuis and Dres-
chlera oryzae).
a
-mangostin,
c
-mangostin, gartanin, garcinone D,
BR-xanthone and euxanthone showed high inhibitory activity
against the three fungi; they used 1, 10, 100 and 1000 ppm in
the culture medium. Substitution in A and C rings has been shown
to modify the bioactivities of the compounds.
Several natural products have been identified because of their
capacity to inhibit different stages in the replication cycle of hu-
man immunodeficiency virus (HIV-1). Among them, xanthones
have been shown to inhibit proteolytic cleavage by protease inhi-
bition (reviewed in Vlietinck et al., 1998).
Chen et al. (1996) showed that ethanolic extract of GML effec-
tively inhibited HIV-1 protease. Two xanthones were isolated from
the ethanolic extract:
a
- and
c
-mangostins, which exhibited an
IC
50
value of 5.12 ± 0.41 and 4.81 ± 0.32
l
M, respectively. Pepstatin
A (IC
50
= 76 ± 5.5 nM) was used as positive control.
Recently, Rassameemasmaung et al. (2007) showed that a her-
bal mouthwash containing the pericarp extract of GML has some
effect against volatile sulfur compounds, plaque and papillary
bleeding in sixty subjects who were diagnosed as having mild or
moderate chronic gingivitis, so the pericarp extract may be used
as an adjunct in treating oral malodor.
4.5. Antimalarial properties
Several xanthones isolated from GML have shown antimalaria
activity in vitro against Plasmodium falciparum.b-mangostin and
a
-mangostin exhibited a comparable IC
50
value (7 and 5.1
l
M
respectively), whereas mangiferina, a xanthone-glucoside, exhib-
ited an IC
50
value higher than 50
l
M(Riscoe et al., 2005). In the
other hand, Mahabusarakam et al. (2006) found that
a
-mangostin
exhibited an IC
50
value of 17
l
M against P. falciparum.
Laphookhieo et al. (2006) found that b-mangostin isolated from
roots of C. cochinchinense had an IC
50
value of 7.2
l
g/mL against P.
falciparum.
5. Medicinal properties of xanthones isolated from sources
other than G. Mangostana
The following medicinal properties have been described about
xanthones that are isolated from sources other than GML: antima-
larial (Pinto et al., 2005; Laphookhieo et al., 2006; Riscoe et al.,
2005; Mahabusarakam et al., 2006; Azebaze et al., 2006; Likhitwit-
ayawuid et al., 1998a,b); antidiabetes, antihiperlipidemic and anti-
atherogenic (Muruganandan et al., 2005; Pinto et al., 2005);
antibacterial (Pinto et al., 2005; Azebaze et al., 2006; Dharmaratne
and Wijesinghe, 1999), anticancer (Pedro et al., 2002), antitumoral
(Pinto et al., 2005; Laphookhieo et al., 2006; Liou et al., 1993), car-
dioprotective (Pinto et al., 2005; Jiang et al., 2004) and hepatopro-
tective, immunomodulator, anti-inflammatory, antiulcer, antiviral
and antifungal (reviewed in Pinto et al., 2005).
6. Conclusions
Following the discovery of medicinal properties in components
of G. mangostana, many studies have been conducted. These stud-
ies include both natural extracts and synthetic derivatives. In this
review, the potential beneficial effect of GML in both acute and
chronic disease has been discussed. This suggests possible thera-
peutic applications that relate to GML. Nevertheless, further stud-
ies need to be done in order to investigate the effects of GML
extracts in humans.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgements
This work was supported by Programa de Apoyo a Proyectos de
Investigación e Innovación Teconológica, Direccion General de
Asunto del Personal Académico (DGAPA, Grant No. IN207007) from
Universidad Nacional Autónoma de México (UNAM).
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