A Comprehensive Review of Punica Granatum (Pomegranate) Properties in Toxicological, Pharmacological, Cellular and Molecular Biology Researches
A Comprehensive Review of Punica Granatum (Pomegranate) Properties in Toxicological, Pharmacological, Cellular and Molecular Biology Researches
A Comprehensive Review of Punica Granatum (Pomegranate) Properties in Toxicological, Pharmacological, Cellular and Molecular Biology Researches
Review Article
Abstract
Punica granatum (Pg), commonly known as pomegranate (Pg), is a member of the
monogeneric family, Punicaceae, and is mainly found in Iran which is considered to be its
primary centre of origin. Pg and its chemical components possess various pharmacological
and toxicological properties including antioxidant, anti-inflammatory (by inhibiting proinflammatory cytokines), anti-cancer and anti-angiogenesis activities. They also show
inhibitory effects on invasion/motility, cell cycle, apoptosis, and vital enzymes such as
cyclooxygenase (COX), lipooxygenase (LOX), cytochrome P450 (CYP450), phospholipase
A2 (PLA2), ornithine decarboxylase (ODC), carbonic anhydrase (CA), 17beta-hydroxysteroid
dehydrogenase (17-HSDs) and serine protease (SP). Furthermore, they can stimulate cell
differentiation and possess anti-mutagenic effects. Pg can also interfere with several signaling
pathways including PI3K/AKT, mTOR, PI3K, Bcl-X, Bax, Bad, MAPK, ERK1/2, P38,
JNK, and caspase. However, the exact mechanisms for its pharmacological and toxicological
properties remain to be unclear and need further evaluation. These properties strongly suggest
a wide range use of Pg for clinical applications. This review will discuss the areas for which Pg
has shown therapeutic properties in different mechanisms.
Keywords: Punica granatum; Chemical components; Toxicological properties; Signaling
pathway; Clinical applications.
Introduction
Punica granatum (Pomegranate) is a
small tree which measures between five and
eight meters tall and mainly found in Iran, the
Himalayas in northern India, China, USA and
throughout the Mediterranean region (1). Pg
is one of the important endemic plants of Iran,
growing in most regions throughout the country,
in arid and semiarid regions due to its ability to
adapt to adverse ecological conditions. Over 764
cultivars of Punica granatum (Pg) have been
* Corresponding author:
E-mail: [email protected]
Anti-inflammatory effect
Acute inflammation is a beneficial host
response for prevention of tissue injury, but it
may also cause immune-associated diseases
such as rheumatoid arthritis, inflammatory bowel
disease and cancers (28, 29). Interestingly, Pg,
Pg has been shown to inhibit inflammation by
different mechanisms.
Cyclooxygenase (COX) and lipooxygenase
(LOX), which are key enzymes in the
conversion of arachidonic acid to prostaglandins
and leukotrienes (important inflammatory
mediators), respectively, are inhibited by Pg
(30, 31). Non-steroidal anti-inflammatory
drugs (NSAIDs) have more adverse effects on
cardiovascular function by inhibiting COX and
suppressing PGI2 (prostacyclin) in comparison
to Pg (32). Ahmed et al. have shown that Pg has
a significant inhibitory effect on osteoarthritis
(OA) by suppressing the expression of matrix
metalloproteinases (MMPs) in OA chondrocyte
cultures and preventing collagen degradation.
It may also inhibit joint destruction in OA
patients (33). Pro-inflammatory cytokines
386
Carcinogenesis
Pg possesses inhibitory effects on different type
of cancers such as prostate (39,40), breast (41),
colon (42,43), and lung cancers (44). Different
mechanisms have been outlined for pomegranates
anti-cancer activities in these studies. Pg inhibits
NF-kBand cell viability of prostate cancer cell
lines in a dose-dependent manner in the LAPC4
xenograft model, in-vitro (45). Pg polyphenols,
ellagitannin-rich extract and whole juice extract
inhibited gene expression of HSD3B2 (3betahydroxysteroid dehydrogenase type 2), AKR1C3
(aldo-ketoreductase family 1 member C3) and
SRD5A1 (steroid 5alpha reductase type 1), which
are key androgen-synthesizing enzymes in LNCaP,
LNCaP-AR, and DU-145 human prostate cancer
cells (46). Because Pg inhibits CYP activity/
expression which is necessary for activation of
procarcinogens, it may have anti-carcinogenesis
effects (16). Some metabolites of pomegranates
chemical components such as 3,8-dihydroxy-
Apoptosis
Apoptosis is the process of programmed cell
death, which is a useful marker for predicting
tumor response after anti-cancer treatment. Pg
causes apoptosis by different mechanisms. PE
388
Cellular differentiation
Cellular differentiation, in developmental
biology, is the process by which a less specialized
cell becomes a more specialized cell type. Study
has shown that Pg stimulates the differentiation
of osteoblastic MC3T3-E1 cells and affects the
function of these cells (4). Pg seed oil (but not
aqueous extracts of fermented juice, peel or seed
cake) has been shown to stimulate keratinocyte
proliferation in monolayer culture, without
effecting fibroblast function, and as a result
facilitates skin repair and promotes regeneration
of dermis and epidermis (56). flavonoid-rich
fractions from fermented Pg juice and aqueous
extraction of Pg pericarps are strong promoters
of differentiation in human HL-60 promyelocytic
leukemia cells, which are detected by nitro
blue tetrazolium reducing activity, non specific
esterase activity, specific esterase activity,
and phagocytic activity, whereas flavonoidrich fractions from fresh Pg juice only show a
relatively mild differentiation-promoting effect.
Furthermore, the effect of Pg on differentiation
has been observed in breast and prostate cell
lines (90).
Anti-mutagenicity
A mutagen is a physical orchemical agent
that alters the genetic material of an organism,
usually DNA, permanently and thus increases
the frequency of mutations above the natural
390
Molecular weight
(MW)
Plant Part
2,3-(S)-HHDP-D-glucosea
C20H18O14
482.35
Bark, peel
Castalagin
C41H26O26
934.63
Bark
Casuariin
C34H24O22
784.54
Bark
Pomegranate Phytochemicals
Ellagitannins and Gallotannins
Casuarinin
936.65
Bark, pericarp
Corilagin
C27H22O18
634.45
Cyclic 2,4:3,6-bis(4,4,5,5,6,6-hexahydroxy
[1,1-biphenyl]- 2,2-dicarboxylate)
1-(3,4,5-trihydroxybenzoate) b-D-Glucose
C41H28O26
936.65
leaves
Granatin A
C34H24O23
800.54
Pericarp
Granatin B
C34H28O27
952.64
Peel
Pedunculagin
C34H24O22
784.52
Bark, pericarp
Punicacortein A
C27H22O18
634.45
Bark
Punicacortein B
C27H22O18
634.45
Bark
Punicafolin
C41H30O26
938.66
Leaves
Punigluconin
C34H26O23
802.56
Bark
Strictinin
C27H22O18
634.45
Leaves
Tellimagrandin I
C34H26O22
786.56
Leaves, pericarp
Tercatain
C34H26O22
786.56
Leaves
2-O-galloyl-4,6(S,S) gallagoyl-D-glucose
C41H26O26
934.63
Bark
5-O-galloyl-punicacortein D
C54H34O34
1222.8
Leaves
Punicacortein C
C47H26O30
1070.7
Bark
Punicacortein D
C47H26O30
1070.7
Bark, heartwood
Punicalin
C34H22O22
782.53
Bark, pericarp
Punicalagin
C48H28O30
1084.7
Terminalin/gallayldilacton
C28H20O16
602.37
Pericarp
Ellagic acid
C14H6O8
302.19
C16H10O8
330.25
Seed
C17H12O8
344.27
Seed
C16H8O8
328.23
Heartwood
Eschweilenol C
C20H16O12
448.33
Heartwood
C40H30O24
894.65
Heartwood
(-)-Catechin
C15H14O6
290.27
Juice
Catechin-(4,8)-gallocatechin
C30H26O13
594.52
Peel
Gallocatechin
C15H14O7
306.27
Peel
Gallocatechin-(4,8)-catechin
C30H26O13
594.52
Peel
Gallocatechin-(4,8)-gallocatechin
C30H26O14
610.52
Peel
Procyanidin B1
C30H26O12
578.52
Juice
Procyanidin B2
C30H26O12
578.52
Juice
C15H11O6
287.24
Peel
392
Table 1. (Continued)
Formula
Molecular weight
(MW)
Plant Part
Cyanidin-3-glucoside
C21H21O11
449.38
Juice
Cyanidin-3,5-diglucoside
C27H31O16
611.52
Juice
Cyanidin-3-rutinoside
C27H31O15
595.53
Juice
Delphinidin
C15H11O7
303.24
Juice
Delphinidin-3-glucoside
C21H21O12
465.38
Juice
Delphinidin 3, 5-diglucoside
C27H31O17
627.52
Juice
Pelargonidin 3-glucoside
C21H21O10
433.38
Juice
Pelargonidin 3,5-diglucoside
C27H31O15
595.53
Juice
Apigenin-4-O--D-glucoside
C21H20O11
448.32
Leaves
Kaempferol
C15H10O6
286.24
Peel, fruit
Luteolin
C15H10O6
286.24
Peel, fruit
Luteolin-3-O--D-glucoside
C21H20O10
432.11
Leaves
Luteolin-4-O--D-glucoside
C21H20O10
432.11
Leaves
Luteolin-3-O--D-Xyloside
C21H18O10
418.09
Leaves
Myricetin
C15H10O8
318.04
Fruit
Quercetin
C15H10O7
302.04
Peel, fruit
Quercimeritrin
C21H20O12
464.38
Fruit
Quercetin-3-O-rutinoside
C27H30O16
610.52
Fruit
C28H32O16
624.54
Bark, peel
Eriodictyol-7-O--Larabinofuranosyl (1-6)--Dglucoside
C26H30O15
582.51
Leaves
C27H32O14
580.53
Leaves
Caffeic acid
C9H8O4
180.16
Juice
Chlorogenic acid
C16H18O9
345.31
Juice
Cinnamic acid
C9H8O2
148.16
Juice
Citric acid
C6H8O7
192.12
Juice
o-Coumaric acid
C9H8O3
164.16
Juice
p-Coumaric acid
C9H8O3
164.16
Juice
Ferulic acid
C10H10O4
194.18
Juice
Gallic acid
C7H6O5
170.12
Juice
L-Malic acid
C4H6O5
134.09
Juice
Oxalic acid
C2H2O4
90.03
Juice
Protocatechuic acid
C7H6O4
154.12
Juice
Quinic acid
C7H12O6
192.17
Juice
Succinic acid
C4H6O4
118.09
Juice
C9H8O4
180.16
Juice
Pomegranate Phytochemicals
(Continued)
Flavonols
Organic Acids
Organic Acids
Caffeic acid
393
Table 1. (Continued)
Pomegranate Phytochemicals
Formula
Molecular weight
(MW)
Plant Part
Chlorogenic acid
C16H18O9
345.31
Juice
Cinnamic acid
C9H8O2
148.16
Juice
Citric acid
C6H8O7
192.12
Juice
o-Coumaric acid
C9H8O3
164.16
Juice
p-Coumaric acid
C9H8O3
164.16
Juice
Ferulic acid
C10H10O4
194.18
Juice
Gallic acid
C7H6O5
170.12
Juice
L-Malic acid
C4H6O5
134.09
Juice
Oxalic acid
C2H2O4
90.03
Juice
Protocatechuic acid
C7H6O4
154.12
Juice
Quinic acid
C7H12O6
192.17
Juice
Succinic acid
C4H6O4
118.09
Juice
Tartaric acid
C4H6O6
150.09
Juice
Brevifolin
C12H8O6
248.19
Leaves
C13H8O8
292.2
Leaves
C13H7KO10S
394.25
Leaves
1,2,3-Tri-O-galloyl--D-glucose
C27H24O18
448.32
Leaves
1,2,4-Tri-O-galloyl--D-glucose
C27H24O18
286.24
Leaves
1,2,6-Tri-O-galloyl--D-glucose
C27H24O18
286.24
Leaves
1,4,6-Tri-O-galloyl--D-glucose
C27H24O18
432.11
Leaves
1,3,4-Tri-O-galloyl--D-glucose
C27H24O18
432.11
Leaves
1,2, 4, 6-Tetra-O-galloyl--D-glucose
C34H28O22
418.09
Leaves
1,2,3,4, 6-Pent-O-galloyl--D-glucose
(Continued)
C41H32O26
318.04
Leaves
Methyl gallate
C8H8O5
302.04
Heratwood
3,4,8,9,10-pentahydroxy-dibenzo[b,d]pyran-6-one
C13H8O7
464.38
Leaves
Eicosenoic acid
C20H40O2
312.53
Seed oil
Linoleic acid
C18H32O2
280.45
Seed oil
Linolenic acid
C18H30O2
278.43
Seed oil
Oleic acid
C18H34O2
282.46
Seed oil
Palmitic acid
C16H32O2
256.42
Seed oil
Punicic acid
C18H30O2
278.43
Seed oil
Stearic acid
C18H36O2
284.48
Seed oil
Tri-O-punicylglycerol
C57H92O6
873.34
Seeds
Di-O-punicyl-O-octadeca-8Z-11Z-13Etrienylglycerol
C57H92O6
873.34
Seeds
C21H36O4
352.51
Seed oil
1-O-isopentyl-3-O-octadec-2-enoyl glycerol
C26H50O4
426.67
Seed oil
394
Table 1. (Continued)
Pomegranate Phytochemicals
Formula
Molecular weight
(MW)
Plant Part
Asiatic acid
C30H48O5
488.7
Juice
Betulinic acid
C30H48O3
456.70
Seed
Cholesterol
C27H46O
386.65
Seed oil
Daucosterol
C35H60O6
576.85
Seed
Estrone
C18H22O2
270.37
Seed oil
Estradiol
C18H24O2
272.38
Seed oil
Estriol
C18H24O3
288.38
Seed oil
Friedooleanan-3-one
C30H50O
426.72
Bark
-Sitosterol
C29H50O
414.71
Stigmasterol
C29H48O
412.69
Seed oil
Testosterone
C19H28O2
288.42
Seed oil
Ursolic acid
C30H48O3
456.70
Seed
C8H15NO
141.21
Root bark
Norhygrine
C7H13NO
127.18
Root bark
Pelletierine
C8H15NO
141.21
Bark
N-methyl pelletierine
C9H17NO
155.24
Bark
Alkaloids
Hygrine
(Continued)
Sedridine
C8H17NO
143.23
Bark
Pseudopelletierine
C9H15NO
153.22
Bark
Nor-pseudopelletierine
C8H13NO
139.19
Bark
2,3,4,5-tetrahydro-6-propenyl-pyridine
C8H13N
123.20
Bark
3,4,5,6-tetrahydro-a-methyl-2-pyridine ethanol
C8H15NO
141.21
Bark
1-(2,5-dyihydroxy-phenyl)-pyridium chloride
C11H10ClNO2
223.66
Leaves
Coniferyl 9-O-[-D-apiofuranosyl-(1-6)]-O--Dglucopyranoside
C21H30O12
474.46
Seed
Pseudopelletierine
C9H15NO
153.22
Bark
Nor-pseudopelletierine
C8H13NO
139.19
Bark
2,3,4,5-tetrahydro-6-propenyl-pyridine
C8H13N
123.20
Bark
3,4,5,6-tetrahydro-a-methyl-2-pyridine ethanol
C8H15NO
141.21
Bark
1-(2,5-dyihydroxy-phenyl)-pyridium chloride
C11H10ClNO2
223.66
Leaves
Coniferyl 9-O-[-D-apiofuranosyl-(1-6)]-O--Dglucopyranoside
C21H30O12
474.46
Seed
Sinapyl 9-O-[-D-apiofuranosyl-(1-6)]-O--Dglucopyranoside
C18H36O2
284.48
Seed
Phenylethylrutinoside
C57H92O6
873.34
Seeds
Icariside D1
C57H92O6
873.34
Seeds
Mannitol
C21H36O4
352.51
Bark
Other Compounds
Other Compounds
a HHDP =hexahydroxydiphenoyl.
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