Food and Chemical Toxicology xxx (2016) 1e17

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Food and Chemical Toxicology

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Phytochemical and phytopharmacological review of Perilla frutescens

L. (Labiatae), a traditional edible-medicinal herb in China
Hua Yu a, b, c, 1, Jian-Feng Qiu a, 1, Li-Juan Ma a, Yuan-Jia Hu a, Peng Li a, *, Jian-Bo Wan a, **
a
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
b
HKBU Shenzhen Research Center, Shenzhen, Guangdong, China
c
School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong

a r t i c l e i n f o a b s t r a c t

Article history: Perilla frutescens (L.) Britt., a worldwide distributed plant, is an important economic crop and with a long
Received 30 August 2016 cultivation history in China as well as some other countries in Asia. Except for the edible applications, the
Received in revised form plant of P. frutescens is also traditionally used as a medicinal herb in China for thousands years. The
20 November 2016
leaves, seeds and stems of P. frutescens are recommended by the Chinese Pharmacopeia as three me-
Accepted 23 November 2016
Available online xxx
dicinal materials for various therapeutic applications. In the past decades, amount investigations have
been done about different aspects for P. frutescens. However, no literature review about these works has
been compiled. This review aims to present the findings of research conducted up-to-date (2015) on the
Keywords:
Perilla frutescens (L.) Britt.
traditional use, phytochemicals, pharmacological activities and toxicities of P. frutescens to provide sci-
Edible-medicinal herb entific evidence for well-understanding and future research of P. frutescens. It was found that more than
Traditional use 100 compounds have been reported for P. frutescens and most of them are contributed to its medical
Phytochemical benefits such as anti-allergic, anti-inflammatory, anti-oxidant, anticancer, anti-microbial, anti-depressive
Phytopharmacological and anti-cough effects. Toxicology studies have been conducted to evaluate the safety of P. frutescens to
provide information on their dosages and usages.
© 2016 Elsevier Ltd. All rights reserved.

1. Introduction
Perilla frutescens (L.) Britt. (also called Zisu in China), belonging
to the family Labiatae, is widely distributed worldwide, especially
in China, Japan, Korea, Vietnam and other regions in Asia (Heci,
2001; Asif and Kumar, 2010). As one of the important economic
crops, the cultivation of P. frutescens is more than 2000 years of
history in China as well as other countries in Asia (Lee and Ohnishi,
2001, 2003; Lee and Kim, 2007). The seed of P. frutescens is the
important source of perilla oil and the fresh plant of P. frutescens is a
spicy vegetable in East Asia. In China, people get used to deal with
fish and crab poisoning with P. frutescens based on ancient Chinese
medicine. In Japan and Korea, people get used P. frutescens to be
representative flavors in Japanese food and make pickles as well as
package with roast meat, respectively.
* Corresponding author. Room 6035, Building N22, Institute of Chinese Medical
Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, China.
** Corresponding author. Room 6034, Building N22, Institute of Chinese Medical
Sciences, University of Macau, Avenida da Universidade, Taipa, Macao, China.
E-mail addresses: pengli@umac.mo (P. Li), jbwan@umac.mo (J.-B. Wan).
1
The authors contributed equally to this work.
Except for the edible usages, P. frutescens is also widely used as
traditional Chinese medicines for various diseases, such as cold due
to wind-cold, headache, cough, abdominal fullness and distention,
poisoning from fish and crabs. Since the leaf, stem and seed of
P. frutescens (also called Zisuye, Zisugeng and Zisuzi, respectively) are
differentially prescribed by the TCM practitioners for different
therapeutic purposes in clinical practice, the chemical constituents
and the pharmacological properties of such parts have been
experientially and scientifically identified. From 1963, the leaf, stem
and seed of P. frutescens Zisuye, Zisugeng and Zisuzi were recorded as
three different herbal medicines in the Pharmacopeia of the Peo-
ple's Republic of China (PPRC) for different symptoms in clinical
applications. Moreover, P. frutescens also plays an important role
and involved in various TCM-based prescriptions to enhance the
therapeutic effect of individual herb in clinical applications (Luo
et al., 2000; Huang et al., 2009; Mao et al., 2010).
Nowadays, extensive investigations related to the phytochem-
istry and pharmacology for P. frutescens has been done by many
researchers. Various compounds from this plant have been isolated
and identified, including flavonoids, volatile oils, fatty acids, tri-
terpenes, phenolic compounds and others. The functions of

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Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
2 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17
P. frutescens-derived compounds include anti-allergy, anti-inflam-
mation, anti-oxidant, anticancer, antibacterial, antidepressant and
so on. Moreover, in 2002, P. frutescens and P. frutescens seed have
been listed in the 87 medicine-food plants by the Ministry of Health
of the People's Republic of China (MOH) (2002) which suggests the
potential edible and medicinal values of P. frutescens plant. The aim
of the present review is to compile an up-to-2015 and compre-
hensive knowledge of P. frutescens regarding its traditional uses,
phytochemistry, pharmacology and toxicology, and to provide the
possible tendency and perspectives for future research of this plant.
2. Traditional uses
The traditional uses of P. frutescens include two aspects: edible
and medicinal.
In edible, P. frutescens has been used as a common flavor for fish
and crab cooking with the purposes of detoxification in China for
more than 2000 years (Tian, 2012). The tender leaf of P. frutescens is
a favorite vegetable and with high nutritional values. In addition,
P. frutescens is also a representative flavor in Japan and a spicy
vegetable in Korea. Moreover, the P. frutescens seed is the important
source of perilla oil internationally because it is rich in omega-3
fatty acids.
In medicinal, the herb of P. frutescens has long been used as a
source of medicinal materials. P. frutescens leaf and P. frutescens seed
are commonly used separately in Chinese medicine, as well as the
P. frutescens stem is commonly used with the leaves. The first record
of P. frutescens could be found in “Renown Physician's Extra Records”
which was issued in the Han dynasty. The P. frutescens leaf possesses
efficacy of relieving exterior syndrome and cold-dispelling, promot-
ing the circulation of Qi and harmonizing the stomach; P. frutescens
stem is used for owning function of promoting the circulation of Qi,
relieving the pain and miscarriage prevention and P. frutescens seed
has Qi-descending and phlegm-resolving, relieving cough and
asthma and loosening the bowel to relieve constipation effect (PPRC,
2015). Moreover, P. frutescens is also involved in several classical
prescriptions, such as “Ban Xia Hou Po decoction” for treating
depressive symptoms in China, referring to the synopsis of the
Golden Chamber (Jingui Yaolue). In “San Yin Ji Yi discourse on pre-
scription”, P. frutescens was combined with Citrus reticulata Blanco,
Platycodon grandiflorum (Jacq.) A.D.C., Panax ginseng and Schisandra
chinensis (Turcz.) Baill. in treating shortness in breath when lying
down. In Compendium of Materia Medica (Li Shizhen, the Ming Dy-
nasty), P. frutescens was introduced for dispersing wind and cold,
promoting Qi circulation to alleviate middle energizer and solving
fish and crab poison. Based on the Chinese system of medicine,
P. frutescens could be ethnically used to treat kinds of diseases such as
cold, fever, chills, headache, stuffy nose, cough or chest discomfort.
3. Phytochemical
A wide range of chemical compounds has been reported in
different parts of P. frutescens Based on the chemical properties, the
compounds could be divided into two parts: hydrophilic (phenolic
compounds, flavonoids and triterpenes) and hydrophobic (volatile
compounds, fatty acids, policosanols, tocopherols and phytosterols).
Moreover, some other compounds, such as hydrocarbons, alcohols,
aldehydes and furans are also reported for P. frutescens. In this part,
we describe the main chemical constituents of this plant, their
structures and their isolation parts of this plant (Table 1and Figs.1e3).
3.1. Phenolic compounds
Rosmarinic acid, caffeic acid, ferulic acid, caffeic acid-3-O-
glucoside and rosmarinic acid-3-O-glucoside were identified in the
Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
leaf, stem and seed of P. frutescens (Peng et al., 2005; Zhang et al.,
2009; Ha et al., 2012a; Liu et al., 2013a; Tang et al., 2014; Zhu
et al., 2014). Among them, rosmarinic acid has been demon-
strated to be one of the main phenolic compounds in P. frutescens
leaves (Liu et al., 2013a) and highly concentrated during the period
from flowering to seeding (Zhang et al., 2009).
3.2. Flavonoids and triterpenes
Flavonols were mainly detected in the leaves and seeds of
P. frutescens. The identified flavonols included apigenin, luteolin and
(þ)-catechin, etc. (Peng et al., 2005; Ha et al., 2012a). Moreover, trace
triterpenes including tormentic acid, oleanolic acid and ursolic acid
were determined in P. frutescens by HPLC analysis (Chen et al., 2003).
3.3. Volatile compounds (essential oils)
Volatile compounds (essential oils) are mainly distributed in the
leaves, flowers and stems of P. frutescens plant. The contents of
essential oils have been reported to be 0.821% in leaves, 0.269% in
flowers, 0.022% in stems and 0.011% in seeds (Wang et al., 2013a).
As summarized in Table 1, multifarious volatile compounds have
been identified and reported (Lin et al., 2002; Liu et al., 2008; Seo
and Baek, 2009; Zhong and Fu, 2010; Liu et al., 2013a). Chemi-
cally, these compounds could be further divided into 7 chemotypes.
The reprehensive compounds of each chemotype include peril-
laldehyde and limonene for perillaldehyde type (PA); perillaketone,
isoegomaketone and egomaketone for perillaketone type (PK);
elsholtziaketone and naginataketone for elsholtzoaketone type
(EK); perillene for perillene type (PL); myristicin, elemicin and
dillapiol for phenylpropanoid type (PP); citral for citral type (C); as
well as rosefuran containing type (R).
3.4. Fatty acids
The seeds of P. frutescens are rich in fatty acids. The major con-
stituents of the fatty acid comprise palmitic acid (C17:0), stearic
acid (C18:0), oleic acid (C18:1), linoleic acid (C18:2) and linolenic
acid (C18:3) (Tan et al., 1998; Asif, 2011; Liu et al., 2012; Schantz
et al., 2013). As a good source of polyunsaturated fatty acids
(PUFAs), only the seed oil of P. frutescens contains a-linolenic acid
(ALA), a considerable proportion of omega-3 fatty acids, at 54e64%
while comparing to other plant oils. In addition, the omega-6
(linoleic acid) compound is usually around 14% and omega-9
(Oleic acid) is also present in P. frutescens oil (Asif, 2011). Recently
in United States, by collaborating with the National Institutes of
Health's Office of Dietary Supplements and the Food and Drug
Administration's Center for Drug Evaluation and Research, the
National Institute of Standards and Technology (NIST) developed
Standard Reference Material (SRM) 3274 Botanical Oils Containing
Omega-3 and Omega-6 Fatty Acids, including 3274-4 Perilla
(P. frutescens), which paved a way for this plant being developed for
dietary supplements (Schantz et al., 2013).
3.5. Policosanols
Similar to the structure of fatty acid, policosanols are a mixture
of long chain alcohols. Based on gas chromatography, policosanols
in the P. frutescens seed were determined to be 67e68% octaco-
sanol, 16e17% hexacosanol, 6e9% triacontanol of the total poli-
cosanols composition (Adhikari et al., 2006). In depth, another
research group demonstrated that P. frutescens seed was found to
be abundant sources of policosanols, containing 427.83 mg PCs/kg
oil, ranking the highest in the investigated vegetable oils (Jung
et al., 2011).
 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17 3

Table 1
Chemical compounds isolated from Perilla frutescens.

No Compounds Molecular formula Parts Reference

Phenolic compounds
1 Catechin C15H14O6 Leaves, Seeds (Peng et al., 2005)
2 Ferulic acid C10H10O4 Leaves, Seeds (Peng et al., 2005)
3 Rosmarinic acid C18H16O8 Stems, Leaves, Seeds (Peng et al., 2005; Raudonis et al., 2010;
Ha et al., 2012a; Liu et al., 2013a;
Jun et al., 2014)
4 Caffeic acid C9H8O4 Leaves, Seeds (Peng et al., 2005; Raudonis et al., 2010)
5 Caffeic acid-3-O-glucoside C15H18O10 Seeds (Ha et al., 2012a)
6 Rosmarinic acid-3-O-glucoside C18H15O8 Seeds (Ha et al., 2012a)
Flavonoids
7 Apigenin C15H10O5 Leaves, Seeds (Peng et al., 2005; Ha et al., 2012a)
8 Luteolin C15H10O6 Leaves, Seeds (Peng et al., 2005; Ha et al., 2012a)
9 (þ)-catechin C15H4O6 Leaves, Seeds (Peng et al., 2005)
Triterpene
10 Tormentic acid C30H48O5 Leaves (Chen et al., 2003)
11 Oleanolic acid C30H48O3 Leaves (Chen et al., 2003)
12 Ursolic acid C30H48O3 Leaves (Chen et al., 2003)
Volatile oil
13 Menthol C10H20O Leaves (Lin et al., 2002)
14 p-Cymene C10H14 Seeds (Liu et al., 2013a)
15 Perillaketone C10H14O2 Leaves (Ito et al., 2008a; Bumblauskiene et al., 2009;
Muller-Waldeck et al., 2010; Seo and Baek, 2009)
16 Perillic acid C10H14O2
17 Perillyl alcohol C10H16O Leaves (Bumblauskiene et al., 2009)
18 Perillaldehyde C10H14O Leaves (Bumblauskiene et al., 2009)
9 Limonene C10H16 Leaves (Ito et al., 2008a; Bumblauskiene et al., 2009)
20 b-caryophyllene C15H24 Stems, Leaves, Seeds (Ito et al., 2008a; Bumblauskiene et al., 2009;
Seo and Baek, 2009; Liu et al., 2013a)
21 1-cyclohexane-1-carboxaldehyde C7H12O Stems, Leaves, Seeds (Liu et al., 2013a)
22 b-linalool C10H18O Leaves (Ito et al., 2008a; Seo and Baek, 2009; Liu et al., 2013a)
23 a-terpineol C10H18O Stems (Liu et al., 2013a)
24 Methyl thymyl ether C11H16O Seeds (Liu et al., 2013a)
25 2-methoxy-3-propenyl-phenol C10H12O2 Leaves (Liu et al., 2013a)
26 2-hexanoylfuran C10H14O2 Stems, Leaves, Seeds (Liu et al., 2013a)
27 a-curcumene C15H22 Stems (Liu et al., 2013a)
28 b-farnesene C15H24 Stems, Leaves, Seeds (Ito et al., 2008a; Liu et al., 2013a)
29 1,4,7-cycloundecatriene- C15H24 Stems, Leaves, Seeds (Liu et al., 2013a)
1,5,9,9-tetramethyl-zzz
30 a-farnesene C15H24 Leaves, Seeds (Ito et al., 2008a; Liu et al., 2013a)
31 a-Bergamotene C16H24 Seeds (Liu et al., 2013a)
32 a-copaene C16H26 Seeds (Liu et al., 2013a)
33 b-elemene C15H24 Leaves (Liu et al., 2013a)
34 1,6-cyclodecadiene C10H14 Leaves (Liu et al., 2013a)
35 Elixene C15H24 Leaves (Liu et al., 2013a)
36 caryophyllene C15H24 Stems, Leaves (Bumblauskiene et al., 2009; Liu et al., 2013a)
37 Asarone C12H16O3 Leaves (Liu et al., 2013a)
38 Curlone C15H22O Stems (Liu et al., 2013a)
39 Caryophyllene oxide C15H24O Leaves, Seeds (Bumblauskiene et al., 2009; Liu et al., 2013a)
40 Spathulenol C15H24O Leaves (Liu et al., 2013a)
41 Trans-nerolidol C15H26O Leaves (Seo and Baek, 2009; Liu et al., 2013a)
42 1,2-benzenedicarboxylic acid C8H6O4 Leaves (Liu et al., 2013a)
43 Phthalic acid C8H6O4 Stems (Liu et al., 2013a)
44 Phytol C20H40O Leaves (Liu et al., 2013a)
45 Anisole C7H8O Stems (Liu et al., 2013a)
46 Egomaketone C10H12O2 Leaves (Bumblauskiene et al., 2009; Seo and Baek, 2009)
47 Elemicin C12H16O3 Leaves (Bumblauskiene et al., 2009; Ito et al., 2008a)
48 Myristicin C11H12O3 Leaves (Bumblauskiene et al., 2009; Ito et al., 2008a)
49 Limonene oxide C10H16O Leaves (Bumblauskiene et al., 2009)
50 3-octanol C8H18O Leaves (Bumblauskiene et al., 2009)
51 Myrcene C10H16 Leaves (Bumblauskiene et al., 2009)
52 Eucalyptol C10H18O Leaves (Bumblauskiene et al., 2009)
53 Linalool oxide C10H18O2 Leaves (Bumblauskiene et al., 2009)
54 Trans furanoid C10H18O2 Leaves (Bumblauskiene et al., 2009)
55 Cis pyranoid C10H18O2 Leaves (Bumblauskiene et al., 2009)
56 Terpinolene C10H16 Leaves (Bumblauskiene et al., 2009)
57 Limonen oxide, cis C10H16O Leaves (Bumblauskiene et al., 2009)
58 Limonene oxide, trans C10H16O Leaves (Bumblauskiene et al., 2009)
59 Linalyl oxide cis Leaves (Bumblauskiene et al., 2009)
60 Linalool oxide trans C10H18O2 Leaves (Bumblauskiene et al., 2009)
61 Dihydrocarveol C10H18O Leaves (Bumblauskiene et al., 2009)
62 b-cyclocitral C10H16O Leaves (Bumblauskiene et al., 2009)
63 Carvone C10H14O Leaves (Bumblauskiene et al., 2009)
64 Bornyl acetate C12H20O2 Leaves (Bumblauskiene et al., 2009)
(continued on next page)

Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
4 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17

Table 1 (continued )

No Compounds Molecular formula Parts Reference

65 Methyl geranate C11H18O2 Leaves (Bumblauskiene et al., 2009)

66 Isodihydrocarveol acetate C12H20O2 Leaves (Bumblauskiene et al., 2009)
67 b-murolene C15H24 Leaves (Bumblauskiene et al., 2009)
68 Humulene epoxide II C15H24O Leaves (Bumblauskiene et al., 2009)
Fatty acids
69 Palmitic acid C16H32O2 Seeds (Kim et al., 2007a; Asif, 2011; Liu et al., 2012;
Schantz et al., 2013)
70 Stearic acid C18H36O2 Seeds (Kim et al., 2007a; Asif, 2011; Liu et al., 2012;
Schantz et al., 2013)
71 Oleic acid C18H34O2 Seeds (Kim et al., 2007a; Asif, 2011; Liu et al., 2012;
Schantz et al., 2013)
72 Linoleic acid C18H32O2 Seeds (Kim et al., 2007a; Asif, 2011; Liu et al., 2012;
Schantz et al., 2013)
73 Linolenic acid C18H30O2 Seeds (Kim et al., 2007a; Asif, 2011; Liu et al., 2012;
Schantz et al., 2013)
74 Lauric acid C12H24O2 Seeds (Liu et al., 2012)
Polycosanols
75 Eicosanol C20-ol C20H42O Seeds (Adhikari et al., 2006; Jung et al., 2011;
Kim et al., 2012)
76 C21-ol to C28-ol and C30-ol Seeds (Kim et al., 2012)
Tocopherols
77 a-tocopherol C27H42O6 Frucus (Kim et al., 2012)
78 b-tocopherol C28H48O2 Frucus (Kim et al., 2012)
79 g-tocopherol C28H48O2 Frucus (Kim et al., 2012)
80 d-tocopherol C29H50O2 Frucus (Kim et al., 2012)
Phytosterols
81 Campesterol C28H48O Frucus (Kim et al., 2012)
82 Stigmasterol C29H48O Frucus (Kim et al., 2012)
83 b-sitosterol C29H50O Frucus (Kim et al., 2012)
84 b-amyrin C30H50O Frucus (Kim et al., 2012)
85 Oxalidc acid (Ogawa et al., 1984)
86 Triacylglycerols C6H8O6 Seeds (Adhikari et al., 2006)

3.6. Tocopherols and phytosterols
Four types of tocopherols (a-, b-, g- and d-tocopherol) has been
determined in P. frutescens (Kim et al., 2012). Phytosterols were also
determined in this plant and the contents of b-sitosterol and g-
tocopherol were demonstrated to definitely correlate to the content
of linolenic acid by the metabolite profiling and multivariate sta-
tistical analysis (Kim et al., 2012).
4. Phytopharmacological
An overview on the present status of pharmacological effects is
summarized in Table 2.
4.1. Anti-allergic effect
Dermatitis is a degenerative skin allergic disease and exerts a
ceaseless inflammatory skin condition (Boguniewicz and Leung,
2010). The aqueous extract from P. frutescens (PFAE) has been
demonstrated to present potential effects in treating allergic
diseases. Heo et al. (2011) evaluated the anti-allergic effects of
PFAE on 2,4-dinitrofluorobenzene (DNFB)-induced atopic
dermatitis in C57BL/6 mice. The related results indicated that
PFAE (100 mg/mL) could significantly inhibited DNFB-induced
atopic inflammation by alleviating the expression of MMP-9 and
IL-31 as well as augmenting T-bet activity. In another study, PFAE
was demonstrated to effectively suppress mast cell-mediated
immediate-type allergic reactions both in vivo and in vitro. Oral
administration of PFAE presented dose-dependently inhibitory
effects on compound 48/80-induced systemic allergic reactions
(0.05e1 g/kg, p.o.) and anti-DNP IgE-induced local allergic re-
actions (0.1e1 g/kg, p.o.) in rats (Shin et al., 2000). Recently, an
investigation by Chen et al. indicated that the ethanol extract of
P. frutescens, rather than the water extract, could significantly
suppresses the allergen-specific Th2 responses and alleviates
airway inflammation and hyperreactivity in Ovalbumin-sensitized
murine model of asthma (Chen et al., 2015).
Except for the crude extracts, much attention is being denoted
to anti-allergic substances from P. frutescens extracts. Asada et al.
reported a novel glycoprotein from the hot water extract of
P. frutescens moderately inhibited mast cell degranulation and the
activities of hyaluronidase and protein kinase C (Asada et al., 1999).
Rosmarinic acid (a phenolic compound) has been identified to be
one of the main constituents containing in P. frutescens. In a type I
allergy mice model, orally administered with rosmarinic acid
(13 mg/kg) or equaled dose of P. frutescens decoction (500 mg/kg)
presented similar effect against mice ear-passive cutaneous
anaphylaxis (PCA)-reaction which suggesting the primary contri-
bution of rosmarinic acid to the anti-allergic activity of P. frutescens
decoction (Makino et al., 2001a). Moreover, daily treatment with
rosmarinic acid in P. frutescens extract (PFE) (1.5mg/mouse, orally)
significantly abrogated the increases in the numbers of eosinophils
in bronchoalveolar lavage fluids as well as those around murine
airway in dermatophagoides farinae (Der f) sensitized mice. The
expression of IL-4 and IL-5, and eotaxin in the lungs as well as the
allergen-specific IgG1 of the sensitized mice were significantly
inhibited by rosmarinic acid in PFE (Sanbongi et al., 2004). In this
21-day, randomized, double-blind, age-matched, placebo-
controlled parallel group study, extract of P. frutescens enriched
for rosmarinic acid could be an effective intervention for patients
with mild SAR at least partly through inhibition of poly-
morphonuclear leukocytes (PMNL) infiltration into the nostrils
suggesting the use of this alternative treatment for SAR might
reduce treatment costs for allergic diseases (Takano et al., 2004).

Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17 5

Fig. 1. The chemical structures of main hydrophilic compounds identified in P. frutescens. A: phenolic compounds; B: flavonoids and C: triterpenes.

4.2. Anti-inflammatory effect examples, isoegomaketone ((E)-1-(furan-3-yl)-4-methylpent-2-

Inflammation involved an overproduction of certain
inflammation-associated gene and pro-inflammatory cytokines
(O'Neill, 2006). The P. frutescens leaf extract (PLE) was demon-
strated to significantly reduce the NO production and PGE2 secre-
tion in LPS-induced Raw 264.7 mouse macrophages via down-
regulating the mRNA expression and protein production of pro-
inflammatory mediators and inhibiting the extracellular-signal-
regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK), p38, as
well as NF-kB signaling (Huang et al., 2014). The total flavonoid of
P. frutescens was identified to reveal the significant anti-
inflammatory properties, as reported, such as reducing vascular
permeability, suppressing the production of inflammatory media-
tors, enhancing the scavenging oxygen free radicals and anti-lipid
peroxidation function (Lang and Zhang, 2010). In addition, the
fatty acids from P. frutescens seed possessed anti-inflammatory
activity by probably inhibiting inflammatory lipid mediators,
platelet activating factor (PAF) and leukotrienes (LTs) (Wang et al.,
2001). The P. frutescens fixed oil elicited a great agent for reflux
esophagitis resulted from its lipoxygenase inhibitory, histamine
antagonistic, anticholinergic and antioxidant effects (Arya et al.,
2013).
Besides, some single compounds derived from P. frutescens have
also been identified to present anti-inflammatory activities. For
en-1-one) (a perillaketone type compound) and its derivative
could inhibit the production of nitric oxide, monocyte chemo-
attractant protein-1 IL-6 by inhibiting the transcriptional activities
of NF-kB and AP-1 in LPS-induced Raw 264.7 mouse macrophage
(Park et al., 2011). Luteolin (a flavonoid compound) was demon-
strated to exert beneficial effects for neuro-inflammatory diseases
through suppressing the expression of iNOS (Kim et al., 2006). In
addition, rosmarinic acid could potently inhibit PMA, TNF-a, IL-
induced endothelial protein C receptor (EPCR) shedding by sup-
pression of TACE expression (Ku et al., 2013) and should be granted
as a good therapeutic agent for treating some inflammatory perti-
nent diseases via inhibiting the high mobility group box 1 (HMGB1)
signaling pathway (Yang et al., 2013a).
4.3. Anti-oxidative effect
Antioxidants are the substances which can scavenge free radi-
cals, reactive oxygen species (ROS) and nitric oxide (NO); and help
to decrease the incidence of oxidative stress induced damage.
Plants are the excellent source of natural antioxidants (Kasote et al.,
2015). Thus far, antioxidant activity of P. frutescens has been studied
(Ha et al., 2012a; Zhu et al., 2014) and the phenolic compounds and
flavonoids have been identified to play a pivotal role in anti-
oxidative effect of P. frutescens (Zekonis et al., 2008; Lee et al., 2013).

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6 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17

Fig. 2. The chemical structures of main hydrophobic identified in P. frutescens. A: fatty acids; B: tocopherols; and C: phytosterols.

Rosmarinic acid is one of the most potential antioxidants which
are found in several herbs in the Lamiaceae family, such as
P. frutescens. In vitro, rosmarinic acid could significantly inhibit the
adriamycin-induced apoptosis in H9c2 cardiac muscle cells by
inhibiting ROS generation and JNK and ERK activation (Kim et al.,
2005) and dose-dependently attenuate ROS production and DNA
and protein synthesis in aflatoxin B1/ochratoxin A-induced HepG2
cells (Renzulli et al., 2004). Rosmarinic acid could also inhibit the
formation of reactive oxygen and nitrogen species in LPS-
stimulated RAW264.7 macrophages (Qiao et al., 2005). In vivo,

Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17 7

Fig. 3. The chemical structures of reprehensive volatile compounds identified in P. frutescens.

rosmarinic acid was found to protect LPS-induced liver injury
induced in D-GalN-sensitized mice which was due to the scav-
enging or reducing activities-superoxide or peroxynitirite rather
than to inhibition of TNF-alpha production (Osakabe et al., 2002).
Besides, luteolin, elicited a reversion in the increased ROS pro-
duction and the decreased in activities of mitochondria, catalase
and glutathione in ROS-insulted primary neurons (Zhao et al.,
2012), whereas it merely had a slow-binding inhibition of soy-
bean lipoxygenase-1, an enzyme related to catalyzation of lipid
peroxidation (Ha et al., 2012b). Moreover, perillaldehyde (a peril-
laldehyde type compound) was found to activate the Nrf2-Keap1
system and that the lysine and arginine residues juxtaposed to the
critical cysteine residues of Keap1 are required for signal sensing
(Masutani et al., 2009).
4.4. Anticancer effect
P. frutescens has been traditionally used for treatment of cancers.
Several in vivo and in vitro study reports are available on the
possible anticancer potential of P. frutescens. In Lin's (Lin et al.,
2007) study, P. frutescens leaf extract (PLE) was found to effec-
tively influence the expression of various apoptosis-related genes
in HepG2 cells and inhibit cell proliferation in HepG2 cells. The
anti-cancer effect of PLE was observed to be better than the equaled
dose of rosmarinic acid which suggested some other potential
compounds with higher potency on anti-cancer in PLE. Particularly,
Kwak et al. (2009) provided insight into the fact that ethanol
extract of P. frutescens leaf induced apoptosis and G1 phase arrest
through the combinations of death receptor-mediated, mitochon-
drial and endoplasmic reticulum stress-induced pathway. In vivo in
a murine two-stage skin carcinogenesis model, topical application
of P. frutescens extract (2.0 mg/mouse) could markedly reduce 7,12-
dimethylbenz[a]anthracene (DMBA)-initiated and 12-
tetradecanoylphorbol 13-acetate (TPA)-promoted tumorgenesis in
mice by inhibiting the inflammatory response and scavenging the
reactive oxygen radicals. These effects of P. frutescens extract were

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edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
 Table 2
Pharmacological activities of Perilla frutescens.

8
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional

Activity Part used Extract/compound/dose Animal/Cell Model/Diseases Results Reference

lines/Bacterials

Anti-allergic and Leaves Aqueous extract (500 mg/kg) and ddY mice OVA-induced PCA reaction Significant suppression of PCA-reaction, which (Makino et al.,
anti- rosmarinic acid (19 mg/kg) partially attributed to rosmarinic acid 2003a)
inflammatory Leaves Water decoction (500 mg/kg) ddY mice OVA-induced PCA reaction Significant suppression of PCA-reaction (Makino et al.,
effects 2001a)
Seed Aqueous extract (100 mL, injected C57BL/6 mice OVA-induced asthma Significant reduction of lung weight, the (Yim et al., 2010)
subcutaneously at acupoint ST36) number of inflammatory cells in the lung and
BALF, reduction of the levels of IgE and Th2
cytokines in BALF and serum, down-regulation
of mRNA expression of Th2 cytokines in the
lung
Rosmarinic acid Endothelial cell LPS or CLP-mediated Potent inhibition of the HMGB1 release, down- (Yang et al., 2013a)
and mice release of HMGB1 and regulation of HMGB1-dependent inflammatory
HMGB1-mediated responses, inhibition of HMGB1-mediated
modulation of hyperpermeability and leukocyte migration
inflammatory responses
Isoegomaketone 3a and its Raw 264.7 cell LPS-induced inflammatory Compound 3d displays the most potent (Park et al., 2011)
derivatives 3b-3f response inhibitory activities against production of nitric

H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17

oxide, MCP-1 and IL-6; 3a- 3f inhibit the
transcriptional activities of NF-kB and AP-1
Seeds P. frutescens seed fixed oil (1, 2, and Wistar strain albino rats Pylorus and forestomach Significant inhibition of the gastric secretion, (Arya et al., 2013)
3 mL/kg) ligation induced total acidity, and esophagitis index, recovery of
esophagitis the altered levels of oxidative stress parameters
Leaves 1.0% (w/v) citric acid aqueous Patients Seasonal allergic Effective intervention for mild SAR at least (Takano et al.,
extract (200 mg/day or 50 mg/day) rhinoconjunctivitis (SAR) partly through inhibition of polymorphonuclear 2004)
leukocytesinfiltration into the nostrils
Leaves Aqueous extract and Luteolin (1 ICR mice AA-, TPA- and oxazolone- Suppression of TNF-a production both in vitro (Ueda et al., 2002)
mg/mouse) induced ear edema and in vivo, and inhibition of inflammation and
allergic response in mice; which partially
attributed to luteolin
Leaves Luteolin from alcoholic extract BV-2 microglial cells LPS-stimulated NO Inhibition of NO production; suppression of I- (Kim et al., 2006)
(IC50 ¼ 6.9 mM) production and iNOS kB-a degradation and protein/mRNA expression
expression of iNOS
Leaves 30% ethanol extract, rosmarinic acid Mice; human mast cells OVA-induced allergic Amelioration of allergic rhinitis and allergic (Oh et al., 2011)
rhinitis and rhinoconjunctivitis both in vitro and in vivo.
rhinocojunctivitis In vivo: decrease of OVA-induced number of
rubs; serum levels of IgE and histamine; protein
levels and mRNA expressions of interleukin
(IL)-1b, IL-6 and tumor necrosis factor (TNF)-a
in the nasal mucosa tissue or spleen; mast cell
and eosinophil infiltration; cyclooxygenase-2
protein expression and caspase-1 activity in the
same nasal mucosa tissue.
In vitro: decrease of NF-kB/Rel A and caspase-1
activation.
Leaves Aqueous extracts (0.01 g/kg) SD rats, Rat peritoneal Compound 48/80 or anti- Dose-dependently against mast cell-mediated (Shin et al., 2000)
mast cell DNP IgE-induced allergic immediate-type allergic reactions in vitro and
reaction in vivo
Leaves Glycoprotein from the hot water Rat peritoneal mast cell Antigen (DNP-BSA, 200 ng/ Inhibition of mast cell degranulation, and (Asada et al., 1999)
extract (IC50 ¼ 0.42 mg/mL) mL) and hyaluronidase activity
phosphatidylserine
(10 mg/mL) induced
histamine release
Leaves Methanol extract (5e50 mg/mL) Nontumorigenic human Mite major allergen Der p2 Significant suppression of mRNA expression (Liu et al., 2013b)
bronchial epithelial (DP2)-induced gene and protein levels of pro-allergic and pro-
cells BEAS-2B expression of pro-allergic inflammatory cytokines in DP2-stimulated
and pro-inflammatory BEAS-2B cells through inhibition of P38/JNK and
cytokines NK-kB activation
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
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Rosmarinic acid (cell: 0e2 mM;
mouse: 1.4 mg/mouse/12 h)
Rosmarinic acid (1.5 mg/mouse/
day)
Leaves Nine triterpene acids from ethanol
extract:
ursolic acid, corosolic acid, 3-
epicorosolic acid, pomolic acid,
tormentic acid, hyptadienic acid,
oleanolic acid, augustic acid and 3-
epimaslinic acid (ID50 ¼ 0.09e0.3
mg/ear)
Leaves Aqueous extract (400mL/mouse)
Leaves Aqueous extract (200mL/mouse)
Leaves Aqueous extract
Leaves Aqueous extract
Seeds P. frutescens oil
Leaves Aqueous decoction (50 and 500 mg
dried decoction/kg/day);
rosmarinic acid from the
methanolic extract (50 mg/kg/day)
Leaves Aqueous decoction (100 and
500 mg/kg/d, oral)
P. frutescens extract
HUVECs, C57BL/6 mice PMA, TNF-a, IL-1b and CLP-
mediated EPCR shedding in
HUVECs; CLP-induced
septic mice
C3H/He mice Dermatophagoides farinae
(Der f)-induced allergic
asthma
Raji cells, ICR mice TPA-induced ear edema
inflammationin mice, TPA-
induced EBV-EA activation
in Raji cells, and
two-stage carcinogenesis
test on mouse skin
papillomas
ICR mice AA-, TPA-induced ear
edema
C3H/He mice (Muramyl dipeptide and
OK-432)-induced serum
TNF-a production
Murine vascular smooth
muscle cells (VSMC)
Murine mesangial cells Cytokine-induced
mesangial cell proliferation
and NO production
IgA ddY mice
ddY mice IgA nephropathy in high
serum IgA (HIGA) mice
Wistar rats Rabbit anti-rat thymocyte
serum (ATS)-induced
mesangioproliferative
glomerulonephritis
ddY mice
Inhibition of PMA, TNF-a, IL-1b induced EPCR (Ku et al., 2013)
shedding via suppressing TACE expression, and
reduction of PMA-stimulated p-38, ERK1/2 and
JNK phosphorylation
Effective intervention for allergic asthma, (Sanbongi et al.,
possibly through the amelioration of increases 2004)
in cytokines, chemokines, and allergen-specific
antibody
Marked inhibition of TPA-induced ear edma (all (Banno et al., 2004)
componets); inhibition of TPA-induced EBV-E)
activation (ursolic acid, corosolic acid, 3-
epicorosolic acid, tormentic acid, 3-epimaslinic
acid); strong antitumor-promoting activity in
two-stage carcinogenesis test of mouse tumor
(tormentic acid)
Inhibition of AA- or TPA-induced ear edma (Ueda and
(anti-inflammation); inhibition of oxazolone- Yamazaki, 2001)
induced ear edema (anti-allergy)
H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17
Inhibitory activity against TNF-a production (Ueda and
Yamazaki, 1997)
Synergistical augments of INF-g- or TNF-a- (Makino et al.,
induced NO release; significant inhibition of 2002b)
(INF-g þ LPS)-induced NO release; significant
inhibition of platelet derived growth factor
(PDGF) or TNF-alpha-induced VSMC
proliferation.
Inhibition of cytokine-induced mesangial cell (Makino et al.,
proliferation, partially through the induction of 1999a)
NO production.
P. frutescens oil decreases the blood urea (Sakurai et al.,
nitrogen level and urinary protein excretion, 2011)
suppresses the expansion of mesangial matrix
and the expression of glomerular transforming
growth factor-b1 mRNA.
Both P. frutescens extract and rosmarinic acid (Makino et al.,
decrease the proteinuria, serum IgA levels and 2003b)
glomerular IgA depositions in HIGA mice;
P. frutescens extract but not rosmarinic acid
suppresses the IgG depositions in HIGA mice.
Both P. frutescens extract and rosmarinic acid
suppresses the IgA production by spleen cells
from drug-treated mice; P. frutescens extract but
not rosmarinic acid suppresses the IgA
production by Peyer's patches cells from drug-
treated mice.
Suppression of mesangial cells proliferation (Makino et al.,
in vivo by inhibiting the glomerular infiltration 2001c)
of macrophage/monocytes and the production
of circulating growth factors
Prevention of IgA nephropathyby by (Makino et al.,
suppressing proteinuria and glomerular IgA 1999b)
deposition, serum IgA concentration, and
increasing the serum level of NO; inhibition of
(continued on next page)
9
 Table 2 (continued )

10
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
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Activity Part used Extract/compound/dose Animal/Cell Model/Diseases Results Reference

lines/Bacterials

mesangial cell proliferation by regulating

Leaves Rosmaninic acid from methanolic
extract (100 mg/kg/day, oral)
Wistar rats Rabbit anti-rat thymocyte
serum (ATS)-induced
mesangioproliferative
glomerulonephritis
circulating cytokines.
Anti-oxidative and fibrinolytic activities; (Makino et al.,
suppression of mesangial cell proliferation and 2002a)
glomerular matrix expansion.

Antioxidative Leaves 1,2-di-O-a-linolenoyl-3-O-b- HL-60 cell TPA-induced O

2 generation Dose-dependent inhibition of O
2 generation (Takahashi et al.,
effects galactosyl-sn-glycerol (DLGG) 2011)
(IC50 ¼ 21 mM)
Leaves Aqueous extract (in vitro: HUVECs, healthy female Azo-radical-induced LDL High antioxidant activity and prevention the (Saita et al., 2012)
IC50 ¼ 7.9 mg/mL; in vivo: 1000 mg volunteers oxidation and endothelial- oxidation of LDL
polyphenols/120 mL extract/ cell-mediated LDL
person) oxidation
Rosmarinic acid (50 mM) HepG2 cells Aflatoxin B1 and ochratoxin Dose-dependent attenuation of OTA- and AFB1- (Renzulli et al.,
A - induced cell damage induced ROS production and DNA/protein 2004)
synthesis inhibition; prevention of apoptosis

H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17

Fragrant unsaturated aldehydes,
perillaldehyde from essential oil of
P. frutescens (0e300 mM)
Seeds Luteolin from the ethanol extract (5
e20 mM)
Rosmarinic acid (20 mg/mL)
Rosmarinic acid (10e50 mM)
Leaves 20 ,3’-dihydroxy-40 ,6’-
dimethoxychalcone from ether
extract (30 mM)
Leaves (Z,E)-2-(3,4-dihydroxyphenyl)
ethenyl ester (IC50 ¼ 0.021 mg/mL),
and (Z,E)-2-(3,5-dihydroxyphenyl)
ethenyl ester (IC50 ¼ 0.124 mg/mL)
Seeds 5-(3, 4-dihydroxyphenylmethyl)
oxazolidine-2, 4-dione, and 3-(3, 4-
dihydroxyphenyl)lactamide
Leaves Polyphenols from the aqueous
extract
Seeds 80% methanol extract (50 mg/mL)
Leaves Aqueous extract (32 mg/mL)
Leaves P. frutescens powder (5 g/day,
equaled to 5 mg lutein/day)
K562 cells, RGM-1 cells, H2O2-induced cytotoxicity
293 cells
Primary neurons from H2O2-induced cytotoxicity
newborn rat cortex
H9c2 cardiac muscle cells Adriamycin-induced
apoptosis
RAW 264.7 cells PMA-induced superoxide
production, LPS-induced
NO production, and
Peroxynitrite-induced 3-
nitrotyrosine formation
Rat adrenal 6-hydroxydopamine-
pheochromocytoma induced cytotoxicity and
PC12 cells intracellular ROS formation
N/A N/A
N/A Ferruc thiocyanate method,
and 1,1-diphenyl-2-picryl-
hydrazyl (DPPH) methods
N/A 1,1-diphenyl-2-
picrylhydrazyl (DPPH)
method
N/A DPPH and ABTS radical
scavenging method
Neutrophil leukocytes from ROS generation in
patients with acute oral nonopsonized Escherichia
inflammatory disorders coli-stimulated neutrophil
leukocytes
Human volunteers N/A
cell death by reduction of DNA fragmentation
and inhibition of caspase-3 activation
Novel thioredoxin inducers and ARE activators, (Masutani et al.,
protection against oxidative stresseinduced 2009)
cellular damage
Dose-dependent attenuating the increase in (Zhao et al., 2012)
ROS production and preventing the decreases in
activities of mitochondria, catalase, and
glutathione in ROS-insulted primary neurons
Inhibition of adriamycin-induced apoptosis by (Kim et al., 2005)
inhibiting ROS generation and JNK and ERK
activation
Inhibition of LPS-induced NO production and (Qiao et al., 2005)
iNOS protein synthesis; suppression of PMA-
induced superoxide production; inhibition of
peroxynitrite-induced 3-nitrotyrosine
formation
Enhancement of cellular resistance to oxidative (Izumi et al., 2012)
damage through activation of the Nrf2-ARE
pathway
Potent inhibitors of xanthine oxidase (Nakanishi et al.,
1990)
Potent antioxidant activity and free radical (Nagatsu et al.,
scavenging activity 1995)
High activity on scavenging of DPPH free radical (Meng et al., 2009)
Potent antioxidant activities against DPPH and (Lee et al., 2013)
ABTS radicals
Significant inhibition of free radical production (Zekonis et al.,
by neutrophil leukocytes 2008)
Decrease in lipid peroxidation, and without (Schirrmacher
influence on antioxidative capacity of plasma et al., 2010)
 Leaves Rosmarinic acid (135 mg/kg);
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
rosmarinic acid-riched fraction
from the acid aqueous extracts with
1.0% w/v citric acid (200 mg/kg,
equaled to 135 mg/kg of rosmarinic
acid)
Seeds Luteolin (IC50 ¼ 5.0 mM)
Anticancer effects Leaves Aqueous extract (IC50 ¼ 8.8 mg/mL),
rosmarinic acid
Leaves Aqueous extract (Topical: 1 mg/
mouse, twice/week; oral: 0.5% in
drinking water, 7.8 mL/mouse/day),
luteolin (Topical: 1 mg/mouse)
Leaves Isoegomaketone from methanol
extract (1e100 nM for cells, and 2
mmol/mouse/day)
Leaves Aqueous extract (105 mg/mL)
Leaves Fractions from the acetone/extract
(7:3) extract (IC50 values, 3.3 mg/mL
for PDGF-induced model, 1.4 mg/mL
for TNF-a-induced model
Isoegomaketone from the methanol
extract (50 mM)
Leaves Ethanol extract (1000 mg/mL)
Antibacterial effects Leaves Ethanol extract
Leaves Ethanol extract
Seeds Phenolic compounds (eg. Luteolin)
from 70% ethanol extract
Essential oil
Antidepressive Rosmarinic acid (1.0, 2.0 or 4.0 mg/
effects kg/bw, i.p.)
Leaves Fractions from the aqueous extract,
rosmarinic acid
Leaves Methanol extract (2.0 g/kg) and
Dillapiol from the methanol extract
(0e100 mg/kg)
Leaves Perillaldehyde- and stigmasterol-
riched fraction from methanol
extract (equaled to [2000 mg
methanol extract]/kg)
Rosmarinic acid(2 mg/kg) and
caffeic acid(4 mg/kg)
Rosmarinic acid and caffeic acid
Balb/c mice LPS-induced liver injury in Liver protection of RA by the scavenging or (Osakabe et al.,
D-GalN-sensitized mice reducing activities-superoxide or peroxynitirite 2002)
rather than to inhibition of TNF-a production
N/A Soybean lipoxygenase-1(EC Slow-Binding Inhibition of Soybean (Ha et al., 2012b)
1.13.11.12,type1)-catalyzed Lipoxygenase-1
peroxidation of linoleic acid
Murine mesangial cell 1% fetal calf serum-induced Significant inhibition on DNA synthesis and cell (Makino et al.,
DNA synthesis and cell proliferation in Murine mesangial cells 2001b)
proliferation
ICR mice DMBA/TPA-induced skin Potent prevention of skin-tumor promotion (Ueda et al., 2003)
carcinogenesis
Huh-7 and Hep3B cells; Huh-7-xenografted nude Significant inhibition of HCC tumor growth via (Wang et al.,
BALB/c nude mice mouse blocking PI3K/Akt signaling pathway 2013b)
HepG2 cells N/A Inhibition of HepG2 cell proliferation and (Lin et al., 2007)
H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17
induction of the cell apoptosis
Murine cultured PDGF- or TNF-a- stimulated Anti-proliferative activity (Makino et al.,
mesangial cells proliferation 1998)
Human colon cancer N/A Induction of apoptosis through caspase- (Cho et al., 2011)
DLD1 cells dependent and capase-independent pathways
Human leukemia N/A Induction of apoptosis and G1 phase arrest (Kwak et al., 2009)
HL-60 cells through the combinations of death receptor-
mediated, mitochondrial, and endoplasmic
reticulum stress-induced pathways
Pseudomonas aeruginosa Evolutionary operation- Decrease in the population of P. aeruginosa (Choi et al., 2010)
factorial design technique
Staphylococcus aureus Evolutionary operation- Decrease in the population of S. aureus (Kim et al., 2011)
ATCC6538 factorial design technique
Porphyromonas gingivalis N/A Strong antimicrobial activity (Yamamoto and
Ogawa, 2002)
Staphylococcus aureus ATCC N/A Decrease in the production of a-toxin, SEA, SEB (Qiu et al., 2011)
29213 and TSST-1 in S. aureus
ddY mice Forced swimming test and Dose-dependent antidepressant-like effect at (Ito et al., 2008b)
open field test least in part via the proliferation of newborn
cells in the dentate gyrus of the hippocampus
mice Forced swimming test Significant reduction of the duration of (Takeda et al.,
immobility in mouse forced-swimming test 2002b)
mice Hexobarbital-induced sleep Prolongation of the sleep time (Honda et al., 1988)
ddY mice Prolongation of Prolongation of the sleep time (Honda et al., 1986)
hexobarbital-induced sleep
ICR mice Forced swimming test Production of antidepressive-like activity via (Takeda et al.,
some mechanism(s) other than the inhibition of 2002a)
monoamine transporters and monoamine
oxidase.
ddY mice The conditioned fear stress Inhibition of the emotional abnormality (Takeda et al.,
paradigm produced by stress. 2002c)
(continued on next page)
11
 Table 2 (continued )

12
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional

Activity Part used Extract/compound/dose Animal/Cell Model/Diseases Results Reference

lines/Bacterials

l-Perillaldehyde (PAH, 0.0965 and ddY mice Stress-induced depression- Inhalation of PAH shows antidepressant-like (Ito et al., 2011)
0.965 mg/mouse/day, inhalation) like model activity through the olfactory nervous function.
Apigenin ddY mice Forced swimming test Apigenin presents antidepressant properties via (Nakazawa et al.,
the dopaminergic-mediated mechanisms in 2003)
mouse brain.
PAH (60 and 120 mg/kg, ICR mice LPS-induced depression- PAH exhibits significant antidepressant-like (Ji et al., 2014b)
intragastrically) like behavior effects in LPS-induced depression mice which
might be related to the alteration of
monoaminergic responses and the anti-
inflammatory effects.
Leaves Essential oil ICR mice Chronic unpredictable mild Restore of the CUMS-induced decreased sucrose (Yi et al., 2013)
stress (CUMC) preference and increase of immobility time,
without affecting body weight gain and
locomotor activity.

Anti-cough Luteolin Hartley guinea pig Histamine-, carbachol-, and Relax of the precontractions and contractions of (Ko et al., 2005)
KCl-induced guinea-pig trachea by inhibiting on both PDE

H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17

precontractions; and
cumulative histamine-, and
carbachol-induced
contractions using isolated
guinea-pig trachea
Natural isoegomaketone and HEK293 cells rTRPA1 over-expressed
synthetic derivatives of HEK293 cells
perillaketone
Leaves Perillaldehyde (commercial) and HEK293 cells rTRPA1 over-expressed
perillaketone (isolated from the HEK293 cells; rTRPM8
leaves) over-expressed
HEK293 cells
activities and its reduction on [Ca2þ]i of the
trachealis.
Isoegomaketone and some perillaketone (Bassoli et al., 2013)
derivatives as highly potent agonists of TRPA1
channel.
Activation of TRPA1 receptor; slight inhibition (Bassoli et al., 2009)
of
TRPM8 response to icilin.

Other Leaves Water extract and Vicenin 2 Isolated rat proximal ileum Acetylcholine or Ba2þ Decrease of acetylcholine- or Ba2þ-induced (Verspohl et al.,
pharmacological -induced contraction contraction for rat ileum. 2013)
activities Seeds Apigenin from methanolic C57BL/6J mice; Mouse N29-2 Pro-opiomelanocortin Improve appetite: Up-regulation of pPOMC-Luc (Myoung et al.,
extract(in vivo: 10 mg/kg, i.p.; hypothalamic cells and human (POMC) and “cocaine and and pCART-Luc in cells; suppression of short- 2010)
in vitro: EC50 of 0.93 mM for POMC neuroblastoma SHSY5Y cells amphetamine-related term food intake in mice
and 0.67 mM for CART) transcript” (CART)
promoter-driven luciferase
plasmids-transfected N29-
2 and SHSY5Y cells
Aerial Methanolic extract B16 melanoma cells N/A Anti-melanogenesis by inhibiting tyrosinase (Hwang and Lee,
activity, L-DOPA auto-oxidation and melanin 2007)
synthesis
Leaves Acetone, ethanol, 70% ethanol and HTLV-I-infected cell line MT-4; LAV-1 and HTLV-IIIB strains Aqueous extract with higher potency on (Yamasaki et al.,
aqueous extracts human leukemic T-cell line of HIV-1 inhibiting giant cell formation in co-culture of 1998)
Molt-4 Molt-4 cells with/without HIV-1 infection, and
higher activity against HIV-1 reverse
transcriptase.
Leaves Glycoprotein from aqueous extracts Human leukemic T cell lines HIV-1 induced cytopathic Effective inhibition of HIV-1-induced CPE, giant (Kawahata et al.,
MT-4 and Molt-4 effect cell (syncytium) formation, and reverse 2002)
transcription at the early stage of HIV-1
replication
Seeds Omega-3-fatty acids enriched seed Dunkey Hartley guinea pigs Nitrosative stress Improvement on the vulnerability of brain cells (Eckert et al., 2010)
oil (oral, 0.5 g/kg and 1.0 g/kg b.w.) from nitrosative stress via decreasing the levels
of reactive oxygen species, stabilizing the
mitochondrial membrane potential and
enhancing the levels of adenosine-
triphosphate.
 Seeds Luteolin from the ethanol extract
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
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Rosmarinic acid
Leaves Luteolin (IC50 of 0.5 mM) and
rosmarinic acid (IC50 of 21 mM) from
methanolic extract
P. frutescens oil
Seeds luteolin and apigenin from
ethanolic extract
Leaves Aqueous extract (in vitro: EC50 of
407 mg DM/mLfor DPPH scavenging,
EC50 of 2.32 mmol FeSO4$7H2O/g
DM for Ferric-reducing antioxidant
power; in vivo: 1000 or 3000 mg/kg,
oral)
Leaves Aqueous extract (1000 mg/kg/day,
oral), caffeic acid (1.32 mg/kg/day,
oral) and rosmarinic acid
(26.84 mg/kg/day, oral)
Leaves Polysaccharide from aqueous
extract
P. frutescens extract (100 mg/kg,
oral)
Perillaldehyde (0.01e1 mM)
Leaves Perillaketone from methanolic
extract
SD rat
MES23.5 dopaminergic cells
SD rats
Monoamine-transporter
transgenic Chinese hamster
ovary (CHO) cells, wild
dopaminergic cell lines
SD rat; isolated rat's
hepatocytes
SD rats; Human hepatoma
HepG2 cells
ICR mice; L929 cell line and
peritoneal exudate cells from
ICR mice
Isolated myocardial
preparations from Chinchilla
rabbits
Isolated aorta from Wistar rats
ddY mice
Ischemia-reperfusion
injury in a rat middle
cerebral artery occlusion
model
6-
Hydroxydopamine(OHDA)-
induced neurotoxicity
N/A
T-maze tests
N/A
In vitro: Antioxidants: DPPH
free radical-scavenging,
Ferric-reducing antioxidant
power; t-BHP-induced
hepatotoxicity in
hepatocytes
In vivo: tert-butyl
ydroperoxide-induced
oxidative hepatotoxicity
t-BHP-induced oxidative
liver injury
N/A
Myocardial contractility
Prostaglandin F2a or
norepinephrin-induced rat
aorta contractions
N/A
Preventing behavioral and histological injuries; (Zhao et al., 2011)
lowering the increased level of mitochondrial
ROS and substantially up-regulating the
decreased activity of catalase and glutathione in
I/R rat brains.
Increase the MES23.5 dopaminergic cells (Ren et al., 2009)
viability by partially reversing the 6-OHDA
induced intracellular reactive oxygen species
generation and decreased the mitochondria
membrane potential.
Non-competitive and specific b-secretase (Choi et al., 2008)
inhibitors
Improvement on the cognitive function by (Lee et al., 2012)
differential expression of the cognitive-related
proteins in hippocampus; improvement on
learning and memory by particularly enhancing
the immunoreactivities in the hilus of dentate
gyrus.
Potential monoamine transporter activators for (Zhao et al., 2010)
improvement of hypermonoaminergic
H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17
neuropsychological disorders.
Effective activities on ferric-reducing (Kim et al., 2007b)
antioxidant power and free radical scavenging;
Effective protection on hepatocytes from tert-
butyl hydroperoxide-induced oxidative
hepatotoxicity both in vitro and in vivo.
The aqueous extract is more effective on liver (Yang et al., 2013b)
protection than CA and RA by increasing the
endogenous antioxidant enzymes and
glutathione and decreasing the lipid
peroxidation in livers; CA plays a role in the
increased hepatic GSH concentration and
provides additive hepatoprotection with RA
against oxidative liver damage.
Immunopotentiator and biological response (Kwon et al., 2002)
modifier by stimulating NO and TNF-a release
in vitro and IL-6 and GMCSF production in vivo.
Enhancements on the contractility of (Korotkich et al.,
myocardium by increasing the force of the 2006)
isometric contraction, velocity of force
development and velocity of relaxation for
atrial and ventricular.
Potential Ca2þ channel blocker, vasodilation of (Takagi et al., 2005)
rat aorta via blocking the Ca2þ channels
Promotion of intestinal propulsion, by (Koezuka et al.,
stimulating of the motility of circular muscles of 1985)
the intestine
13
14 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17
comparative to those of equaled dose of rosmarinic acid (1.35 mg/
mouse) (Osakabe et al., 2004). Recently, isoegomaketone, an
essential compound isolated from P. frutescens, was identified to be
another potential compound with anti-cancer activity. Iso-
egomaketone was found to dose-dependently trigger cleavage of
Poly (ADP-ribose) polymerase (PARP) in Human colon adenocarci-
noma DLD-1 cells and induce cell apoptosis through caspase-
dependent and capase-independent pathways (Cho et al., 2011).
In Wang's study, isoegomaketone was observed to suppress in vitro
Huh-7 hepatoma cell carcinoma-derived cell growth and in vivo
tumorigenicity in tumor-xenografted nude mice via blocking PI3K/
Akt signaling pathway (Wang et al., 2013b).
4.5. Antibacterial effect
Essential oils derived from plants have been recognized to
exhibit antimicrobial activities intensively explored in recent years
(Kuorwel et al., 2011; Solo rzano-Santos and Miranda-Novales,
2012; Seow et al., 2013). The antimicrobial activity of P. frutescens
essential oils on bacteria and fungi has been widely investigated by
many researchers. Exposure under vapor of P. frutescens essential
oils in a closed box, the growth of trichophyton mentagrophytes
was observed to be effectively inhibited (Inouye et al., 2006). In
addition, P. frutescens oil also dose-dependently decreased the
production of a-toxin, enterotoxins A and B (the major staphylo-
coccal enterotoxins), and toxic shock syndrome toxin 1 (TSST-1) in
Staphylococcus aureus suggesting P. frutescens oil may be useful for
the treatment of S. aureus infections when used in combination
with b-lactam antibiotics (Qiu et al., 2011). Furthermore,
P. frutescens oil could be rationally applied in food systems as a
novel food preservative both to inhibit the growth of S. aureus and
to repress the production of exotoxins, particularly staphylococcal
enterotoxins.
4.6. Antidepressant effect
Recent epidemiological surveys conducted in general pop-
ulations have found that the lifetime prevalence of depression is in
the range of 10%e15%. Unipolar depressive disorder may become
one of the major leading causes of disease burden by 2030 ac-
cording to the World Health Organization (WHO) (Le pine and
Briley, 2011). Thus, the discovery of antidepressive foods is attrac-
tive and could have considerable impacts worldwide. In various
studies, the extracts and/or purified compounds of P. frutescens
have been demonstrated to present antidepressant-like effects. Fed
with P. frutescens seed oil-rich diet was found to improve the
depressant-like behaviors in rats through modulating fatty acid
profiles and BDNF expression in the brain (Lee et al., 2014) and
inhalation of perillaldehyde was found to exhibit antidepressant-
like activity through the olfactory nervous function in mice (Ito
et al., 2011) during the force swimming test (FST). Daily adminis-
tration of perillaldehyde (20 mg/kg, oral) exhibited significant
antidepressant-like effects in mice with LPS-induced depression (Ji
et al., 2014b). In addition, both P. frutescens essential oil and peril-
laldehyde were found to exhibit significant antidepressant-like
effects in mice with CUMS-induced depression (Yi et al., 2013; Ji
et al., 2014a). Moreover, apigenin and 2,4,5-trimethoxycinnamic
acid (Nakazawa et al., 2003), rosmarinic acid and it metabolites
caffeic acid (Takeda et al., 2002a; Nakazawa et al., 2003; Ito et al.,
2008b) also showed decent antidepressant-like effects in
different animal models.
4.7. Other pharmacological activities
Except for the above-mentioned biological activities, other
Please cite this article in press as: Yu, H., et al., Phytochemical and phytopharmacological review of Perilla frutescens L. (Labiatae), a traditional
edible-medicinal herb in China, Food and Chemical Toxicology (2016), http://dx.doi.org/10.1016/j.fct.2016.11.023
pharmacological activities of P. frutescens as well as P. frutescens-
derived compounds are also summarized in Table 2. The neuro-
protection of P. frutescens-derived omega-3-fatty acids (Eckert et al.,
2010) and luteolin (Zhao et al., 2011) as well as the improvement of
cognitive function by P. frutescens oils (Lee et al., 2012) were iden-
tified by in vivo examinations. P. frutescens oil could ameliorate lung
function in asthma by regulating eicosanoid production and inhib-
iting LT generation (Deng et al., 2007). Luteolin, a flavonoid derived
from P. frutescens, was found to concentration-dependently relax
histamine-, carbachol- and KCl-induced precontractions, and
inhibited cumulative histamine- and carbachol-induced contrac-
tions in a non-competitive manner (Ko et al., 2005). The antispas-
modic effects of P. frutescens extract and P. frutescens-derived
Vicenin-2 were investigated for the treatment of gastrointestinal
discomfort (Verspohl et al., 2013). More recently, a research group
from Italy provided compelling evidence that perillaldehyde and
perillaketone (a perillaketone type compound), aromatic extract
from P. frutescens, were shown activation on transient receptor po-
tential 1 channel, which was involved in nociception and in sensory
perception of many pungent compounds (Bassoli et al., 2009, 2013).
5. Toxicity
Only few studies have addressed the toxic potential of
P. frutescens. P. frutescens has been associated with atypical intersti-
tial pneumonia for a quarter of a century. Acute pulmonary
emphysema was observed for P. frutescens in bovine (Linnabary et al.,
1978) and perilla ketone was identified to be a potent pulmonary
edemagenic agent for laboratory animals and livestock (Wilson et al.,
1977; Guerry-Force et al., 1988; Snapper et al., 1985). The highest
accumulation of perilla ketone was found in flower or seed parts of
this plant (Kerr et al., 1986). The acute toxicity of P. frutescens
essential oil was studied in mice and with the LD50 value of 3.0 g
herb/kg after an intragastric administration (Wen, 2006). Although
perillyl alcohol was identified to be an non-toxic compound, its
active metabolites of perillaldehyde and perillic acid were observed
to present higher toxicity both in vitro and in vivo (Boon et al., 2000).
The toxicities of P. frutescens in human are also noticed and reported.
Occupational contact dermatitis is a very well-known disease in
Japan to those people who contact with P. frutescens (Kanzaki and
Kimura, 1992). In addition, anaphylaxis caused by P. frutescens
seeds (Jeong et al., 2006) and occupational asthma caused by
inhaling smoke from roasting P. frutescens seeds (Jung et al., 2013)
with IgE-mediated mechanism were reported in Korea.
6. Perspectives
In practice, the leaves, stems and seeds of P. frutescens are used
as three different Chinese medicines with different therapeutic
functions. Although these parts come from the same plant, they are
differentially prescribed by the TCM practitioners for different
therapeutic purposes. The leaves are used for relieving exterior
syndrome and cold-dispelling, promoting the circulation of Qi and
harmonizing the stomach; the stems are used for promoting the
circulation of Qi, relieving the pain and miscarriage prevention; as
well as the seeds are mainly used for descending Qi and resolving
phlegm, relieving cough and asthma, loosening bowel to relieve
constipation. Therefore, distinguishing the usages of different parts
of P. frutescens should be carefully considered.
Recent pharmacological studies demonstrated various biolog-
ical and pharmacological activities to P. frutescens. The findings of
anti-allergic, anti-inflammatory and anti-oxidative activities of
P. frutescens validate its well-known traditional and ethno-
pharmacological uses in the treatment of respiratory diseases.
However, current studies are insufficient to establish P. frutescens as
 H. Yu et al. / Food and Chemical Toxicology xxx (2016) 1e17
authentic antimicrobial and anticancer agents. Hence, further in-
depth studies regarding possible synergy, antagonism and poten-
tial against multi drug-resistant human pathogen is essential.
Moreover, stems of P. frutescens have showed potent and wide
range of biological and pharmacological activities whereas the
available literature reports are insufficient to establish the exact
medicinal value of parts. Further detail phytochemical and phar-
macological studies for P. frutescens stems should be warranted.
Although the three parts of P. frutescens are differentially pre-
scribed by the TCM practitioners, the distinctions of such parts in
phytochemistry and pharmacology are still not clear and need be
further demonstrated and elucidated. In recent years, the plant of
P. frutescens is becoming widely used in food preparations, such as
cookies or cakes. Since the data for toxicity and pharmacokinetics of
this plant are insufficient, further investigations on the pharma-
cokinetic and toxicological properties for P. frutescens should be
more considered in future. Moreover, establishment on the efficient
assay methods for the qualitative and qualitative determinations of
the P. frutescen-derived compounds or metabolites should be more
considered to ensure the safety for the further development and
utilization of P. frutescens.
With a rising attention of this plant in recently years, distinct
species of P. frutescens across the globe have been investigated for
their phytochemistry and pharmacology. Owing to the fact that this
plant possesses a variety of variants, it will renew our knowledge of
this plant. From what have been discussed above, the collected
information reviewed here exert as a resource for future studies
and medicinal exploitations of P. frutescens.
Acknowledgements
This study was financially supported by the grants from the
Research Committee of the University of Macau (MYRG123-
ICMS12-WJB and MYRG111-ICMS13-WJB), and from Macao Sci-
ence and Technology Development Fund (010/2013/A1 to JB Wan);
and the National Natural Science Foundation of China (NSFC, No.
81470170).
Transparency document
Transparency document related to this article can be found
online at http://dx.doi.org/10.1016/j.fct.2016.11.023.
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