Curr Opin Complement Alternat Med 1:1, 8-11; January/February 2014; © 2014 STM Publishing
Advances in Pharmacological Research of
Eugenol
Xiaojun KONG, Xiwang LIU, Jianyong LI, Yajun YANG
Key Laboratory of Veterinary Pharmaceutical Development, Ministry of Agriculture/Key Laboratory of New Animal Drug Project, Gansu Province, Lanzhou
Institute of Husbandry and Pharmaceutical Sciences of CAAS, Lanzhou 730050, China
Summary
Eugenol, a main constituent of clove oil, is an organic phenol with antipyretic, analgesic, anti-inflammatory, and anesthetic effects.
Pharmacological studies showed that eugenol also has antibacterial, antifungal, antioxidant, anticancer, and insect repellent
activities. Given its minimal side effects, low toxicity, and non-metabolized residue, eugenol is widely accepted in many fields such as
pharmaceuticals and cosmetics. Further elucidation of the functional groups, action sites, and action model of eugenol, along with the
establishment of related database, is expected to widen the applications of eugenol. This paper briefly reviews the pharmacological
effects of eugenol.
Curr Opin Complement Alternat Med 2014; 1:8-11
Key words
eugenol; pharmacological; analgesic; antibacterial
Eugenol (4-allyl-2-methoxyphenol), with a molecular formula
of C10H12O2 and a molecular weight of 164.21, mainly exists
in clove oil, camphorated oil, cinnamon leaf oil, and nutmeg
oil. In normal temperatures, eugenol is a pale yellow viscous
oily liquid with a strong clove flavor and a special hot taste.
Eugenol is slightly soluble in water and easily dissolved in organic
solvents. Eugenol is widely applied in dentistry, anesthetics,
analgesics, anti-inflammatory agents,1 and flavoring agents.
In recent years, the pharmacodynamics of eugenol has been
developed to immunological function, central nervous regulation,
reproductive effects, cardiovascular system, digestive system,
blood biochemistry,2 and urinary system.
Pharmacological action of eugenol
Abirritation
Low doses of eugenol can inhibit the activity of peripheral nerves
and has local analgesic and anesthetic effects. However, high
doses of eugenol can cause coma. Studies found that eugenol can
significantly inhibit the generation of prostaglandin E2 (PGE2).3 Exogenous prostaglandin (PG) can cause pain response or
improve the sensitivity of a model organism to the sense of touch.
Prostaglandin E1 (PGE-1) and PGE-2 in exogenous PG have
stronger effects than in other types of PG. Eugenol elicits analgesic
activity by inhibiting PGE-2 generation.
Correspondence to: Jianyong LI, Lanzhou Institute of Husbandry and
Pharmaceutical Sciences of CAAS (Chinese Academy of Agricultural Sciences),
Lanzhou 730050, China; Email: lijy1971@163.com
Submitted: 09/06/2013; Revised: 19/07/2013; Accepted: 01/08/2013
DOI: 10.7178/cocam.7
8
Yang et al.4 used eugenol as a compound nanoemulsion
transdermal agent and observed wriggle frequency of mouse after
injection of chemical irritants and hot plate-induced pain model,
respectively. They found that compound nanoemulsion can
reduce wriggle frequency of mouse and that the inhibitory rates
to the chemical irritant pain are 37.9% and 60.5%, respectively,
whereas the effective rates to the hot plate-induced pain model
are 54.4% and 96.5%, respectively. Obvious differences were
observed among compound nanoemulsion, ordinary mixture, and
positive control. Its active ingredient, eugenol, can increase the
pain threshold of mouse model and has a clear analgesic function.
In the study of Kurian et al.5 on the analgesic activity of eugenol,
the efficiency of eugenol on induced pain mouse model in the
inflammatory stage is better than that in the neurological stage.
Guenette et al.6 also found that 40 mg/kg eugenol can extend the
response time of Sprague-Dawley mice to pain.
Anesthetic effect
Anesthesia of aquatic products
One of the important factors that restrict the development of the
aquatic product industry is the changes in aquatic products because
of physiological stress in long-distance transportation. Physiological
stress can cause loss of aquatic products. However, anesthetics can
effectively solve this problem.7 Among routine fish anesthetics,
including 2-phenoxyethanol, eugenol, 3-Aminobenzoic acid
ethyl ester methanesulfonate (MS-222), hypnodil V, anaesthesine,
urethane, acetochloral, and other chemical anesthetics, eugenol is
approved by the Food and Drug Administration (FDA) of the USA
as being harmless to humans because its cost and residual quantity
are lower than other anesthetics. Thus, eugenol is widely applied
to the long-distance transportation of fish. The mechanism of
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Table 1. Anesthetic concentration and onset time of eugenol on five fishes
Categories
Anguilla reinhardtii
Cynoglossus semilaevis Günther
Ictalurus punctatus
Pseudosciaena crocea
Spinibarbus sinensis
Concentration (mg/L)
Onset time (min)
References
20-120
10
61
3-40
12-30
10
3
4
20
12
8
9
10
11
12
anesthetic action of eugenol on fish first starts with the inhibition
of the cerebral cortex (period of tactile loss), followed by the basal
ganglion and cerebellum (excitation period), and finally the spinal
cord (narcosis stage). In this paper, we summarized the anesthetic
effects of eugenol on different types of aquatic products. The
results8-12 are listed in Table 1.
Renault et al.13 studied the effects of eugenol on gene expression
of Anguilla anguilla. They found that eugenol can increase the
content of stress response protein encoding oxidability. They also
found that adenosine triphosphate (ATP) synthetase, nicotinamide
adenine dinucleotide phosphate (NADP) dehydrogenase, and
mitochondrial superoxide dismutase increased in muscle of
anabiotic A. anguilla after 21 day.
Scholars studied the anesthetic effects of eugenol on common
carp, tilapia, juvenile Chinese sturgeon, Japanese Macrobrachium,
Chinese shrimp, juvenile southern catfish, and other aquatic
products, and the oxygen consumption rate. The results showed
that eugenol content is negatively related to the onset time of
anesthesia. Compared with the most common anesthetic of
aquatic products, MS-222, eugenol has less residual activity and
does not need three weeks as metabolic time. Thus, the use of
eugenol can be widely popularized.
Local anesthesia
Eugenol is widely applied to current local nerve anesthesia. As
an herbal anesthetic, eugenol is becoming increasingly used
by patients and researchers. Moreira-Lobo et al.14 studied the
adjustment of eugenol to the excitability of sciatic nerve of mouse.
They found that eugenol mainly inhibits Na+-dependent channel
receptor, activates transient receptor potential vanilloid receptor 1
(TRPV1) subfamily of ion channel receptors, and inhibits the flow
of sodium ions, thus, blocking nerve conduction and decreasing
the conduction rate gradually. Low eugenol content can inhibit
complex action potential and decrease nerve excitability.
Antioxidant function
The antioxidant function of eugenol has gained universal
acceptance in academia. Increasing scientific researchers have
made in-depth studies on eugenol. Ou et al.15 revealed that
eugenol can avoid functional disorders of endothelial cells
resulting from oxidized low-density lipoprotein (LDL) and
increase antioxidant activity to inhibit active oxygen generation.
Fujisawa et al.16 believed that eugenol, butylated hydroxyanisole,
and other phenols have important antioxidant activity because
they can capture the oxygen atom from alkyl radical over the
oxidation group by devoting a hydrogen atom of the phenolic
hydroxyl group. Its reaction rate is significantly higher than that
of the substrate of over-oxidized group to attack the organs.
Masae et al.17 studied the inhibition of eugenol on ironwww.cocam.org
dependent lipid peroxidation and oxidation of copper-dependent
LDL. They believed that its mechanism reduces transition metal
ions, particularly divalent copper ion, thus delaying the generation
of hydrogen peroxide and alkoxy from polyunsaturated fatty acids
in the body.
The current research results of antioxidant function of
eugenol show that its antioxidant function is similar to that of
most phenols. Eugenol captures oxygen atoms by devoting
hydrogen atoms and reducing free radical generation to achieve
its antioxidant function. However, further studies are needed
to determine the mechanism of eugenol that is related to some
enzymes and the electron transport system and to reveal further
its antioxidant function.
Antibiotic activity
Numerous studies on the antimycotic,18 antiviral,19 desinsection,20
and antiparasitic21 activities of eugenol and other volatile oils
were implemented. Katayama et al.22 studied the structure of
antibiotic substance in flavoring agents. Their results showed
that the benzene ring compound containing hydroxyl group
has antibacterial efficacy even when diluted to more than 2000
times. Eugenol also contains this structure. Sara et al.23 studied the
antibiotic mechanism of eugenol and other flavoring agents, in
which the cell wall becomes degraded, which damages the plasma
membrane and membrane protein and exposes the cell contents.
The cytoplasm coagulates, causing the proton-motive force to
move far away. Lu et al.24 investigated the in vitro antibacterial
activity of eugenol by microdilution test and found that eugenol
has better antibacterial action on 12 common bacteria (Table 2).
The hydrophobicity of eugenol is an important factor affecting
its antibacterial activity. The hydrophobic property of eugenol can
separate the lipids of cell membrane and mitochondria of bacteria
and change its structure to increase penetrability of cell membrane.
Eugenol also has antibiotic activity because it can block the
proton-motive force, electron stream, and active transport, and
cause coagulation of cell contents.
Anticancer activity
The anticancer activity of eugenol has become an important
research topic in recent years. Chemically synthesized anticancer
drugs have toxic side effects and usually cause potential damage
to normal cells. Eugenol shows better application potential in
the prevention and treatment of some cancers. Hussain et al.25
studied the effect of eugenol combined with gemcitabine on
cervical carcinoma. They found that the combination of eugenol
and gemcitabine can inhibit cancer cell growth, even in low
concentrations. In addition, eugenol can reduce the toxic side
effect of gemcitabine on normal cells. Studies on the related gene
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Table 2. Minimum inhibitory concentration (MIC) of eugenol on 12
bacteria
Categories
Escherichia coli ATCC5922
E. coli O54
Salmonella typhimurium
Salmonella choleraesuis
Salmonella Dublin
Shigella flexnert
Staphyloccocus aureus
Streptococcus hemolytis
Streptococcus suis
Listeria monocytogenes
Pesudomonas aeruginosa
Bacillus cereus
MIC (μg/mL)
5.0
20.0
40.0
10.0
160.0
20.0
40.0
40.0
10.0
160.0
320.0
320.0
also found that eugenol can reduce the possibility of apoptosis
of B-cell lymphoma-2 (Bcl-2), Cyclooxygenase-2 (COX-2), and
interleukin-1β (IL-1β), reduce inflammation, and increase the
treatment efficacy of gemcitabine. Manikandan et al.26 studied the
treatment effect of eugenol on gastric cancer in Wistar rats caused by
N-methyl-N’-nitryl-N-nitrosoguanidine by regarding apoptosis,
cancer cell invasion, and angiogenesis as the main indices. They
found that eugenol inhibits cell apoptosis, cancer cell invasion,
and cancer angiogenesis by regulating the Bcl-2 protein family,
apoptotic protease-activating factor-1 (Apaf-1), cytochrome
C, and cysteine aspartic protease, and changes the activity of
mesenchymal metalloprotease and the expression of Matrix
Metalloproteinase-2 (MMP-2), Matrix Metalloproteinase-9
(MMP-9), vascular endothelial growth factor (VEGF), vascular
endothelial growth factor receptor 1 (VEGFR-1), and tissue
metalloprotease inhibitor (TIMP-2). MMP, VEGF, and TIMP
are important observations indicating tumorigenesis. Rita et al.27
studied the curative effect of the combination of eugenol and
2-methoxyestradiol on non-androgen-dependent prostate cancer.
They found that this combination can effectively inhibit the
proliferation of prostate cancer cells and enhance the expression of
apoptosis precursor protein to prevent prostate cancer. Moreover,
eugenol shows better curative effects in skin cancer and melanoma.
Anti-insect activity
The anti-insect activity of eugenol depends on the structure of its
phenolic hydroxyl. Pessoa et al.28 studied the inhibition of eugenol
on small ruminants of Haemonchus contortus by ovum hatching
test and obtained the highest inhibition rate when concentration
was 0.5%. Machado et al.29 studied the effect of eugenol on the
growth, activity, adherence, and ultrastructure of Giardia lamblia.
Their results showed that eugenol inhibits the adherence of
trophosome after being administered for 3 h and does not cause
cytolysis. They also found that eugenol can affect the cell shape
and cause the coagulation of cytoplasm and autophagy in cells.
These studies show that eugenol can be used as a drug to prevent
giardiasis and verminosis.
Other pharmacological activities of eugenol
Except the aforementioned pharmacological activities, eugenol also
10
can promote percutaneous absorption and treat angiocardiopathy.
Eugenol has a certain effect in reproductive regulation and
immunoregulation. Eugenol also has obvious killing or repellent
action on worldwide agricultural insects, such as red flour beetle30
and citrus fruit fly males31.
Toxic side effects of eugenol
Eugenol has many pharmacological effects, but it also has some
toxic side effects. For example, eugenol has a certain corrosive
action, but its strength is less than that of phenol. The reason for
this action is that eugenol is not dissolved in water. In addition,
the stimulation of eugenol can cause respiratory syndrome, and its
ingestion can cause metabolic acidosis. For infants, eugenol can
cause hypoglycemia and liver failure. Some experiments showed
that eugenol ingestion can cause a seven-month-old infant to suffer
from protein and hematotoxicity with disseminated intravascular
coagulation. Animal experiments showed that eugenol can cause
gastroenteritis and anorexia.
Summary and prospect
The development and application of natural drugs have been
done for thousands of years. As a type of plant extract, eugenol
has a very long application history.
In recent years, given its low toxicity and less residual
activity, eugenol has been widely used in agriculture, forestry,
animal husbandry, and veterinary medicine. Eugenol also has
some treatment effects after being combined with classic drugs.
Aspirin eugenol ester,32 Ibuprofen eugenol ester,33 and other
non-steroidal anti-inflammatory drugs not only possess the
anti-inflammatory action of Aspirin and Ibuprofen but also
can reduce the toxic side effects of these two drugs on stomach
and liver. These studies revealed another method of eugenol
application. However, its application still has some bottlenecks.
For example, the achievements in scientific research on eugenol
have not been integrated with industrial production. Although
eugenol has a simple structure and few toxic side effects, its
target effects and mechanism of substrate interactions have
not been clearly investigated, and no credible data exist to
verify its toxicity. A complete toxic database has also not been
established yet. Thus, the molecular mechanisms for all types of
pharmacological actions need further analysis and explanation.
In addition, reproductive regulation and immunoregulation
are in the preliminary stages. In the future, we look forward
to more detailed and complete data and materials related to
eugenol so that this natural drug can have wide applications,
particularly in the prevention and treatment of cancer and
oxidation resistance.
Acknowledgement
This paper was funded by Basic Scientific Research Funds in
Central Agricultural Scientific Research Institutions (2012ZL085).
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