Toxicol. Res.
Vol. 33, No. 2, pp. 97-106 (2017)
Open Access https://doi.org/10.5487/TR.2017.33.2.097
plSSN: 1976-8257 eISSN: 2234-2753 Review Article
Terpenes from Forests and Human Health
Kyoung Sang Cho1,2, Young-ran Lim1, Kyungho Lee1,2, Jaeseok Lee1,2, Jang Ho Lee1 and Im-Soon Lee1,2
1Department of Biological Sciences, Konkuk University, Seoul, Korea
2Research Center for Coupled Human and Natural Systems for Ecowelfare, Konkuk University, Seoul, Korea
(Received February 6, 2017; Revised February 14, 2017; Accepted February 16, 2017)
Forest bathing has beneficial effects on human health via showering of forest aerosols as well as physical
relaxation. Terpenes that consist of multiple isoprene units are the largest class of organic compounds pro-
duced by various plants, and one of the major components of forest aerosols. Traditionally, terpene-con-
taining plant oil has been used to treat various diseases without knowing the exact functions or the
mechanisms of action of the individual bioactive compounds. This review categorizes various terpenes
easily obtained from forests according to their anti-inflammatory, anti-tumorigenic, or neuroprotective
activities. Moreover, potential action mechanisms of the individual terpenes and their effects on such pro-
cesses, which are described in various in vivo and in vitro systems, are discussed. In conclusion, the stud-
ies that show the biological effectiveness of terpenes support the benefits of forest bathing and propose a
potential use of terpenes as chemotherapeutic agents for treating various human diseases.
Key words: Cancer, Forest therapy, Health, Immune function, Neuronal health, Terpene
INTRODUCTION
Exposure to natural environment is beneficial to human
health (1). Among environmental exposures, the effects of
forest have been emphasized in many studies (2). Recently,
it has been shown that a short trip to forest environments
has therapeutic effects in children with asthma and atopic
dermatitis (3). Based on these studies, healthcare programs to
use forest have been developed in several countries (2,4,5).
For example, in the United States, “forest recreation” became
recognized as the most valuable use of forest in the 1960s in
light of social welfare (4). In Germany, a complementary
and alternative medicine practice called “Kneipp therapy” is
Correspondence to: Im-Soon Lee, Department of Biological Sci-
ences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul
05029, Korea
E-mail: islee@konkuk.ac.kr
The list of abbreviations: BCP, β-caryophyllene; GPP, geranyl pyro-
phosphate; DMAPP, dimethylallyl pyrophosphate; IPP, isopentenyl
pyrophosphate; MAPK, mitogen-activated protein kinase; NF-κB,
nuclear factor kappa B; IL, interleukin; TNF-α, tumor necrosis fac-
tor-α; NO, nitric oxide; LPS, lipopolysaccharide; MMP, matrix metal-
loproteinases; AD, Alzheimer’s disease; PD, Parkinson’s disease.
This is an Open-Access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0) which permits unrestricted
non-commercial use, distribution, and reproduction in any
medium, provided the original work is properly cited.
frequently used (6). Kneipp therapy includes five preven-
tive and curative methods created by Sebastian Kneipp, a
German priest (5), in which exercise in a forest is one of the
five core methods (2). Japan is one of the countries where
the forest usage programs for human health are well devel-
oped. The Forest Agency of the Japanese government intro-
duced the term “Shinrin-yoku,” defined as “taking in the
forest atmosphere or forest bathing” in 1982, and instituted
the “Therapeutic effects of forests plan” in 2005 (2).
Many studies have shown meaningful physiological effects
of forest atmosphere on people (2,7,8). These effects are
believed to be achieved by inhaling the forest atmosphere,
which includes various phytochemicals mainly produced by
trees. The major components of the forest atmosphere are
terpenes, which are the largest class of naturally occurring
organic compounds (9) with more than 40,000 structures
reported so far (9,10). Their basic chemical structure con-
sists of an isoprene unit (C5H8) (11). Depending on the number
of isoprene units, terpenes are classified as mono-, sesqui-,
and di-terpenes (C10, C15, and C20, respectively) (Fig. 1A)
(12). Terpenes have enormous chemical structural diversity
that is generated by various terpenoid metabolic pathways
as well as the specialized cell types that participate in their
biosynthesis (13). The biosynthesis of terpenes uses two
common C5 building blocks, dimethylallyl pyrophosphate
(DMAPP) and isopentenyl pyrophosphate (IPP), derived
from acetyl coenzyme A (14). Head-to-tail condensation of
DMAPP and IPP generates the monoterpene precursor, ger-
97
98
K.S. Cho et al.
Fig. 1. Structures of various terpenes (A) and terpene biosynthesis pathway for pinenes (B). (A) Depending on the carbon number,
terpenes are classified as mono-, sesqui-, and di-terpenes. (B) Using DMAPP and IPP as building blocks, monoterpenes are produced
from GPP. Especially, α-pinene and β-pinene are generated via cyclisation of linaloyl pyrophosphate and the loss of a proton from the
carbocation equivalent.
anyl pyrophosphate (GPP, C10) (Fig. 1B) (15). Furthermore,
sesquiterpenes and diterpenes are created by condensation
of additional IPP units to GPP (Fig. 1B) (15,16).
Terpenes are produced by various plants, particularly
conifers (13). Many of the terpenes are associated with not
only the defense mechanism of the plant against herbivores
and the environment (11,17) but also their developmental
physiology (9). Korean forests mainly consist of various
types of conifers, and many terpenes derived from them
have been detected, such as α-pinene, β-pinene, camphor,
camphene, sabinene, limonene, menthol, cymene, and
myrcene (18). Conifer oleoresins contain monoterpenes (e.g.,
pinene and camphor) and diterpenes (e.g., taxadiene and
phytane) as major components and sesquiterpenes (e.g.,
nerolidol and (E)-α-bisabolene) as minor components (17).
Given that the forest atmosphere is beneficial to human
health and that terpenes are the main components of forest
aerosols, we reviewed the effects of various terpenes from
Korean forests on human health, especially on immunity,
cancer, and neuronal health.
TERPENES WITH ANTI-INFLAMMATORY
FUNCTION
Studies in recent decades have demonstrated that ter-
penes exert anti-inflammatory effects by inhibiting various
proinflammatory pathways in ear edema, bronchitis, chronic
obstructive pulmonary disease, skin inflammation, and osteo-
arthritis (19-23).
α-Pinene, found in oils of coniferous trees and rosemary,
showed anti-inflammatory activity by decreasing the activ-
ity of mitogen-activated protein kinases (MAPKs), expres-
sion of nuclear factor kappa B (NF-κB), and production of
interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and
nitric oxide (NO) in lipopolysaccharide (LPS)-induced mac-
rophages (24). In ovalbumin-sensitized mouse model of
allergic rhinitis, pretreatment with α-pinene decreased clini-
cal symptoms and levels of immunoglobulin E and IL-4
(25). In human chondrocytes, α-pinene inhibited IL-1β-
induced inflammation pathway by suppressing NF-κB, c-
Jun N-terminal kinase (JNK) activation, and expression of
Terpenes and Human Health
99
iNOS and matrix metalloproteinases (MMP)-1 and -13,
suggesting its role as an anti-osteoarthritic agent (19). Strong
anti-inflammatory activity was observed when α-pinene
was used in combination with two active ingredients of
frankincense, linalool and 1-octanol (22).
Another naturally occurring monoterpene d-limonene was
reported to reduce allergic lung inflammation in mice prob-
ably via its antioxidant properties (26). It also reduced car-
rageenan-induced inflammation by reducing cell migration,
cytokine production, and protein extravasation (27). Simi-
lar to α-pinene, d-limonene exerted an anti-osteoarthritic
effect by inhibiting IL-1β-induced NO production in human
chondrocytes (28). d-Limonene treatment reduced doxoru-
bicin-induced production of two proinflammatory cytokines,
TNF-α and prostaglandin E-2 (PGE2) (29).
Monoterpene p-cymene treatment reduced elastase-induced
lung emphysema and inflammation in mice. It reduced the
alveolar enlargement, number of macrophages, and levels
of proinflammatory cytokines such as IL-1β, IL-6, IL-8,
and IL-17 in bronchoalveolar lavage fluid (BALF) (30).
Similarly, p-cymene showed a protective effect in a mouse
model of LPS-induced acute lung injury by reducing the
number of inflammatory cells in the BALF and expression
of NF-κB in the lungs (31) and by reducing production of
proinflammatory cytokines and infiltration of inflammatory
cells (32). Mechanistically, p-cymene blocks NF-κB and
MAPK signaling pathways. It has been reported that p-
cymene reduces production of TNF-α, IL-6, and IL-β in
LPS-treated RAW 264.7 macrophages. In C57BL/6 mice,
TNF-α and IL-1β were downregulated and IL-10 was upreg-
ulated by p-cymene treatment. It also inhibited LPS-induced
activation of ERK 1/2, p38, JNK, and IκBα (32,33).
Treatment with linalool, a natural compound found in
essential oils of aromatic plants, inhibited cigarette smoke-
induced acute lung inflammation by inhibiting infiltration
of inflammatory cells and production of TNF-α, IL-6, IL-
1β, IL-8, and monocyte chemoattractant protein - 1 (MCP-
1), as well as NF-κB activation (20). In another lung injury
model, linalool attenuated lung histopathologic changes in
LPS-induced mice. In in vitro experiments, linalool reduced
production of TNF-α and IL-6 and blocked phosphorylation
of IκBα protein, p38, and JNK in LPS-stimulated RAW
264.7 macrophages (34). Similarly, linalool inhibited pro-
duction of TNF-α, IL-1β, NO, and PGE2 in LPS-stimulated
microglia cells (35). Li et al. (35) showed that the anti-
inflammatory effect of linalool is involved in activation of
Nrf2/heme oxygenase-1 (HO-1) signaling pathway. Frank-
incense oil extract, which contains linalool, exhibited anti-
inflammatory and analgesic effects in a xylene-induced ear
edema model and a formalin-inflamed hind paw model by
inhibiting COX-2 (22).
The monoterpene γ-terpinene, present in the essential oil
of many plants including Eucalyptus, reduced the acute
inflammatory response. It reduced carrageenan-induced paw
edema, migration of neutrophil into lung tissue, and IL-1β
and TNF-α production and inhibited fluid extravasation
(36). Terpinene-containing essential oil from Liquidambar
formosana leaves reduced inflammatory response in LPS-
stimulated mouse macrophages by reducing reactive oxy-
gen species (ROS), JNK, ERK, p38 MAP kinase, and NF-
κB (37). Another terpinene-containing essential oil from
Citrus unshiu flower or fingered citron (C. medica L. var.
sarcodactylis) reduced LPS-stimulated PGE2 and NO pro-
duction in RAW 264.7 cells. Furthermore, production of
inflammatory cytokines, such as IL-1β, TNF-α, and IL-6,
was also reduced in macrophages (38,39).
Borneol, a bicyclic monoterpene present in Artemisia,
Blumea, and Kaempferia, has been used in traditional medi-
cine. Borneol alleviated acute lung inflammation by reduc-
ing inflammatory infiltration, histopathological changes, and
cytokine production in LPS-stimulated mice. It suppressed
phosphorylation of NF-κB, IκBα, p38, JNK, and ERK (40).
Oral administration and intrathecal injection of borneol
showed antihyperalgesic effects on inflammatory pain in
complete Freund’s adjuvant-induced hypersensitive animal
models by enhancing GABAAR (Gamma-Aminobutyric Acid
Type A Receptor)-mediated GABAergic transmission (41).
Borneol inhibited migration of leukocytes into the perito-
neal cavity in carrageenan-stimulated mice, suggesting its
anti-inflammatory function (42). In addition, borneol inhib-
ited TRPA1, a cation channel that is involved in inflamma-
tion and noxious-pain sensing, suggesting that its use as an
anti-inflammatory agent for neuropathic-pain and trigemi-
nal neuralgia (43).
A natural sesquiterpene β-caryophyllene (BCP) was re-
ported to protect against neuroinflammation in a rat model
of Parkinson’s disease (PD) by attenuating production of
proinflammatory cytokines and inflammatory mediators such
as COX-2 and iNOS (44). Chronic treatment with BCP
attenuated alcohol-induced liver injury and inflammation by
reducing the proinflammatory phenotypic switch of hepatic
macrophages and neutrophil infiltration. The beneficial
effects of BCP on liver injury are mediated by cannabinoid
2 (CB2) receptor activation (45). Prolonged administration
of BCP reduced proinflammatory cytokines in pancreatic
tissue of streptozotocin-induced diabetic rats (46). BCP
reduced expression of Toll-like receptor 4 and macrophage
inflammatory protein-2, and phosphorylation of ERK, p38,
JNK, and NF-κB in D-galactosamine and LPS-induced
liver injury mouse model (47).
Besides the aforementioned terpenes, anti-inflammatory
effects have been reported with sabinene itself or sabinene-
containing oil (48,49), bornyl acetate (50) and myrcene (28).
TERPENES AND TUMOR
Tumorigenesis is a multifaceted process, the progression
of which is associated with several hallmarks, including
100
K.S. Cho et al.
uncontrolled cell growth, dysregulation of apoptosis, activa-
tion of invasion, induction of angiogenesis, and metastasis.
Terpenes have been shown to exert anti-tumorigenic effects
against such processes in a number of in vivo and in vitro
systems, thus suggesting their potential uses as chemothera-
peutic agents for treating tumors.
A number of monoterpenes have been reported to exert
chemopreventive effects against tumors (51). Of these, the
anti-tumorigenic activity of d-limonene is well-established.
Numerous studies have demonstrated the protective effects
of d-limonene against chemical-induced tumors in various
tissue types such as breast, intestine, pancreas, liver, and
colon (52-57). Lu et al. (57) revealed that d-limonene could
inhibit the proliferation of human gastric cancer cells by
inducing apoptosis. Later, it was demonstrated that apopto-
sis of tumor cells by d-limonene could be mediated by the
mitochondrial death pathway via activated caspases and
PARP cleavage as well as by the suppression of the PI3K/
Akt pathway (58,59). In addition, positive effects on NK
(Natural Killer) activities were demonstrated not only in the
in vitro treatment of tumor cell lines with monoterpenes
released from trees, such as d-limonene and α-pinene, but
also in forest bathing trips by increasing intracellular levels
of anti-tumor proteins such as perforin, granulysin, and
granzymes A/B (60).
Anti-tumor effects of pinenes are well established on
tumor lymphocytes as well as tumor cell lines (61). Matsuo
et al. (62) identified proapoptotic and anti-metastatic activi-
ties of α-pinene in a melanoma model. Later, it was revealed
in human hepatoma Bel-7402 cells that the proapoptotic
effect of α-pinene is associated with induction of G2/M cell
cycle arrest (63). In addition, α-pinene triggers oxidative
stress signaling pathways in A549 and HepG2 cells (64).
However, Kusuhara et al. (65) reported that mice kept in a
setting enriched with α-pinene showed reduction in mela-
noma sizes, while in vitro treatment of melanoma cells with
α-pinene had no inhibitory effect on cell proliferation, sug-
gesting that the in vivo result may not be due to a direct
effect of α-pinene. Investigation of β-pinene also revealed
its cytotoxic activity against cancer and normal cell lines
with a more pronounced effect on neoplastic cells in the
majority of cases, showing acceptable chemotherapeutic
potency (66,67).
Perillyl alcohol is a naturally occurring monoterpene, and
a metabolite of limonene. Despite preclinical evidence of
anticancer activity, perillyl alcohol appeared to have no clini-
cal antitumor activity upon oral administration to patients
with advanced colorectal carcinoma (68). However, currently,
it is under preclinical development as a potential clinical
treatment for patients with brain tumor (69). Perillic acid is
a major metabolite of perillyl alcohol. Upon examining the
effects of perillic acid on lung metastasis induced by mela-
noma cells in mice, it was observed that administration of
perillic acid remarkably reduced the metastatic tumor nod-
ule formation by exerting an inhibitory effect on cell growth
by G1 arrest (70,71).
p-Cymene has been reported to have cytotoxic effects on
tumor cell lines (72). Recently, Li et al. (73) evaluated ben-
eficial effects of p-cymene on in vitro TPA-augmented inva-
siveness of HT-1080 cells, and found that it inhibits MMP-9
expression, but enhances TIMP-1 production along with the
suppression of ERK1/2 and p38 MAPK signal pathways in
tumor cells, suggesting that p-cymene is an effective candi-
date for the prevention of tumor invasion and metastasis.
Myrcene, the acyclic monoterpene, also exhibits signifi-
cant antiproliferative and cytotoxic effects in various tumor
cell lines such as MCF-7 (breast carcinoma), HeLa (human
cervical carcinoma), A549 (human lung carcinoma), HT-29
(human colon adenocarcinoma), P388 (leukemia), and Vero
(monkey kidney) as well as mouse macrophages (74,75).
Essential oil from Vepris macrophylla demonstrated a strong
cytotoxic effect, suggesting that the effect may be attributed
to the presence of specific components, among which is
myrcene (76).
Terpenes with more complex structures than monoterpenes,
including sesquiterpenoids derived from sesquiterpenes by
biochemical modifications, have demonstrated anticancer
ability as well. The anticancer effect of various sesquiter-
penoids is mediated via inhibition of inflammatory responses,
prevention of metastasis, and induction of apoptosis (77).
α-Caryophyllene, known as humulene, is a naturally occur-
ring monocyclic sesquiterpene. BCP, an isomer of α-caryo-
phyllene, has been identified as an active component of an
essential oil mixture that not only prevents solid tumor
growth and proliferation of cancer cell lines but also inhib-
its lymph node metastasis of melanoma cells in high-fat
diet-induced obese mice (78,79). Sarvmeili et al. (80) re-
ported that Pinus eldarica essential oil, of which BCP was
the major component, exerts cytotoxic effects on HeLa and
MCF-7 cell lines.
As described above, numerous in vitro and in vivo experi-
mental results have demonstrated that the toxicity of ter-
pene affects mainly cancer cells without harming healthy
ones, confirming their efficiency in chemotherapeutic treat-
ment of cancer. Thus, it is noteworthy that the use of ter-
pene and its derivatives can be considered to potentiate the
action of existing conventional therapies (81,82).
TERPENES AND NEURONAL HEALTH
Numerous studies have shown that essential oils derived
from various plants have neuroprotective effects against neu-
rodegenerative conditions in vivo and in vitro (83-90). There-
fore, as a main component of plant essential oils, terpenes
may be beneficial to human neuronal health. However, only
few studies have focused on the beneficial effects of ter-
pene components of plant essential oils on neuronal health.
So far, several terpenes, produced by a variety of plants,
Terpenes and Human Health
Table 1. Studies reporting the effects of terpenes on human health
Class
Terpene
Structure
Mono-
1,8-Cineole
Effect
Antioxidation
Neuroprotection
1-Octanol
Borneol
Bornyl acetate
Anti-inflammation
Anti-inflammation
Antioxidation
Neuroprotection
Anti-inflammation
101
Related literature
(106)
(106)
(73)
(40-43)
(91-101)
(91-94)
(50)
Cymene
Limonene
Linalool
Myrcene
Perillyl alcohol
Anti-inflammation
Anti-cancer
Neuroprotection
Anti-inflammation
Antioxidation
Anti-cancer
Anti-inflammation
Anti-inflammation
Anti-cancer
Anti-cancer
(30-33)
(72,73)
(107)
(26-29)
(52-60)
(20,22,34,35)
(20,22,34,35)
(28)
(74-76)
(68-71)
Pinene
Sabinene
Terpinene
Sesqui-
Caryophyllene
Anti-inflammation
Anti-cancer
Antioxidation
Neuroprotection
Anti-inflammation
(19,22,24,25)
(60-66)
(105)
(106)
(48,49)
Anti-inflammation
(36-39)
Anti-inflammation
Anti-cancer
Antioxidation
Neuroprotection
(31,44-47)
(78-80)
(44,103)
(44,103-105)
102
K.S. Cho et al.
have been associated with neuronal health. Among those,
borneol is a bicyclic monoterpene present in several medici-
nal plants (91-94). Previous studies showed that borneol has
free radical scavenging activity (95) and is a major compo-
nent of essential oil of SuHeXiang Wan (92) whose neuro-
protective function has been reported in in vivo and in vitro
models of Alzheimer’s disease (AD) (96-99). Moreover, a
recent study showed that borneol exerts a neuroprotective
effect against β-amyloid (Aβ) cytotoxicity via upregulation
of nuclear translocation of Nrf2 and expression of Bcl-2
(100). In addition, treatment with isoborneol, a monoter-
penoid alcohol, significantly reduced 6-hydroxydopamine-
induced ROS generation and cell death in human neuroblas-
toma SH-SY5Y cells, suggesting that isoborneol may be a
potential therapeutic agent for treatment of neurodegenera-
tive diseases associated with oxidative stress (101). Salvi-
anic borneol ester, a new compound synthesized from salvianic
acid A and borneol, also exerts anti-amyloid and neuropro-
tective effects in both SH-SY5Y cells and motor neuron
hybridoma VSC 4.1 cells (102).
BCP also has neuroprotective functions. It has been
reported that BCP has antioxidant effects (103), and func-
tions as a regulator of several neuronal receptors and shows
various pharmacological activities including neuroprotec-
tion (104). Neuroprotective effects of BCP have been reported
in both AD and PD animal models. Oral treatment with BCP
prevented AD-like phenotype such as cognitive impair-
ment and activation of inflammation through CB2 receptor
activation and the PPARγ pathway (105). As described above,
BCP administration also exerts neuroprotective effects in
rotenone-challenged rat model of PD by reducing neuro-
inflammation (44).
Other monoterpenes such as α-pinene and 1, 8-cineole
also exert neuroprotective effects by regulating gene expres-
sion. They protected PC12 cells against oxidative stress-
induced apoptosis through ROS scavenging and induction
of nuclear Nrf2 factor followed by enhanced expression of
antioxidant enzymes including catalase, superoxide dis-
mutase, glutathione peroxidase, glutathione reductase, and
HO-1 (106). Similarly, p-cymene has cholinergic effects
through regulation of expression of several genes in Caenor-
habditis elegans (107). Given that terpenes are major com-
ponents of essential oils of various medicinal plants with
neuroprotective functions, studies to find the beneficial roles
of terpenes in neurodegenerative diseases will provide a
promising way to develop therapeutics.
CONCLUSION AND PERSPECTIVES
Essential oils obtained from plants have been used in
diverse traditional medicines because of their broad benefi-
cial effects on human health (108). To date, many terpenes
from essential oils as well as forest bathing have been
reported to exhibit strong biological activities. This review
categorized the terpenes that have presented important results
in cell and animal systems according to their anti-inflamma-
tory, anti-tumorigenic, or neuroprotective activities (Table
1). Although data elucidating the possible action mecha-
nisms of these compounds are increasing, numerous stud-
ies still present only preliminary screening results. Thus, to
investigate the future chemotherapeutic uses of terpenes, it
is necessary to explore further the detailed action mecha-
nisms including signaling pathways that are associated with
their biological functions. In addition, understanding of the
relationship between the diverse chemical structures of ter-
penes and the in vivo physiological roles of these compounds
may provide critical insights for the future development of
therapeutics with enhanced selectivity and specificity.
So far, many studies have extensively reported the phar-
maceutical activities of monoterpenes among the terpenes.
Monoterpenes, formed from the coupling of two isoprene
units (C10), are the major molecules consisting 90% of the
essential oils (109). However, in recent years, small sub-
groups of other terpenes and terpenoids that exhibit diverse
biological activities have been isolated or synthesized, pro-
viding a source of novel chemotherapeutic molecules. The
use of various terpenes in clinical trials is currently limited
due to insufficient data from human studies. However, their
use as potent chemotherapeutic compounds alone, as well
as in combination with previously proven chemotherapeu-
tic drugs, to increase effectiveness and decrease doses is
expected to increase as data on their safety and efficacy in
in vivo and in vitro systems are accumulated.
CONFLICT OF INTEREST
The authors declare that they have no competing inter-
ests.
ACKNOWLEDGMENTS
This research was supported by the National Research
Foundation of Korea (NRF) funded by the Ministry of Sci-
ence, ICT and Future Planning (NRF-2016M3C1B6928005).
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