全 文 ：
Journal of Chinese Pharmaceutical Sciences http://www.jcps.ac.cn 388
Hypericin in hypericum: chemistry, botanical sources and biological activities
Linfang Huang, Shilin Chen*
Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing
100193, China
Abstract: Hypericin, a secondary metabolite first reported in 1830, is a natural photosensitizing naphtodianthrone and is mainly
from the natural plant sources of genus Hypericum. Hypericin exhibits a wide variety of biological and pharmacological activities,
such as antiviral, antidepressant, antitumor, antimicrobial, and antioxidant activity. Hypericin can also be utilized in photodynamic
diagnosis. Accumulating evidence is pointing to the effects of hypericin with potential pharmaceutical and clinical interests in the
past decades. The present review gives a comprehensive outline of the chemistry, botanical occurrence and biological activities
of this powerful compound.
Keywords: Hypericin; Botanical sources; Chemistry; Biological activities
CLC number: R282.6 Document code: A Article ID: 1003–1057(2012)5–388–13
Received date: 2012-05-16.
Foundation items: Key National Natural Science Foundation of
China (Grant No. 81130069), Selected Program of Personnel
Department for Oversea Scholar (2009–2011); the Chinese National
S&T Special Project on Major New Drug Innovation (Grant No.
2011ZX09307-002-01); the Key Technologies of the Quality
Standards and the Safety of Health Food, “863 Program” (Grant
No. 2010AA023006).
*Corresponding author. Tel./Fax: 86-10-57833197; 15801545922;
E-mail: slchen@implad.ac.cn
doi:10.5246/jcps.2012.05.052
1. Introduction
Hypericin was initially isolated from the plant
Hypericum perforatum by Buchner, who called this
substance hypericum red in 1830[1]. About one cen-
tury later, in 1911, the constituent was once again
isolated and renamed hypericin by Cerny[2] together
with other similar compounds. It was wrongly attributed
to the class of anthocyanidin compounds in 1927, and








the correct structure of hypericin was established
and determined in 1953 by Brockman and Sanne[3,4].
Since then, various hypericin derivatives were isolated
and characterized in Hypericum species[5,6].
Meanwhile, a wide range of investigations into the
biological activities of hypericin has been reported.
It was identified as the compound responsible for
the light-reduced photosensitivity and exhibits strong
photodynamic antitumor activity[7]. Also, hypericin has
been linked to the inhibition of depression[8]. Recently,
it was reported that hypericin displays considerable
antiviral activity against several viruses, particularly
the human-immunodeficiency virus I[9]. Thus, there
is a growing interest in using hypericin for various
pharmacological purposes and it has become one
of the most important compounds from the pharma-
cological point of view.
Review
Contents
1. Introduction....................................................................................................................................................................... 388
2. Botanical source................................................................................................................................................................ 389
3. Chemistry.......................................................................................................................................................................... 390
4. Biological activities........................................................................................................................................................... 391
4.1. Antiviral activity ........................................................................................................................................................ 391
4.2. Antidepressant activity............................................................................................................................................... 391
4.3. Antitumor activity ...................................................................................................................................................... 392
4.4. Other activities ........................................................................................................................................................... 393
4.5. Adverse effect and toxicology.................................................................................................................................... 394
5. Conclusion ........................................................................................................................................................................ 395
Acknowledgements ........................................................................................................................................................... 395
References......................................................................................................................................................................... 396

389 L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400
2. Main botanical sources
Hypericin can be obtained from plants, insects, and
protozoa. However, the main natural plant sources
of hypericin occur in a number of species of
Hypreicum from the genus Hypericum[5]. The genus
Hypericum contains approximately 460 species, which
can be divided into 30 subgroups that spread
throughout the temperate and tropical regions
worldwide[10]. A survey of more than 200 Hypericum
species demonstrated that all hypericin-containing
species belong to the sections Euhypericum and
Campylosporus of Keller’s classification[11]. In China,
there are 55 species of Hypericum, 18 of which
have records of ethnomedicinal usage by the native
residents[12].
The most extensively investigated and heavily
consumed species in Hypericum genus, however, is
the H. perforatum (Fig. 1), commonly known as
St. John’s Wort (SJW) due to its ancient usage as
the treatment for jaundice, gastritis, eczema, and
diarrhea, as well as its more recently widespread
application as an antidepressant for psychological
disorders. H. perforatum is a perennial herbaceous
plant widely distributed in Asia, Europe, North
Africa, and Northern America. It is abundant in
Southwest of China on waste grounds, in the plain,
and on hillsides, up to an altitude of 4500 meters.
H. perforatum is recorded in the monographys of
numerous pharmacopoeia, including the American
Herbal Pharmacopoeia, the British Herbal Medicine
Association (BHMA, 2003), the British Herbal
Pharmacopoeia (BHP, 1996), the Complete German
Commission E, European Scientific Corporation of
Phytotherapy (ESCOP, 2003), the Martindale 35th
edition (Ph Eur 2007, USP29/NF24, WHO volume 2,
2002), the European Commission (2002), the German
Pharmacopoeia, the Natural Sources of Flavoring,
the Council of Europe Publishing (July 2000), and
so on.
Hypericum species is a prolific producer of secon-
dary metabolites, which have very complex active
constituents including anthraquinones, naphtodian-
thrones, phloroglucins, volatile oils, flavonoids,
xanthones, cumarins, carotenoids, carbolic acids,
and proanthocyanidins. The most influential compound















is hypericin and pseudohypericin, which are naptho-
dianthrones in SJW, and have been extensively
investigated because of their implications in human
health[13]. Hypericin localizes within specialized
minute glands on different parts of the plants, pre-
dominantly in flowers and leaves. The traditional
crude drug is based on the usage of dried flowers,
leaves, and upper aerial parts of the plant, which
are harvested shortly before or during flowering
season. After harvesting, the herb should be dried
immediately to prevent the decomposition of its
bioactive compounds. The hypericin concentration
varies depending on the part of the plant, whether it
is fresh or dried prior to extraction, and the develop-
mental stage of the plant[14]. It was reported that the
concentrations of hypericin and other two active
metabolites of H. perforatum show significant transient
increase after exposure to UV light while the plants
were still vegetative. Therefore, short exposure of
the plants to UV light before harvesting and extraction
may increase the yield of hypericin. The author also
recommended an optimal single 40-minute dose of
UV-B exposure before harvesting[15].
More recently, it was reported that the inoculation
of H. perforatum with Arbuscular mycorrhizal fungi
(AMF) can enhance the concentration of secondary
metabolites, particularly hypericin, resulting in the
improvement of the quality of raw material obtained
from the cultivation[16]. Hypericin concentration in the
leaves varies from 0.01% to 0.47%; in the flowers it
can reach 0.09%[17]. The environmental factors exert
Figure 1. Photograph of H. perforatum.

390 L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400
effects on the amount of hypericin in plant. Lower
light levels, reduced precipitation, and increased
nitrogen can all lower the content of hypericin in
H. perforatum[18,19].
3. Chemistry
Hypericin (4,5,7,4,5,7-hexahydroxy-2,2-dimethyl-
meso-naphthodianthrone) is a natural photosensitiz-
ing polycyclic aromatic quinone (dianthrone) with a
molecular formula of C30H16O8[20]. Pseudhypericin is
an analog and pseudoprotohypericin, protohypericin
are very important precursors (Fig. 2). This photo-
dynamic is one of the most characteristic constituents
of H. perforatum. It is red pigmented and is exuded
when the buds and flowers of H. perforatum are
squeezed. A single crystal X-ray diffraction of the
pyridinium salt of hypericin shows that the molecule
is distorted and possesses a helical twist[21]. Hypericin
is an acidic compound according to the result of
pH-dependent absorption spectral analyses. Hypericin
shows a limited solubility in various solvents, and is
almost insoluble in water at room temperature[22].
Its solubility strongly depends on its form; the free
hypericin is only slightly soluble in polar solvents,
while the salts formed between hypericin and inorganic
bases (pH 4–11) are generally much more soluble[23].
The poor solubility of hypericin is a major drawback
as it restricts the bioavailability of this compound.
Great effort was dedicated to find better soluble forms
of hypericin in both water and organic solvents (e.g.
by preparing esters, ethers, salts, amino acid com-
plexes, and polyphosphazene-bound conjugates[24–27],
by modifying the molecule[28], or by the preparation
of ion pairs[29]). Other possibilities of solubility
improvement include the introduction of polar
functional groups such as carboxylic acid groups.
The hypericin used in most of the biological and
clinical trials is in fact a monosodium salt. In the
plants, it occurs mainly as a potassium salt[23,30].
Hypericin salts are bright red in organic solvents;
the solution is highly absorbent at 548 and 591 nm
and exhibits red fluorescence[21,31]. Mohamed A. Farag
et al.[32] used an ultra-performance liquid chroma-
tography method (UPLC) coupled with quadrupole time
of flight mass spectrometry (qTOF-MS) method for
the large-scale analysis and the commercial prepara-
tions of the hypericin from H. perforatum plant.
Hypericin is considered one of the most photody-
namically active agents in nature due in part to its
ability to produce singlet oxygen with a high
quantum efficiency[33–35] and superoxide anion radicals
as well[36–39]. And the photochemical reaction of
hypericin is closely associated with its various bio-
activities. Protohypericin and protopseudohypericin,
two compounds that are structural-related of hypericin,
are efficiently converted into the stable form of
hypericin and pseudohypericin under the action of
light[40–43].
Hypericin is a commonly used active ingredient of
Hypericum species and is used for the standardization
of H. perforatum extracts (preparations)[44]. The content
of ‘total hypericins’ (hypericin+pseudohypericin) is
around 0.10%–0.15% in the extracts[45]. According
to the British Pharmacopoeias (BP) and European
Pharmacopoeias (EP), H. perforatum herb consists
of the whole or cut dried flowering tops, and contains
no less than 0.08% of total hypericins, expressed as
hypericin, calculated with reference to the dried drug.
Most commercially available products are standardized
based on a 0.30% content of hypericin. The United
States Pharmacopoeia (USP) recommends that all
preparations are standardized to no less than 0.2%
hypericins (hypericin + pseudohypericin) by HPLC,
and EP (2010) requires hypericin to be 0.1%–0.3%
in H. perforatum dried extract[46].


Figure 2. Chemical structures of hypericin (I), pseudohypericin (II),
pseudoprotohypericin (III), protohypericin (IV).
O
O
OH
OH
OH
OH
HO
HO
OH
HO
HO
OH
OH
CH3
CH2OH
OH
O
O
OH
HO
HO
OH
OH
CH3
CH2OH
OH
O
O
OH
HO
HO
OH
OH
CH3
CH3
OH
O
O
I II
III IV

L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400 391
4. Biological activities
4.1. Antiviral activity
Evidence of antiviral properties has especially
been shown for hypericin[23,47,48]. Hypericin is a
particularly effective virucidal agent. The compounds
have been shown to be active against a broad range
of viruses[49,50] and retroviruses[47,51,52], including
herpes[49] simplex virus types 1, 2 (HSV-1, HSV-2),
varicella-zoster virus[53,54], sindbis virus[55], human and
murine immunodeficiency virus type 1 (HIV-1)[56–59],
Rausher viruses[50], equine infection anaemia viruses[51],
murine[50] human cytomegaloviruses, influenza[50]
vesiculostomatitis virus, sendai virus[52], and ducks
hepatitis B and chronic hepatitis C viruses[49,60,61]. In
a recent report, hypericin cured all poultry infected
by the deadly H5N1 avian flu. The in vitro experi-
ments suggested that hypericin is effective against
H5N1 and H9N2 avian flu viruses when used at
different concentrations[62].
Some studies suggested that the hypericin is a
potent and irreversible inhibitor of tyrosine kinases,
including protein kinase C[63,64] and its antiretroviral
activity can be attributed to the inhibition of protein-
kinase C-mediated phosphorylation, occurring during
the viral infection of the cells[65].
Others believe that the antiviral activity of hypericin
involves a photoactivation process that forms singlet
oxygen, which inactivates both the viral fusion and
the syncytia formation processes. Hypericin is the
first photodynamic metabolite that has been shown
to have virucidal efficacy both in vivo and in vitro.
The photo activation of hypericin occurs in two
possible ways: type I system and type II system. In
the type I process, the quantum energy generated by
the excitation of the photosensitized compound is
dissipated via an electron transfer involving the
formation of free radicals. The type II system is the
most common type of photoactivation. It is an
oxygen dependent system in which singlet oxygen
formation occurs via energy transfer from the triplet
state of the photosensitizer to the ground triplets
state of oxygen molecule[66]. Hypericin is activated
via the type II oxygen-dependent mechanism under
normal circumstances, but hypericin can still be
activated via the type I photo activation mechanism
when oxygen is limited. Laboratory results, however,
demonstrated that hypericin is rather effective at
virus eradication in vitro, both in the presence and
absence of light[67]. Photo activation of hypericin
leads to the formation of active oxygen species that
likely react with viral components and thus disrupts
the assembly into complete virus particles. The
photosensitization effects of hypericin include
oxidation of membrane lipids, inhibition of reverse
transcriptase, inhibition of enzyme activity including
protein kinase C, mitochondrial succinoxidase, and
the tyrosine kinase activity of epidermal growth
factor receptor[65,68].
In addition, the hypericin is thought to be directly
toxic to enveloped DNA retroviruses[69]. And virus
inactivation by hypericin seems to involve inhibition
of various stages of virus replication (e.g. assembly,
budding, or shedding of newly synthesized viruses)
depending on the integrity of the viral envelope. The
evidences has also been suggested that antiviral activity
of hypericin by immediate virucidal effects[47,56].
4.2. Antidepressant activity
Early studies suggested that hypericin is a monoamino
oxidase (MAO) inhibitor and is the active agent
responsible for the antidepressant effects of hypericum
extracts[63]. The SJW (LI 160, a commercially
available product) contains 0.3% hypericin and
exerts antidepressant-like effects, both in vivo and
in vitro, experimentally and clinically[58,70,71].
The effects of SJW extracts (LI 160, 0.3% hypericin)
on the concentrations of neurotransmitters in brain
regions were studied in rats. And the results showed
that LI 160 induced a significant increase in 5-HT
concentrations in the rat cortex. Furthermore, LI 160
also caused increases in noradrenaline (norepinephrine)
and dopamine in the rat diencephalon[72]. Butter-
weck et al.[73] used in situ hybridization histochemistry
to examine in rats the effects of short-term (two
weeks) and long-term (eight weeks) administration
of SJW extract and hypericin on the expression of
genes that may be involved in the regulation of
the hypothalamic-pituitary-adrenal axis. Several other
investigations of in vivo antidepressant activity of this

L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400 392
extract suggested that hypericin shows pronounced
activity in selected animal bioassays. The forced
swimming test and the tail suspension test were
used to determine the antidepressant activity. Tests
indicating activity on the central nervous system
were also performed, such as body temperature and
ketamine-induced sleeping time[58,70]. It was also
suggested that the antidepressant-like effect of
Hyperici Herb in the forced swimming test may be
mediated by interaction with receptors and to some
extent by increased serotonergic neurotransmission[74–76].
In vitro experiments using peripheral blood mono-
nuclear cells showed that an alcoholic extract of H.
perforatum containing 0.25 mg/mL hypericin down-
regulated mitogen mediated tryptophan degradation
in a concentration-dependent manner[77].
Raffa[78] investigated a crude Hypericum extract
and a sample of pure hypericin in a battery of in vitro
receptor assays and two enzyme assays. Hypericin
had affinity only for N-methyl-D-aspartate (NMDA)
receptors while the crude extract had significant
receptor affinity for adenosine (nonspecific), GABA
A and B, benzodiazepine, inositol triphosphate and
monoaminooxidase A and B. Simmen et al.[79]
studied the effect of extracts and some constituents
of SJW on various central nervous system receptors.
Binding inhibition was examined for the G-protein
coupled opioid, 5-HT, histamine, neurokinin, and
corticotropin releasing factor receptors, for the
steroid estrogen-receptor, and for the ligand-gated
ion channel GABA A receptor. Hypericin showed
the most potent binding inhibition of all tested
constituents. Butterweck et al.[80] have investigated
the chronic effects of SJW and hypericin on regional
brain amine metabolism. These data clearly show
that long-term, but not short-term, administration of
SJW and its active constituent hypericin modify
levels of neurotransmitters in brain regions involved
in the pathophysiology of depression.
Recently, in vitro screening of the activities of
hypericin, using 42 biogenic amine receptors and
transporters, showed that the compound significantly
inhibited ligand binding at the following receptors in par-
ticular: dopamine-D3, dopamine-D4, and adrenergic[81],
which helps to alleviate the mild to moderate de-
pression. More recently, it was found that irradiation
of a mixture of hemoglobin and hypericin with
visible light can activate hypericin to generate
reactive oxygen species, which changes the structure
of hemoglobin and enhances the catalytic activity of
the protein for H2O2 reduction. The process depends
on the irradiation time and the concentration of
hypericin. This study not only confirmed the photo-
sensitization by hypericin and revealed the enhanced
peroxidase activity of hemoglobin but may also have
revealed the potential of hypericin to be developed
into a more sensitive H2O2 biosensor[82]. Moreover,
it was shown that hypericin leads to red blood cell
(RBC) destruction in light, whereas without light it
penetrates the cell and interacts with subcellular
components, e.g. hemoglobin that causes its structural
and functional modifications[83–85].
Surprisingly, some contradictory evidence indicates
that hypericin does not possess the activity of
MAO[85–87]. Hypericin has also been reported to be
responsible for much of the antidepressant activity
of the herb[88–90]. Purified hypericin lacked any
significant MAO (type A or B) inhibitory activity at
concentrations up to 10 μM, and had affinity only
for NMDA receptors in rat forebrain membranes[84].
In addition, purified hypericin does not inhibit MAO
type A either in vitro or ex vivo. Furthermore, it has
been reported that depressed patients receiving
Hypericum extract WS 5572 and WS 5573, which
contain 5% and 0.5% hypericin, respectively, displayed
lower scores on the Hamilton Depression Scale in a
randomized, double-blind, placebo controlled, and
multicenter study[91].
4.3. Antitumor activity
Besides the antiviral activities, hypericin exhibits
interesting potential as an antineoplastic and photo-
cytotoxic agent. Hypericin was shown to impair
tumor cell growth, both in conjunction with whole
plant extracts and separately[92,93]. A methanolic
extract of H. perforatum (containing hypericin 0.3%)
administrated intraperitoneally ten days before
implantation of PC-3 human Caucasian prostate

L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400 393
adenocarcinoma cells in nude mice remarkably
reduced tumor growth and the number of regional
lymph node metastases[94]. The extract at a concen-
tration of 1.41 mg/mL also significantly inhibited
the proliferation of PC-3 cells in vitro. The in vitro
experiment indicated that hypericin together with
flavonoid constituents and hyperforin, contributes to
the anti-proliferative effects on K562 and U937 cell
lines[92].
Recent studies have demonstrated that the naphto-
dianthrone hypericin is one of the most potent
natural photosensitizing and photocytotoxic agent so far
described, with cytotoxic effects in neoplastic cell lines.
As a result, hypericin can potentially be utilized in anti-
tumoral photodynamic therapy (PDT)[95]. PDT refers
to the use of low-energy, visible, and near-infrared
light to treat various pathological conditions including
wound healing, nerve regeneration, and several types
of cancer[96]. Photosensitisation of hypericin has been
documented for various cancer cell lines in vitro[97–106].
Photocytotoxic effects of hypericin to human
leukaemic HL-60 cells can be potentiated in vitro
by co-incubation with acetazolamide[107]. And inhi-
bition of hypericin on interleukin-12 production was
possibly via the reduction of NF-κB activation[108].
Agostinis et al.[95] reviewed the signaling pathways
underlying the photocytotoxic action of hypericin.
Anticancer activity of hypericin is mediated through
multiple pathways. Hypericin seems to bind selectively
to protein kinase C and other kinases[13,109], affecting
their activities, thus inhibiting the growth of cancerous
cells[65,109,110]. Additionally, the following in vitro
anticancer actions of hypericin were reported:
inhibition of mitochondrial function[111,112], inhibi-
tion of proliferation[113,114], inhibition of hexokinase
activity[115], oxidation of lipids, amino acids, and
proteins, and inhibition of an epidermal growth
factor receptor and tyrosine kinase activity[116].
Phototoxicity and induction of apoptosis also
occur with exposure to hypericin in vitro[110,117–120].
Photo-induced apoptosis in the presence of hypericin
may involve the tumour necrosis factor (TNF)-related
apoptosis-inducing ligands[121], the inhibition of
proteasome function (which is involved in caspase
activation)[122], and the activation of caspases, such
as caspase-8[123]. A recent investigation suggested
that hypericin’s inhibitory effect on tumor growth is
via inducing apoptosis and the competitive binding
of the pregnane X receptor, which regulates the
transcription of multiple CYP450 genes and the
MDR1 gene[124]. In addition, hypericin’s antitumor
activity has been demonstrated in several in vivo
experimental models of cancer[98,113,125–128]. Bis-DOTA-
hypericin labeled with 64Cu also demonstrated a
high affinity to damaged tumor cells. And the
mechanism of the affinity of hypericin to necrotic
cells may associate with the breakdown of the cell
membrane and the exposure of phosphatidylserine
or phosphatidylethanolamine to the radiotracer,
which binds selectively to these phospholipids[129].
In regards of hypericin’s photodynamic property, a
recent clinical trial demonstrated that hypericin can
induce apoptosis in normal and malignant B and T
lymphocytes, and has the potential to treat benign
and malignant disorders of the skin, including plaque
psoriasis and patch and plaque phase cutaneous T-cell
lymphoma[130].
The mechanism of tumor eradication and mode of
cell death induced by in vivo photodynamic therapy
with hypericin involves vascular damage and apop-
tosis in the RIF-1 mouse tumor model[131]. Francesca
et al. tested hypericin and pseudohypericin’s effect
on both cytosolic and mitochondrial thioredoxin
reductases. The results showed that the thioredoxin
system is highly overexpressed in cancer cells, and
both compounds can act as inhibitors of thioredoxin
reductases both in the dark and in ambient light,
suggesting appreciable anticancer properties[132].
4.4. Other activities
4.4.1. Antimicrobial activity
Avato et al.[133] investigated the antimicrobial proper-
ties of different extracts (methanol, petroleum ether,
chloroform and ethyl acetate) of the aerial parts of
H. perforatum. Extracts of H. perforatum aerial parts
have antibacterial activity against gram-positive
bacteria, particularly Bacillus subtilis and B. cereus.
However, the same antibacterial activity was not
observed against gram-negative bacteria and yeasts,
according to the findings of a series of in vitro assays.

L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400 394
And the ethyl acetate fraction was the most active
against selected microorganisms. Hypericins was
one of the main constituents of this extract and pure
hypericin showed significant inhibitory effect on the
growth of microorganisms. Moreover, hypericin shows
selective photoinactivation of two microorganism
species (Candida albicans and C. dubliniensis),
which is the most common cause of skin, nail, and
mucous infections. Hence, hypericin can be a promising
candidate for antifungal drugs in antimicrobial photo-
dynamic inactivation (PDI)[134].
4.4.2. Antioxidant activity
Antioxidant properties have been reported for
methanolic extract (containing hypericin) and related
commercially available formulations of H. perforatum
obtained in the USA and labeled as containing
hypericin (0.3%–0.5%), indicating that hypericin is
potent in inhibiting free radical production in an
inverse concentration-dependent manner both in
cell-free system and human vascular tissue[135,136].
Results from a pilot clinical observational study
suggested that taking hypericum tablet supplements
for two complete menstrual cycles (1–300 mg of
hypericum extract per day standardized to 900 mg
of hypericin) is a promising treatment for symptoms
of premenstrual syndrome (PMS). The degree of
improvement in overall PMS scores between
baseline and the end of the trial was 51%, with over
two-thirds of the sample demonstrating at least a
50% decrease in symptom severity[137].
4.4.3. Photodynamic diagnosis (PDD)
Additionally, since hypericin is a potent photosen-
sitizer and is characterized by high quantum yields
and low photo bleaching, it is considered an out-
standing diagnostic tool for the fluorescence detection
of early cancer. The first clinical use of hypericin-
induced PDD in detecting flat carcinoma in situ (CIS)
lesions of bladder was described by D’Hallewin
et al.[138]. Thereafter, it has successfully been used in
photo-diagnosis and is far better than other diagnostic
tools used for the same purpose[139–141]. The studies
of hypericin mostly focused on the diagnosing of
bladder cancer[142–145]. Other types of cancer such as oral
cancer[146], stomach cancer[147,148], and gliomas
[149,150] are also included. Malini Olivo gave a compre-
hensive review on the recent development of hy-
pericin-mediated diagnosis of cancer with current
optical technologies, and highlighted the trend in
nanotechnology that gradually reinforces the appli-
cation of hypericin for combined therapeutics and
multimodality imaging[151].
4.5. Adverse effect and toxicology
One downfall of hypericin is its unique phototoxic
effects[97,101,110,116,152–164] that can result in hypericism
(photodermatitis) on humans and animals when taken
in high dosages and exposed to sunlight[96,165].
Excessive cutaneous phototoxicity was observed
with a dose of 0.5 mg/kg of body weight associated
with AIDS treatments. The toxic effects are attributed
to an acidification of the surrounding environment
caused by the transfer of hydrogen between hydroxyl
groups upon receiving light energy. Human lens
epithelial cells and human retinal pigment epithelial
cells were both damaged by exposure to a combina-
tion of hypericin and visible or UV light radiation. It
has been reported that hypericin produces singlet
oxygen and superoxide anions[29,111,153,154,166]; and
other excited-state intermediates, which indicates
that it’s very phototoxic to the eye and could cause
damage in the lens α-crystallin proteins, retina and
could lead to the formation of cataracts, as has been
found to occur in calves.
Some other adverse effects for hypericin included
gastrointestinal symptoms, skin reactions, fatigue and
sedation, restlessness or anxiety, dizziness, headache,
and dry mouth[167–170]. Several meta-analyses and a
clinical trial concluded that the rates of adverse
events are comparable to those of placebo and
less than that of standard antidepressant treatment.
Data from observational studies indicated that
adverse events may occur in 1%–3% of patients.
A survey of adverse events in patients under treat-
ment with 1.08 mg/day of hypericin from 1991 to
1999, involving approximately 8 million people,
documented 95 reports of adverse events[170]. It’s
noteworthy that allergic skin reactions, including rash,
itching, and pruritus have been reported in clinical
trials. A review of adverse events documented 27
adverse skin allergy reactions. The phenomenon was
found to be transient and diminishes a few days after

L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400 395
hypericin is discontinued. Photosensitization in
fair-skinned people can be caused by hypericin and
pseudohypericin. A European drug-monitoring study
of 3250 patients receiving 1.08 mg/day of hypericin
reported an overall rate of adverse reactions of
2.4%.
Cell cultures of human keratinocytes incubated
with hypericin and exposed to UV-A resulted in a
reduction in the LC50 for hypericin. And it was
estimated that at least 30 times the therapeutic dose
would be necessary to produce phototoxic effects in
humans[171].
In animal experiment (exposing to sunlight), it was
found that 1–2 mg/rat resulted in death of the animals
within 1–2 h when hypericin was administrated orally.
Mice treated with 0.25–0.5 mg of hypericin and
exposed to a 2000 W lamp for 30 min died within
24 h. In contrast, mice injected with 3–4 mg of
hypericin and kept in the dark survived. The
minimum phototoxic dose is 30–50 times the amount
of hypericin ingested with the recommended daily
dose of hypericum extracts based on animal toxicity
studies.
Although numerous studies suggest that the SJW
extract is well tolerated and generally safe to use,
there is evidence that many of the herb’s compounds
interact with other drugs, mainly those metabolized
by the hepatic cytochrome enzyme system. In vitro
experiments described that SJW extracts inhibit the
CYP enzymes CYP3A4 and CYP2C19[172,173], and
P-glycoprotein[174]. Consequently, it can interact
with a number of different drugs. Majority of studies
show a decrease in plasma levels of the drugs,
thereby reducing therapeutic effectiveness. Interaction
can be very severe such as with cyclosporine. It is
therefore recommended to avoid concomitant use of
the herb and any drug affected by these isoenzymes,
such as anticoagulants, antiretrovirals, and oral
contraceptives.
5. Conclusion
Recently, widespread interest in the antiviral property
of H. perforatum has provoked the investigation of
secondary metabolites from other related Hypericum
species. Hypericin shows outstanding biological
activities, such as antiviral, antidepressant, cytotoxic
and antitumor properties, although they are relatively
rare in nature compared with other phenolic com-
pounds. This overview summarizes some aspects of
the history, chemical property, botanical sources and
biological activities of hypericin. The main applica-
tions discussed in the review focus on the biological
activities of hypericin.
Despite numerous in vivo, in vitro, and clinical
studies conducted on the medicinal attributes of
hypericin, various aspects on its therapeutic value,
mechanisms of action, and adverse interactions
remain unclear. Particularly, the role of hypericin in
the antidepressant activity of the extract has been
much debated. Hypericin has initially been demon-
strated as the only candidate responsible for the
antidepressant property. Later, it was reported that
this was due to the impurity of the hypericin that
was used in the experiment[85]. More recently, the
constituent of hyperforin was reported responsible
for the antidepressant activity of the extract. Today,
hypericin’s role and its therapeutic value in treating
depression are still not very clear. We assume that
more than one active compounds contribute to the
antidepressant activity of the extract H. perforatum
through different mode and site of actions. Conse-
quently, more caution should be given to the
standardizing for extract or herb based on hypercin,
hyperforin, or hyperin content alone. In addition,
the insights into the molecular mechanisms of
hypericin actions are still far from complete. More-
over, phototoxicity and adverse interactions of
hypericin deserve further elucidation.
Acknowledgements
This work was supported by Key National Natural
Science Foundation of China (Grant No. 81130069),
Selected Program of Personnel Department for
Oversea Scholar (2009–2011); the Chinese National
S&T Special Project on Major New Drug Innova-
tion (Grant No. 2011ZX09307-002-01); the Key
Technologies of the Quality Standards and the
Safety of Health Food, “863 Program” (Grant No.
2010AA023006).

L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400 396
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400 L. F. Huang et al. / Journal of Chinese Pharmaceutical Sciences 21 (2012) 388–400
金丝桃属植物中的金丝桃素: 化学、植物来源和生物活性
黄林芳, 陈士林*
中国医学科学院 北京协和医学院 药用植物研究所, 北京 100193
摘要: 金丝桃素是金丝桃属植物中一种重要的次生代谢产物, 1830年首次被正式报道, 它是一种天然光敏型的二蒽
酮类化合物。金丝桃素具有抗病毒, 抗抑郁、抗肿瘤、抗菌、抗氧化等广泛的生物和药理活性, 并用于光动力治疗。在
过去的几十年中越来越多的证据表明金丝桃素具有很大的药用潜力和临床价值。本篇综述了金丝桃素的化学、植物来
源和生物活性。
关键词: 金丝桃素; 植物来源; 化学; 生物活性
Prof. Shilin Chen is the director of Institute of Medicinal Plant Development (IMPLAD),
Chinese Academy of Medical Sciences & Peking Union Medical College and the director of the WHO
Center for Collaboration on Traditional Medicine. Prof. Chen obtained his Ph.D degree from Chengdu
University of Traditional Chinese Medicine and he has been the Visiting Professor in Hong Kong
Polytechnic University. Prof. Chen has been trained in Royal Botanic Garden, Kewl. Now he holds a
concurrent position as the editor of such reputed Chinese medicinal research journals as Chin. Tradit.
Herb. Drugs, Acta Pharm. Sin. etc. He has so far published more than 200 scientific papers such as
Nature Commun., Cladistics, PNAS, Nat. Prod. Rep.
陈士林 博士, 教授, 现任中国医学科学院药用植物研究所所长、世界卫生组织传统医学合作中心主任。曾担任香港
理工大学访问教授, 并在英国皇家植物园丘园接受专业培训, 哈佛医学院Mclean 医院做访问学者等。教育部长江学者创
新团队负责人, 并担任《Chinese Herbal Medicines》(CHM, 中草药英文版) 杂志副主编、《药学学报》杂志副主编, 国际
国内十余种学术刊物的编委。首次自主完成了基于GIS中国常用中药材的产地生态适宜性数值区划, 编著出版《中国药
材产地生态适宜性区划》。在国际上首次验证并提出ITS2作为药用植物鉴定的通用DNA条形码序列, 完成了常用中药材
原植物DNA条形码鉴定, 主编《中药DNA条形码分子鉴定》、《中国药典中药材及原植物彩色图鉴》等书籍。通过全基
因组解析推动灵芝成为中药活性成分生物合成研究的首个药用模式真菌，论文在《自然》子刊发表。担任美国药典传
统中药咨询组顾问, 获得国家科技进步二等奖2项; 发表论文200余篇, 其中SCI论文100余篇, 包括Nature Commun., Cladistics,
PNAS, Nat. Prod. Rep. 等国际著名期刊。