Hinokinin, an Emerging Bioactive Lignan

Abstract

Hinokinin is a lignan isolated from several plant species that has been recently investigated in order to establish its biological activities. So far, its cytotoxicity, its anti-inflammatory and antimicrobial activities have been studied. Particularly interesting is its notable anti-trypanosomal activity.

Full text

Molecules 2014, 19, 14862-14878; doi:10.3390/molecules190914862
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Review
Hinokinin, an Emerging Bioactive Lignan
Maria Carla Marcotullio *, Azzurra Pelosi and Massimo Curini
Department of Pharmaceutical Sciences, University of Perugia, via del Liceo 1, 06123 Perugia, Italy;
E-Mails: azzurra.pelosi@gmail.com (A.P.); massimo.curini@unipg.it (M.C.)
* Author to whom correspondence should be addressed; E-Mail: mariacarla.marcotullio@unipg.it;
Tel.: +39-075-585-5100; Fax: +39-075-585-5116.
Received: 24 June 2014; in revised form: 10 September 2014 / Accepted: 10 September 2014 /
Published: 17 September 2014
Abstract: Hinokinin is a lignan isolated from several plant species that has been recently
investigated in order to establish its biological activities. So far, its cytotoxicity, its
anti-inflammatory and antimicrobial activities have been studied. Particularly interesting is
its notable anti-trypanosomal activity.
Keywords: cubebinolide; cytotoxicity; Trypanosoma; Chagas disease; antigenotoxic activity
1. Introduction
Lignans are important components of foods and medicines biosynthetically deriving from the
radical coupling of two molecules of coniferyl alcohol at C-8/C-8′ positions (Figure 1). They are
classified in different groups—dibenzylfuran, dihydroxybenzylbutane, dibenzylbutyrolactol,
dibenzylbutyrolactone, aryltetraline lactone and arylnaphtalene derivatives—on the basis of the
skeleton oxidation [1] and of the way in which oxygen is incorporated into the skeleton [2] (Figure 1).
Podophyllotoxin and deoxypodophyllotoxin are, perhaps, the most important biologically active
lignans, and their properties have been broadly reviewed [3,4].
In these last years, the biological activities of several lignans have been studied in depth [5–7] and
among them hinokinin (1) is emerging as a new interesting compound. The aim of this review is to
examine hinokinin (1) from a phytochemical and biological point of view. Peer-reviewed articles on
hinokinin were acquired via the Scopus, SciFinder, and PubMed databases.
OPEN ACCESS

Molecules 2014, 19 14863
Figure 1. General classes of lignans.
2. Phytochemistry
Hinokinin (1, Figure 2) was isolated for the first time by Yoshiki and Ishiguro in 1933 from the
ether extract of hinoki wood (Chamecyparis obtusa Sieb. et Zucc.) as a colorless crystalline
compound [8] and later Mameli, Briggs and Keimatsu established the identity of hinokinin with
cubebinolide [9–11]. Haworth and Woodcock determined the trans configuration of the lactone ring by
synthesis [12]. Biosynthesis of (−)-hinokinin was recently studied in Linum corymbulosum Reichenb
by Bayindir et al. [13]. Starting from the observation that callus cultures of L. corymbulosum
accumulate 1 [14], and according to the lignan composition found in Chamaecyparis obtusa by
Takaku [15], the authors proposed two different pathways for the biosynthesis of hinokinin starting
from (+)-pinoresinol (Scheme 1).
O
O
Aryltetralin Arylnaphtalene
Dibenzocyclooctadiene
O
O
OH
OH
O
O
O
O
Furofuran Furan
O
OH
O
O
O
OH
O
O
Dibenzylbutane Dibenzylbutyrolactol Dibenzylbutyrolactone
OH
OH
A
B
1'
2'
6'
7' 8'
9'
1
2
6
7
8
9

Molecules 2014, 19 14864
Scheme 1. Proposed biosynthetic pathways for hinokinin (1). PS, pinoresinol synthase;
PLR, pinoresino-lariciresinol reductase; SDH, secoisolariciresinol dehydrogenase; PLS,
pluviatolide synthase; HS, hinokinin synthase; PSS, piperitol-sesamin synthase; SDR,
sesamin-dihydrosesamin synthase; DDH, dihydrocubebin dehydrogenase [13].
O
O
HH
O
O
O
O
(+)-sesamin
O
HH
HO
O
O
O
O
(+)-dihydrosesamin (-)-dihydrocubebin
?HS
H
H
O
O
O
O
O
O
(-)-hinokinin
OH
OH
H
H
O
O
O
O
PSS
PSS
PS PLR PLR
coniferyl alcohol
OH
OH
OMe
2x
O
O
HO
OMe
OH
OMe
HH
(+)-pinoresinol
O
HO
OMe
OH
OMe
HH
HO
(+)-lariciresinol
OH
OH
MeO
HO
H
H
OH
OMe
(-)-secoisolariciresinol
SDH
?
PLS
O
O
OH
OMe
HH
O
O
(+)-piperitol
H
H
OH
OMe
O
O
O
O
(-)-pluviatolide
MeO
HO
H
H
OH
OMe
O
O
(-)-matairesinol
DDH
SDR
SDR

Molecules 2014, 19 14865
Figure 2. Hinokinin’s structure.
O
O
O
O
O
O
1
In the first pathway, pinoresinol is reduced to secoisolariciresinol by a pinoresinol-lariciresinol
reductase (PLR-Lc1), followed by the formation of the methylenedioxy bridges. In the second
pathway, there is the formation of the methylenedioxy bridges on pinoresinol to give sesamin and the
latter is then converted into dihydrocubebin and hinokinin. By the isolation of (PLR-Lc1), the enzyme
responsible of the enantiospecific conversion of (+)-pinoresinol to (−)-secoisolariciresinol, they
established that the first pathway is operative in hinokinin biosynthesis.
3. Distribution
After the first isolation from C. obtusa, hinokinin was isolated from C. formonensis [16] and from
several other plants[17–23], such as for example Zanthoxylum simulans [24], Z. naranjillo [25],
Z. lemairie [26], Z. monophyllum [27], Z. pistaciiflorum [28], Z. ailanthoides [29]. It was also found in
different species of Phyllanthus [30–32], Aristolochia [33–43], Piper [44–53], Virola [54–58],
Linum [59–63]. Another genus that produces hinokinin is Bursera. Compound 1 was found in
B. cuneata and B. citronella by Koulman [64] and in B. simaruba by Maldini et al. [65].
4. Biological acitivities
4.1. Cytotoxic Activity
Hinokinin (1) was found to be a component of several cytotoxic extracts such as the petroleum
ether fraction of a 75% ethanol extract of Zanthoxylum ailanthoides Sieb. & Zucc. stem bark [66]. The
cytotoxicity of hinokinin (1) has been investigated by several authors against different cancer lines:
P-388 (murine lymphocytic leukemia), HT-29 (human colon adenocarcinoma), A-549 (human lung
adenocarcinoma) and MCF-7 (human breast adenocarcinoma) [18,67].
Ikeda et al. tested hinokinin (1) isolated from Anthriscus sylvestris [68] against B16F10 (murine
metastatic melanoma), HeLa (human cervical cancer) and MK-1 (murine gastric adenocarcinoma) cell
lines using the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide (MTT)-microculture
assay [69]. Results are reported in Table 1.
Hinokinin was also examined as antitumor promoter agent in a human cytomegalovirus (HCMV)
immediate early (IE) antigen expression in human lung adenocarcinoma (A-549) cells [70]. After
establishing the ID50 (dose causing 50% inhibition) in A-549 cell line (40.72 μg/mL), the authors
found that 1 was able to reduce the IE antigen expression in HCMV-infected lung cancer cells in a
dose-dependent manner (ID1: 81, ID10: 57% reduction, respectively).

Molecules 2014, 19 14866
Table 1. Cytotoxicity of hinokinin (1) against selected tumor cell lines a.
P-388 HT-29 A-549 MCF-7 B16F10 HeLa MK-1
Hinokinin (1)
1.54 b 4.61
b 8.01 b 2.72
c 2.58 c 1.67 c
11.4
d 26.1 d 13.8 d
5.87 e 3.52 e 6.61 e
Mithramycin 0.08 b 0.07 b 0.06 b
0.06 e 0.08 e 0.07 e
Adriamycin 0.1
d 0.02 d 0.1 c
Podophyllotoxin e 0.001 0.0025 0.006
a ED50 μg/mL; b [18]; c [68]; d [67]; e [28].
According to Suffness and Pezzuto pure compounds are considered to have antitumor activity if
they show ED50 values less than 4 μg/mL [71]. From this point of view, hinokinin (1) could be
regarded as an antitumoral compound against P-388, HT-29, B16F10, HeLa and MK-1 cell lines.
Mansoor et al. evaluated the apoptosis induction of hinokinin in human hepatoma HuH-7 cells [72].
Hinokinin significantly reduced viability of HuH-7 cells and it showed to be a strong inducer of
apoptosis, inducing 2.4- and 2.5-fold increases in apoptotic cells as compared to controls. Furthermore,
hinokinin was found to be highly toxic using the brine shrimp letality test (BST) [73].
Recently Awale et al. studied the cytotoxicity of several lignans isolated from W. indica, against
Panc-1 cancer cell line (human pancreatic cancer) [74]. They found that (8S,8′S)-(+)-hinokinin as well
as other lignans, such as (+)-arctigenin, with the same stereochemistry, were inactive against Panc-1
cell line, whereas the (−) enantiomers were cytotoxic. These results indicate that the absolute
configuration of (−)-enantiomers is required for the cytotoxicity. Hinokinin resulted ineffective against
HONE-1 (nasopharyngeal carcinoma) and UGC-3 (gastric adenocarcinoma) cell lines [75].
4.2. Anti-Inflammatory Activity
It is well known that inflammation is a key event in cancer development [76] and for this reason
nowadays the anti-inflammatory activity of natural compounds is broadly studied. Hinokinin (1) was
shown to be a potent inhibitory compound on human neutrophil superoxide generation and elastase
release by neutrophils with an IC50 of 0.06 ± 0.12 μg/mL and an inhibitory percentage of 24.7 ± 6.2 at
10 μg/mL, respectively (diphenyleneiodonium: IC50 0.54 ± 0.21, phenylmethylsulfonyl fluoride:
35.24 ± 5.62% of inhibition) [77].
Furthermore, it was able to inhibit LPS-induced nitric oxide generation in RAW264.7 macrophages
(IC50 21.56 ± 1.19 μM; aminoguanidine: 6.51 ± 1.15 μM) [78]. da Silva et al. studied the in vivo
anti-inflammatory activity of hinokinin in the rat paw oedema reduction assay. Hinokinin (1) was
shown to possess a good anti-oedema activity (in terms of efficacy) in a dose dependent manner (at the
dose of 30 mg/kg it induced 63% of reduction, similar to indomethacin at the dose of 5 μg/mL) [79].
This anti-inflammatory activity was accompanied by an analgesic effect as demonstrated by the same
authors in the acetic acid-induced writhing test in mice. Compound 1 produced high inhibition levels
of the algogenic process (97%).
Immunosuppressive activity can play an important role in managing and resolving inflammation.
Regarding the immunosuppressive activity of hinokinin (1), it has no activity against NFAT

Molecules 2014, 19 14867
transcription factor [80], but it was found active in the lipopolysaccharide (LPS) induced cytokine
production assay for IL-10, IL-12, and TNF-α [81] and remarkably active in a lymphocyte
transformation assay [82] (Table 2). Recently, Desal et al. studied the anti-inflammatory effects of
hinokinin against IL-6 and TNF-α, establishing that 1 exerts its anti-inflammatory effects via an
NFκB-dependent mechanism [83].
Table 2. Immunosuppressive activity of hinokinin (1).
Cytokine Production Ratio a LTI d
TNF-α IL-12 IL-10 IL-6c
Hinokinin (1) 0.36 b 0.44 b 0.37 b 25.94 ± 1.02
77.5 c 20.5
LPS b 1 1 1
Prednisolone b 0.6 0.2 0.41
Dexamethasone 9.17 ± 0.53
a Cytokine production ratios were expressed as ratios to cytokine production induced by
LPS; b Hinokinin tested at 10 μg/mL, Prednisolone tested at 0.3 μg/mL [81]; c IC50 values
are given in μg/mL [83]; d Lymphocyte transformation inhibition, IC50 given in μg/mL [82].
Lima et al. evaluated the anti-inflammatory and analgesic activities of bark crude dichloromethane
extract (BCED) of Z. riedelianum [84]. They found that BCED was able to reduce carrageenan-induced
rat paw oedema after 4 h at the dose 100 mg/Kg (% inhibition: 57.4; indometacin 43.2% at 10 mg/Kg).
One of the components of the active extract was hinokinin. The authors suggested that the extract
could display anti-inflammatory activity associated with COX inhibition. Moreover, BCED displayed
a central analgesic activity too.
4.3. Anti-Parasitic Activities
4.3.1. Activity against Trypanosoma cruzi
Hinokinin (1) showed an interesting activity against Trypanosoma cruzi, the responsible of Chagas’
disease, a neglected protozoan disease that affects some 8 million people in Latin America [85,86].
Currently, there are only two effective drugs for Chagas’ disease treatment, namely nifurtimox and
benznidazole (BZN), which both cause serious side effects, therefore, there is an urgent demand for the
discovery of safer and more effective new therapeutic compounds. T. cruzi has a complex life cycle
characterized by several developmental forms present in vertebrate and invertebrate hosts. This
parasite exists in at least three morphologically distinct forms: infective (metacyclic or blood
trypomastigotes), insect borne (epimastigotes) which replicate in the vector, and intracellular
replicative (amastigotes) [87]. Hinokinin (1) in these last years has been studied as an interesting
antitripanosomal compound [86]. In 2005 de Souza et al. tested hinokinin (1) in vitro against free
amastigotes forms of Y strain of T. cruzi [88]. They found that 1 had an IC50 of 0.7 μM compared to
BZN (IC50 0.8 μM) (Table 3).

Molecules 2014, 19 14868
Table 3. In vitro anti-trypanosomal activity of hinokinin (1).a
Free
Amastigotes
Y Strain b
Intracellular
Amastigotes
CL Strain c
Epimastigotes
Forms of CL
Strain c
% of
Parasitaemia
Reduction c
Trypomastigotes d Intracellular
Amastigotes d
Hinokinin (1) 0.7 18.36 0.67 70.8 94.49 >141.24
BZN 0.8 20.00 30.89 29.0 146.02 >190.83
a IC50 (μM); b [89]; c [90]; d [90].
In view of its anti-trypanosomal activity, hinokinin (1) was later selected to be assayed against
epimastigote and intracellular amastigote forms of T. cruzi, both in vitro and in vivo assays [91]
(see Table 3). In the in vivo assays obtained results showed that the treatment with hinokinin (1)
promoted 70.8% of parasitaemia reduction in the parasitaemic peak, while benznidazole displayed
approximately 29.0% of parasite reduction.
The antitrypanosomal activity of hinokinin was determined using the MTT assay by Sartorelli and
coworkers [90]. They evaluated 1 against trypomastigotes and intracellular amastigotes of T. cruzi.
Results are shown in Table 3. In order to study the toxicity of hinokinin (1) in mammalian cells,
Sartorelli also studied hinokinin’s hemolytic activity and cytotoxicity. Hinokinin was shown to be
effective on trypomastigotes, but it resulted toxic to mammalian cells and with a low parasite
selectivity (selectivity index <1) [90].
To obtain better efficacy of this promising lead compound towards the intracellular forms of the
parasite, Saraiva et al. prepared and investigated the effect of a new formulation using biodegradable
polymers, such as poly(D,L-lactide-co-glycolic acid; PLGA), for the controlled release of hinokinin.
The treatment of infected mice with hinokinin-loaded microparticles was able to provoke significant
decrease in parasitemia levels compared with those observed in untreated controls [91]. Furthermore,
Saraiva et al. showed that the administration of hinokinin-loaded microparticles was able to reduce the
number of parasites more than hinokinin itself, in the course of the overall infection.
The reduction of tissue parasitism upon treatment with hinokinin (1), was evaluated in vivo by
Esperandim and coworkers by quantifying the enzyme β-galactosidase expressed by the CLB5 clone
strain of T. cruzi [92,93]. Treatment of mice infected with T. cruzi CLB5 with hinokinin (1) promoted
significant reduction of tissue parasitism (liver, spleen and heart) compared with data recorded for
untreated controls. Treatment with hinokinin (1) or benznidazole at a drug concentration of 50 mg/Kg
a day, furnished a parasitism reduction of 50.5% or 41.7% in the liver; 71% or 16% in the spleen; and
41.4%, or 30.4% in the heart, respectively. The authors noted that there were some differences
between the oral and intraperitoneal administration routes, being the former more effective for all
evaluated organs, while BZN administered intraperitonealy was more effective for spleen and heart
parasitism reduction [92]. Later, Esperandim evaluated in detail the in vivo therapeutic properties of
oral administered hinokinin (1) against CLB5 strain of T. cruzi [93]. Hinokinin was assayed at
concentration of 20 and 50 mg/kg. The authors observed that hinokinin at 20 mg/kg reduced the
number of circulating forms at peak parasitemia of 51%, while at 50 mg/kg of 34.2%. The karyometry
analysis once again showed a better behavior of 20 mg/kg dose (Table 4).
The non-linear behavior between the two doses, with the 20 mg/Kg dose being more effective than
the other, has been explained by an immunomodulatory response that hinokinin (1) can exert. It is well

Molecules 2014, 19 14869
known that the immunosuppression of chronically infected patients can lead to disease reactivation,
with high parasitemia and it has been already reported that hinokinin (1) can act as an
immunosuppressive compound (see above).
Table 4. Karyometry analysis. Mean values of the nuclear area from cells of the spleen,
liver, and heart of control groups and mice inoculated with the CL Brener clone strain of
Trypanosoma cruzi B5.
Groups Area (μm2)
Spleen Heart Liver
CINF a 10.86 ± 2.45 18.20 ± 8.81 32.99 ± 7.78
C b 8.12 ± 2.04 15.05 ± 8.64 28.56 ± 5.69
Hinokinin 20 c 9.32 ± 2.22 17.48 ± 8.53 30.15 ± 7.90
Hinokinin 50 d 10.00 ± 2.68 18.56 ± 7.74 30.50 ± 7.49
BZN 20 c 9.69 ± 2.50 17.59 ± 7.08 29.46 ± 8.03
BZN 50 d 9.62 ± 2.37 20.42 ± 10.75 28.56 ± 6.45
a CINF: infected not treated animals; b C: control, uninfected animals; c Tested dose:
20 mg/kg; d Tested dose: 50 mg/kg.
4.3.2. Antiplasmodial Activity
Hinokinin was tested for its antiplasmodial activity against 3D7-chloroquine sensitive and
Dd2-chloroquine resistant strains of Plasmodium falciparum. The IC50 of hinokinin (90.7 ± 1.4 μg/mL
and 54.4 ± 8.5 μg/mL, respectively; chloroquine IC50 0.094 μg/mL) showed that 1 doesn’t possess
significant antimalarial activity against either strain [94].
4.4. Antimicrobial Activity
Hinokinin (1) has been studied for its bioactivity against several other microorganisms. For
example, Silva et al. examined the activity of this compound against oral pathogens such as
Enterococcus faecalis, Candida albicans and several Streptococcus strains (see Table 5). It can be
pointed out from data reported in Table 5 that, although chlorhexidine is much more active than
hinokinin, 1 nevertheless showed a discrete antimicrobial activity [95]. Considering this antibacterial
activity of hinokinin, Silva et al. evaluated the anti-mycobacterial activity of 1 and others lignans [96].
Hinokinin showed to be moderately active against M. tuberculosis, with a MIC value equal to 62.5 μg/mL
and inactive against M. kansasii and M. avium (MIC 2000 μg/mL and 500 μg/mL, respectively).
Table 5. Minimum inhibitory concentrations (MIC; mM) of hinokinin against oral pathogens.
E.
faecalis
S.
salivarius
S.
sanguinis
S.
mitis
S.
mutans
S.
sobrinus
C.
albicans
Hinokinin (1) 0.38 0.25 0.25 0.25 0.32 0.28 0.28
a
Chlorhexidine b 5.9 1.7 3.9 5.9 5.9 1.5 7.9
a Fungicidal concentration; b MIC: μM.

Molecules 2014, 19 14870
4.5. Antiviral Activity
Several research groups studied the antiviral properties of hinokinin against human hepatitis B virus
(HBV) [97], human immunodeficiency virus (HIV) [29], SARS-virus (SARS-CoV) [98], and in all
cases 1 showed significant antiviral activity.
4.6. Genotoxic and Antigenotoxic Activities
In light of the interesting biological activities of hinokinin (1) and its potential use as therapeutic
agent, it is important to investigate its mutagenic and genotoxic activities. Recently Resende et al. used
the Ames and Comet assays, to assess the safety of using hinokinin as a drug [99]. In the Comet assay,
on Chinese hamster lung fibroblasts (V79), hinokinin was shown to not be genotoxic. In the treatments
with hinokinin associated with the known mutagen doxorubicin (DXR), the lower concentrations of 1
(0.5; 1.0 and 2.0 μM) significantly reduce DXR-induced DNA damage. The reduction in the DNA
damage frequency ranged from 60.8% to 76.0% and it is not dose dependent.
Resende also showed that hinokinin has a protective effect in preventing clastogenic damage caused
by methyl methanesulfonate (MMS), with the percent reduction ranging from 37.4% to 57.6% [100].
Mutagenic activity was evaluated by the Ames test, using the Salmonella typhimurium tester strains
TA98, TA100, TA97a and TA102, using five different concentrations of hinokinin (9.75–78.0 μg/plate)
selected on the basis of a preliminary toxicity test. The mutagenicity assays show that 1 did not induce
any increase in the number of revertant colonies relative to the negative control, indicating the absence
of any mutagenic activity.
Medola and coworkers studied the mutagenic and/or antimutagenic effects of hinokinin (1) in vivo
using the rat peripheral blood micronucleus test. The differences of micronucleated cells between
treated animals and control were not significative, demonstrating no genotoxic effect, while
co-exposition of the animals to hinokinin and DXR showed a significant reduction in the frequencies
of MNPCEs (micronucleated polychromatic erythrocytes). However, this protective effect of hinokinin
was not dose dependent [101].
4.7. Target-Based Studies
Hinokinin (1) was tested for several other biological activities, such as antispasmodic effect on
electrically induced (ECI), acetylcholine induced (AChI) and histamine induced contractions in
isolated guinea-pig ileum, using the Ca2+ channel blocker verapamil as a positive control [102].
Hinokinin (1) significantly inhibited ECI and AChI contractions.
Neurite outgrowth-promoting activity in PC12 cells of hinokinin (1) isolated from C. obtusa in the
presence or absence of Nerve Growth Factor (NGF, 2 ng/mL) was studied [103]. Hinokinin showed potent
neurite outgrowth-promoting activities: 76.0% ± 6.0% at 10 μg/mL, and 50.9% ± 2.6% at 5 μg/mL
when cultured with NGF, and 33.2% ± 5.4% at 10 μg/mL and 16.5% ± 2.6% at 5 μg/mL without NGF.
Nowadays, it is well established that neurons and glia development is regulated by neurotransmitters.
Monoamine neurotransmitters such as dopamine, norepinephrine and serotonine have a positive action
as classical growth factors, while glutamate and GABA (γ-aminobutyric acid) are down-regulating
proliferation agents [104]. Hinokinin (1) showed neuroprotective activity against glutamate induced

Molecules 2014, 19 14871
neurotoxicity in primary cultures of rat cortical cells (at 1.0 μM percentage of protection 42.6 ± 2.4, at
10.0 μM 56.9 ± 3.4; dizocipline maleate, a non-competitive antagonist of NMDA (N-methyl-D-aspartate)
receptor (one of the glutamate receptors) showed at 1.0 μM 71.7 ± 1.2 and at 10.0 μM 77.4 ± 2.1
percentage of protection) [105]. Furthermore, Timple et al. demonstrated that hinokinin is a selective
inhibitor of human dopamine and norepinephrine transporters in a noncompetitive manner with a low
affinity for the serotonine transporter [106].
Cytochrome P450 (CYP) enzymes play an important role in phase I oxidation metabolism of a
widw range of xenobiotics. In humans, 57 isoforms of CYP were identified, CYP3A4, CYP1A2,
CYP2A6, CYP2D6, CYP2C8 and CYP2E1 among others.
Methylenedioxyphenyl compounds were well known to inhibit cytochrome P (CYP) reaction
because they form stable complexes with CYP enzymes [107]. For this reason, several natural
compounds incorporating this structural feature have been studied for their inhibitory activity of CYP
enzymes. Hinokinin (1) containing two methylenedioxyphenyl rings in the molecules, showed potent
CYP inhibition [108]. Later Usia et al. showed that hinokinin is active on CYP3A4 but not on
CYP2D6 [109] and that CYP3A4 is inhibited in a time-, concentration- and NADPH-dependent
manners via the formation of a metabolite intermediate complex [110], therefore, attention should be
paid to a probable drug-drug interaction between hinokinin-containing preparations and molecules that
are substrates of CYP3A4.
5. Conclusions
Lignans represent an important biologically active class of secondary metabolites. The most studied
biological activities of these compounds are their antioxidant and anticancer properties. However, in
recent years the importance of such metabolites, especially hinokinin, as potential antichagasic agents
has been pointed out. In addition, hinokinin was shown to be non-genotoxic and to possess a
neuroprotective effects. For all these reasons, hinokinin is emerging as a promising compound with
broad and interesting biological activity.
Author Contributions
M.C.M. conceived the work. M.C.M. and A.P. collected and organized bibliographic data. M.C.M.
and M.C. wrote the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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