Hepatoprotective leads from plants

Abstract

Liver has a surprising role in the maintenance, performance and regulation of homeostasis of the body. It is involved with almost all the biochemical pathways responsible for growth, fight against disease, nutrient supply, energy provision and reproduction. In the same time, hepatic diseases stand as one of the leading health quandary worldwide. Therapies developed along the principles of western medicine are often limited in efficacy, leads to serious adverse effects which eventually cause hepatic damage, and are often costly. In the absence of reliable liver protective drugs in modern medicine, there exists a challenge for pharmaceutical scientists to explore the potential of hepatoprotective activity of plants based on traditional use. Study of many traditional plants used for liver problems led to the discovery of active compounds yet developed to successful drugs. The effectiveness of most of these phytochemicals were scientifically validated. The present review is a compilation of data on promising hepatoprotective compounds of plant origin.

Full text

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Hepatoprotective leads from plants
P. Pushpangadan, T.P. Ijinu, Vipin M. Dan* and V. George
Amity Institute for Herbal and Biotech Products Development,
3-Ravi Nagar, Peroorkada P.O., Thiruvan anthapura m-695 005, Kerala, India
*Rajiv Gandhi Centre for Biotechnology, Thycaud P.O., Thiruvananthapuram-69 5 014, Kerala, India
Received November 20, 2015: Revised December 5, 2015: Accepted December 15, 2015: Published online December 30, 2015
Copyright @ 2015 Ukaaz Public atio ns. All rights rese rved.
Email: ukaaz@yahoo.com; Website: www.ukaazpubli cati ons.com
Abstract
Liver has a surprising role in the maintenance, performance and regulation of homeostasis of the
body. It is involved with almost all the biochemical pathways responsible for growth, fight
aga inst disease, nutrient supply, energy provision and reproduction. In the same time, hepatic
diseases stand as one of the leading health quandary worldwide. Therapies developed along the
principles of western medicine are often limited in efficacy, leads to serious adverse effects which
eventually cause hepatic damage, and are often costly. In the absence of reliable liver protective
drugs in modern medicine, there exists a challenge for pharmaceutical scientists to explore the
potential of hepatoprotective activity of plants based on traditional use. Study of many tradi-
tional plants used for liver problems led to the discovery of active compounds yet developed to
successful drugs. The effectiveness of most of these phytochemicals were scientifically validated.
The present review is a compila tion of data on promising hepatoprotective compounds of plant
origin.
Key words: Liver diseases, hepatoprotective agents, phytochemicals, silymarin, hepatocellular
carcinoma
1. Introduction
Liver diseases are one of the fatal diseases in the world and over
10% of the world population afflicted liver diseases (Mishra and
Tiwari, 2011). It includes chronic hepatitis, alcoholic steatosis,
fibrosis, cirrhosis and hepatocellular carcinoma, are the most health
threatening conditions, drawing considerable attention from medical
professionals and scientists (Zhang et al., 2013). Modern medicines
have little to offer for alleviation of hepatic diseases and it is chiefly
the plant based preparations which are employed for the treatment
of liver disorders. The current options for the treatment of liver
disease include pharmacotherapy, surgery as well as liver
transplantation, all of which have shown limited therapeutic
benefits and are associated with serious complications (Muriel and
Rivera-Espinoza, 2008; Duvoux, 2001).
The use of natural products to prevent and/or treat various liver
diseases, dates back to several thousand years in many countries.
The 21st century has seen a paradigm shift towards therapeutic
evaluation of herbal products in liver disease models by carefully
synergizing the strengths of the traditional systems of medicine
with that of the modern concept of evidence-based medicinal
evaluation, standardization and randomized placebo controlled
clinical trials to support clinical efficacy (Thyagarajan et al., 2002).
ANNALS OF
PHYTOMEDICINE
An Intern ational Journal
Annals of Phytomedicine 4(2): 4-17, 2015
Journal homepage: www.ukaazpublications.com
ISSN : 2278 -9839
Review
Author for correspondence: Padma Shri Professor P. Pushpangadan
Amity Institute for Herbal and Biotech Products Development,
3-Ravi Nagar, Peroorkada P.O, Thiruvananthapuram -695 005,
Kerala, India
E-mail: palpuprak ulam@yahoo.co.in
Tel.: +91-9895066816
Therapies developed along the principles of western medicine are
often limited in efficacy, carry the risk of adverse effects, and are
often too costly. Some liver protective medicines and their adverse
effects are depicted in Table 1.
2. Hepatoprotective phytochemicals
Phytochemicals that are found in vegetables, fruits, plant extracts,
herbs, etc., have been traditionally used for treating liver diseases.
Many phytochemicals have been clinically available as potent
hepatoprotective agents against commonly occurring liver diseases.
This review summarizes the current progress in the phytochemicals
used in treatment of various liver diseases. The compounds described
herein are silymarin, andrographolide, curcumin, glycyrrhizin,
berberine, ursolic acid, picroside and kutkoside, resveratrol, wogonin,
phyllanthin, emodin, thymoquinon, etc.
2.1 Silymarin
Silybum marianum (L.) Gaertn. (Fam. Asteraceae) is commonly
known as ‘milk thistle’ and is one of the oldest, thoroughly
investigated plant in the treatment of liver diseases. The extracts of
milk thistle are being used as a general medicinal herb from as early
as 4th century B.C. and first reported by Theophrastus. In the 1st
century A.D., Dioskurides used this plant as emetic as well as a
general medicin al herb. It became a favoured medicin e for
hepatobiliary diseases in 16th century and the drug was revived
again in 1960 in central Europe (Luper, 1998; Schuppan et al.,
1999; Pradhan and Girish, 2006).
2.1.1 Chemistry
Silymarin is a mixture of flavonolignans (Wagner and Seligmann,
1985). The principal components of silymarin are silybin A,

5
silybin B, isosilybin A, isosilybin B, silychristin A, silychristin B
and silydianin. The first six compounds exist as equimolar mixtures
as trans diastereoisomers. These diastereomers have very similar
1H and 13C NMR spectra and have no characteristic signals for
facile identification of the individual isomers (Lee and Liu, 2003).
Silymarin
2.1.2 Pharmacology
Hepatoprotective activity of silymarin has been demonstrated by
researchers from all over the world against partial hepatectomy
models (Sonnenbitchler et al., 1986; Srivastava et al.,1996) and
toxic models like carbon tetrachloride (Subramoniam and
Pushpangadan, 1999; Sherlock and Dooley; 2002), acetaminophen
(Neuman et al., 1999; Renganathan, 1999), ethanol (Wang et al.,
1996), galactosamine (Datta et al., 1999), iron (Bhattacharya et al.,
2000) and Amanita phalloides toxin (Vogel et al., 1984) induced
hepatotoxicity.
2.1.3 Mechanism of action
Preclinical studies showed that silymarin has multiple actions in
liver protection. The antioxidant property (Kosina et al., 2002)
and cell-regenerating functions as a result of increased protein
synthesis (Sonnenbichler and Zetl, 1986) are considered as most
important. Action of silibinin in isolated Kupffer cells indicated a
strong inhibitory effect on LTB4 formation (Dehmlow et al., 1996).
Silymarin is found to suppress both NF-B DNA binding activity
and its dependent gene expression induced by okadaic acid in the
hepatoma cell line HEPG2 (Saliou et al., 1998). It has also a
regulatory action on cellular and mitochondrial membrane
permeability in association with an increase in membrane stability
against xenobiotic injury (Munter et al., 1986; Pradhan and Girish,
2006).
2.1.4 Clinical trials
Silymarin significantly decrease ALT and AST levels in patients
with alcoholic liver disease (Salmi and Sarna, 1982). In chronic
alcoholic liver disease, a dose of 420 mg/day of silymarin resulted
in normalization of serum transaminases (AST, ALT and -GT),
total bilirubin, significant decrease in procollagen III peptides and
an improvement in the histological examination of liver biopsies
(Feher et al., 1989). In patients with alcoholic cirrhosis, the survival
rate was 58 per cent in silymarin group and 39 per cent in placebo,
indicated that the treatment was effective (Ferenci et al., 1989).
Trials performed against Amanita mushroom poisoning showed
positive result (Carducci et al., 1996). Coadministration of silymarin
with tacrine (an anticholinesterase drug) showed improvement in
tolerability in the initial phase of treatment (Allain et al., 1999).
The major causes of liver related deaths were upper gastrointestinal
bleeding (UGB), hepatic failure, or primary liver cell carcinoma
(Khan et al., 2000). The data showed that the incidence of hepato
cellular carcinoma was lower in the silymarin treated patients (Saller
et al., 2001). The reduction in lipid peroxidation produced by
silymarin can improve metabolic control and reduce requirements
for endogenous insulin in such patients. Silymarin treatment
produced significant reduction in daily and fasting blood glucose,
daily glucosuria, glycosylated haemoglobin values, malondialdehyde
values and a drop in insulin requirement and fasting insulinaemia
(Velussi et al., 1997; Pradhan and Girish, 2006).
2.1.5 Toxicity and drug interaction
Silymarin is reported to have a very good safety profile (Saller et
al., 2001). Both animal and human studies showed that silymarin is
non-toxic even when given at high doses (>1500 mg/day). However,
a laxative effect is noted at these doses may be due to increased bile
secretion and bile flow (Luper, 1998). Few reports of associated
occurrence of adverse effects related to gastrointestinal tract like
bloating, dyspepsia, nausea, irregular stool, diarrhoea (Jacobs et
al., 2002), pruritus, headache, exanthema, malaise, asthenia and
vertigo (Saller et al., 2001). In vitro studies showed that in higher
concentrations, silymarin has an inhibitory effect on both phase I
and phase II drug metabolizing enzymes such as CYP3A4, CYP2D6
and CYP2C9 (Sridar et al., 2004).
2.2 Andrographolide
And rographis paniculata (B urm.f.) Wall. ex Nees (Fam.
Acanthaceae) is a herbaceous medicinal plant, often cultivated in
India, China, Taiwan, Thailand and many other countries. Due to
its extreme bitter taste, it is often referred to as the “king of bitters”.
The main components of the herb are diterpene lactones.
Andrographolide was the first diterpene lactone identified. Later,
four more diterpene lactones, i.e., neoandrographolide, deoxy-
didehydroandrographolide,deoxy-oxoandrographolide and deoxy-
andrographolide were isolated (Zhu, 1998). Andrographolide,
structurally a labdane diterpenoid, is quantitatively the major bitter
tasting secondary metabolite of the plant and it is now often
considered to be the major bioactive constituent of the plant involved
in its observed therapeutically interesting bioactivities (Lim et al.,
2012; Hidalgo et al., 2013).
H
H
HO
O
H
O
O
O
Me
Me
H2C
Andrographolide

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A crude extract of A. paniculata induce mouse hepatic cytochrome
P450 isoforms CYP1A1 and CY P2B via increases in
ethoxyresorufin-O-dealkylase and pentoxyresorufin-O-dealkylase
activities (Jarukamjorn et al., 2006). Further, it is demonstrated
that andrographolide significantly upregulate the CYP1A1, CYP1A2
(Jaruchotikamol et al., 2007) and CYP1B1 (Chatuphonprasert et
al., 2009) mRNA expression. 14-deoxy-11, 12-didehydro andro
grapholide and andrographolide have been shown to inhibit CYP1A2,
CYP2D6 and CYP3A4 expressions in HepG2 cells (Jarukamjorn
et al., 2010). In contrast, neoandrographolide suppressed BNF
induced CYP1A1 expression (Chatuphonprasert et al., 2011).
Interaction with GSH significantly enhanced the BNF inducible
CYP1A1 mRNA expression in C57BL/6 mouse hepatocytes (Kondo
et al., 2011). Qiu et al. (2012) demonstrated that andrographolide
(1, 10, 100 M) significantly down regulates the mRNA level and
protein level of CYP3A4 in Caco-2 cells in a combination therapy
study. In addition, the A. paniculata 60% ethanol extract or
andrographolide may cause herb-drug interactions through CYP3A
and CYP2C9 inhibition in vitro or CYP2C11 inhibition in vivo
(Pekthong et al., 2008, 2009).
2.3 Curcumin
Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-
3,5-dione] is a bright yellow-colored phenolic compound that was
initially isolated from Curcuma longa L. (Fam. Zingiberaceae)
rhizomes in 1815 (Gupta et al., 2013). Curcumin attenuates liver
injury induced by ethanol, thioacetamide, iron overdose, cholestasis
and acute, subchronic and chronic carbon tetrachloride intoxication;
moreover, it reverses CCl4 cirrhosis to some extent. The curcumin
has the ability to inhibit several factors like NF-B, which modulates
several proinflammatory and profibrotic cytokines as well as its
antioxidant properties, provide a rational molecular basis to use it
in hepatic disorders (Rivera-Espinoza and Muriel, 2009). Numerous
studies demonstrated decreased hepatic expression of NF-B and
its downstream targets by curcumin (Bisht et al., 2011; Tu et al.,
2012b; Xu et al., 2014). It has also been shown that curcumin could
decrease the expression of TLR2 and TLR4 and their ligand molecule
HMGB1 in the rat model of fibrogenesis (Tu et al., 2012b) and T-
cell-mediated hepatitis in concanavalin A-challenged mice (Tu et
al., 2012a, 2013), suggesting a potential to attenuate inflammatory
processes in the liver. Curcumin could ameliorate LPS/D-GalN-
induced liver injury through reduction of hepatic mRNA levels of
SIRT1 (Zhang et al., 2014a). Over expression and hyperactivity of
hepatic protein tyrosine phosphatase 1B (PTP1B) was reduced
by curcumin, with subsequent improvement of insulin and leptin
signaling. Moreover, it decreased the hepatic gene expression of
inflammatory cytokines, procollagen I and TIMP-1 in experimental
steatohepatitis in mice (Vizzutti et al., 2010; Domitrovic and
Potocnjak, 2015).
H
HO O
OO
OCH3OCH3
Curcumin
Curcumin down-regulated Patched (Ptch) and Smoothened (Smo),
two key elements in Hedgehog (Hh) signaling, simultaneously
restoring Hhip (a gene known to be downregulated upon HSC
activation) expression in fibrotic rat livers and cultured HSCs (Lian
et al., 2015). Curcumin also impaired production of ECM proteins
in alcohol-stimulated HSCs and CCl4 induced liver by suppressing
the TGF-/Smad 2/3 signaling and inducing Smad7 (Chen et al.,
2014). Curcumin could also inhibit HBV and HCV replication via
down-regulation of metabolic coactivator PGC-1 and the Akt/
SREBP-1 pathway, respectively (Kim et al., 2010; Rechtman et al.,
2010). However, another study demonstrated inhibition of HCV
replication through suppression of PI3K/Akt and induction of
HO-1 (Chen et al., 2012). Administration of curcumin has been
shown to decrease activity of CYP2B1/2 and CYP1A1 in mice liver
(Sehgal et al., 2013) and inhibit activation of CYP2E1 in chronic
alcohol and high-fat diet-induced liver injury in mice (Lee et al.,
2013). Similarly, microsomal CYP2C and CYP3A activities in bovine
hepatocytes were inhibited by treatment with curcumin (Lemley
and Wilson, 2010; Domitrovic and Potocnjak, 2015).
Curcumin has shown beneficial effects in clinical trials in patients
with arsenic-induced genotoxicity (Biswas et al., 2010; Roy et al.,
2011a). More than 84 clinical studies, including randomized blind
placebo-controlled, non-randomized phase II/III trials, and so on
(www.ClinicalTrials.gov), are investigating the effects of curcumin
on human disorders (Nabavi et al., 2014). The FAO and WHO Expert
Committee on Food Additives in 1996 reported that the acceptable
daily intake (ADI) of curcumin is up to 3 mg/kg body weight. It is
well known that curcumin is a natural product with a long history of
consumption in the human diet, but there appear to be few scientific
studies on its toxicity to both animals and humans, especially at high
doses (Rivera Espinoza and Muriel, 2009; Nabavi et al., 2014).
2.4 Glycyrrhizin
Glycyrrhizin, a triterpenoid glycoside isolated from the roots of the
plant, Glycyrrhiza glabra L. (Fam. Fabaceae), has been shown to
increase antioxidant defence in the liver (Rahman and Sultana, 2006;
Orazizadeh et al., 2014). Glycyrrh izin and its metabolite,
glycyrrhetinic acid, inhibited collagen I(I) gene expression and
progression of liver fibrosis induced by CCl4 (Moro et al., 2008).
The compounds significantly decreased mRNA expression of
TGF-1, Smad2/3 and specificity protein-1 (SP-1) in the liver (Qu
et al., 2015).
Glycyrrhizin

7
The potential of this compound to accelerate recovery from hepatic
injury has been demonstrated in vitro. Glycyrrhizin suppressed
activation of HSCs and induced their apoptosis by blocking nuclear
translocation of NF-B (Qu et al., 2012). Importantly, glycyrrhizin
and its metabolites may induce growth of hepatocytes by binding to
EGFR and stimulating ERK2-mediated hepatocyte DNA synthesis
and proliferation (Kimura et al., 2001), which could contribute to
acceleration of liver regeneration. Glycyrrhizin treatment of HCV-
infected hepatic cells resulted in reduced release of infectious HCV
particles through inhibitory effect on (PLA2), whereas a cotreatment
with glycyrrhizin augmented antiviral effect of IFN- (Matsumoto
et al., 2013). Moreover, glycyrrhizin modified the intracellular
transport and suppressed sialylation of HBsAg in vitro (Takahara et
al., 1994), which was also observed in patients with chronic HBV
infection (Sato et al., 1996; Domitrovic and Potocnjak, 2015).
In patients who failed previous IFN--based therapy, intravenous
administration of glycyrrhizin significantly reduced serum alanine
transaminase (ALT) level after 12 weeks of therapy and improved
necroinflammation and fibrosis after 52-week treatment (Manns et
al., 2012). In another study, a 6-month cotreatment with IFN-2b
and glycyrrhizin was less effective in reducing ALT levels compared
to IFN-2b and ribavirin coadministration. Similar effect of this
compound was observed in another study on 1093 patients
nonresponding to IFN (Veldt et al., 2006). Importantly, usage of the
suppositories of glycyrrhizin improved quality of life for chronic
hepatitis C patients similarly to intravenously treated patients, with
greater benefit in those who did not respond to IFN therapy (Fujioka
et al., 2003; Domitrovic and Potocnjak, 2015).
2.5 Berberine
Berberine is a plant alkaloid present in many medicinal herbs, such
as Hydrastis canadensis, Rhizoma coptidis (Fam. Ranunculaceae),
Berberis aquifolium, B. aristata and B. vulgaris (Fam. Berberidaceae)
(Ye et al., 2009; Tang et al., 2009). Berberine possesses antioxidant
properties which could suppress oxidative stress in the liver (Li et
al., 2014; Othman et al., 2014).
O
O
N
O
O
CH3CH3
Berberine
Berberine alone or in combination with S-allyl-cysteine diminished
these effects and induced apoptosis by stimulating protein
phosphatase 2A (PP2A) and inhibiting JNK activation (Sengupta et
al., 2014). Furthermore, amelioration of the early phase of DEN and
phenobarbital-induced hepatocarcinogenesis by berberine was
accompanied by suppression of iNOS expression and inhibition of
CYP2E1 and CYP1A2 activities (Zhao et al., 2008). Berberine also
ameliorated apoptosis in ischemia-/reperfusion-injured rat livers by
increasing the Bcl-2/Bax ratio and inhibiting caspase-3 cleavage. The
mechanism of its action involved up-regulation of Akt, with
concomitant inhibition of mTOR expression (Sheng et al., 2015).
Moreover, berberine protected against ethanol-induced steatosis in
mice by restoring PPAR/PGC-1 and hepatocyte nuclear factor
4 alpha (HNF4)/microsomal triglyceride transfer protein (MTTP)
pathways, involved in secretion of lipoproteins (Zhang et al., 2014b).
Berberine pretreatment in LPS-induced inflammation in mice reduced
the expression of hepatic proprotein convertase subtilisin/kexin type
9 (PCSK9), a cholesterol homeostasis regulator, and decreased
IFN-, TNF-, IL-1 and 8-isoprostane levels (Xiao et al., 2012).
CCl4-induced acute liver injury was ameliorated by berberine through
suppression of TNF-, COX-2 and iNOS expression, with
concomitant attenuation of oxidative/nitrosative stress (Domitrovic
et al., 2011). In experimental liver fibrosis, berberine decreased TGF-
1 expression, increased MMP-2 levels and stimulated elimination
of fibrous deposits (Domitrovic et al., 2013). Moreover, berberine
treatment attenuated liver fibrosis via activation of AMPK and
decreased expression of NOX4 and phosphorylated Akt (Li et al.,
2014a). In hyperlipidemic patients with HBV, HCV and liver cirrhosis,
treatment with 500 mg of berberine hydrochloride orally twice a day
for 3 months has been shown to markedly improve serum indicators
of liver injury and lipid parameters (Zhao et al., 2008), suggesting its
beneficial potential in hepatic viral infections.
2.6 Ursolic acid
Ursolic acid is a triterpenoid that exists as a major component of
some traditional medicinal herbs like Ocimum sanctum (Fam.
Lamiaceae), Vaccinum myrtillus (Fam. Vacciniaceae), Boerhavia
diffusa (Fam. Nytaginaceae), Harpagophytum procumbens (Fam.
Pedaliaceae), Sambucus nigra (Fam. Caprifoliaceae), Mentha piperita
(Fam. Lamiaceae), Vinca minor (Fam. Apocynaceae), Lavandula
augustifolia (Fam. Lamiaceae), Origanum vulgare (Fam. Lamiaceae),
Thymus vulgaris (Fam. Lamiaceae), Crataegus laevigata (Fam.
Rosaceae), Prunus laurocerasus (Fam. Rosaceae), etc.
O
HO
O
H
H
H
Ursolic acid
Ursolic acid was shown to activate autophagy in mice model of
hepatic steatosis in the NAFLD model in rodents, by inducing the
expression of LC3-II and beclin 1 (Jia et al., 2015). Ursolic acid
treatment significantly decreased hepatic steatosis in db/db mice by

8
modulating -oxidation and ER stress in the liver (Li et al., 2015a).
Mechanistically, it reduced expression of the unfolded protein
response sensor inositol-requiring enzyme-1alpha (IRE-1)
expression and activation of ERK, JNK and CHOP, while increasing
PPAR levels. In addition, ursolic acid decreased palmitic acid-
induced intracellular lipid accumulation in L02 cells, with concomitant
inhibition of ATF6, IRE-1 and CHOP gene expression. In culture-
activated HSCs, ursolic acid activated caspase-3 and caspase-9,
decreased phosphorylation of Akt and diminished nuclear localization
of NF-B (Wang et al., 2011), suggesting their apoptosis and
suppression of survival mechanisms. Treatment of hepatocytes with
ursolic acid in the presence of LPS dose-dependently inhibited ROS
production and NF-B activation. Ursolic acid also prevented CCl4-
induced hepatotoxicity and fibrosis in mice, at least in part, through
modulation of the Nrf2/ARE signaling pathway (Ma et al., 2015;
Domitrovic and Potocnjak, 2015).
2.7 Picroside and kutkoside
The underground parts of Picrorhiza kurrooa Royle ex Benth (Fam.
Scrophulariaceae) have been found to yield a crystalline product
“Kutkin” or “Picroliv”, which usually is a mixture of two major C9
– iridoid glycosides, i.e., picroside I ( 6-O- trans cinnamoylcatalpol)
and kutkoside (10-O-vanilloylcatalpol) in the ratio of 1:2 (Singh et
al., 1992). The plant grows in Himalayan region in moist, rocky
slopes as well as in organic soils, Garhwal to Bhutan, southeast
Tibet, north Burma and west China.
Picroside
P. kurroa forms a major ingredient of many indigenous medical
preparations, especially useful for the treatment of diseases of liver,
such as hepatitis (Mittal et al., 1978; Ansari et al., 1988) and jaundice
(Handa et al., 1986). Picroliv antagonizes paracetamol-induced
decrease in LDL receptor cell-surface expression and increase in
conjugated di-enes in hepatocytes (Singh et al., 1992). In rats, infected
with Plasmodium berghei, picroliv reduced the increased levels of
lipid peroxidation products in the liver and brain and normalized
glutathione metabolism (Chander et al., 1992). Picroliv has been
found to be a potent inhibitor of hepato-carcinogenesis induced by
N-nitrosodiethylamine (NEDA) in male wistar rats. Picroliv was
found to increase the life span of tumor bearing animals (Kumar and
Kuttan, 2000). Aqueous extact of P. kurroa root may have potential
as feed additives to increase the efficiency of utilization of energy
and nitrogen in ruminant diet (Alexander et al., 2008).
In another experimental study, the investigations were carried out on
the effect of oral administration of picroliv, obtained from total alcohol
extractable rhizome of P. kurroa concurrently with toxication of rats
for two weeks with CCl4 and the results showed that administration
of carbon tetra chloride to normal rats increased activities of hepatic
5’-nucleotidase, acid phospahatase, acid ribonuclease while the
activities of succinate dehydrogenase, glucose 6-phosphatse,
superoxide dismutase and cytochrome p450 were decreased. Picroliv
in doses of 6 and 12 mg / Kg provided a significant protection against
most of the biochemical alterations produced by CCl4 (Diwedi et al.,
1990; Pandey and Verma, 2013).
2.8 Resveratrol
Resveratrol (3,5,4’-trihydroxy-trans-stilbene), a natural phytoalexin
present in peanuts, grapes and red wine, possesses several beneficial
actions including antioxidant and anti-inflammatory properties,
prevention of cancer and modulation of lipid metabolism (Fremont,
2000; Dong, 2003; Aggarwal et al., 2004).
O
O
O
H
H
H
Resveratrol
Resveratrol could significantly reduced TNF- and IL-6 mRNA and
decreased the number of Kupffer cells recruited in the injured liver. It
decreased fibrosis and promoted hepatocyte regeneration, which
increased the survival of BDL mice. Resveratrol was beneficial for
the treatment of cholestatic liver injury (Chan et al., 2011). The
histopathological, immunohistochemical, and apoptotic analysis were
used to assess the effect of resveratrol on morphological, oxidative
status in CCl4-challenged liver tissue (Roy et al., 2011b). The
administration of resveratrol either at the early or advanced stages of
hepato-carcinogenesis is equally effective and involves the activation
of the apoptotic pathway in male wistar rats (Rajasekaran et al.,
2011). The inhibitory effect of resveratrol on vascular endothelial
growth factor activity and angiogenesis in hepatocellular carcinoma
may occur partly through suppression of the activation of NF-
kappa B in HepG2 cells (Yu et al., 2010). Resveratrol showed not
only reduced mRNA expression of fibrosis related genes such as
transforming growth factor beta1, collagen type I, and alpha-smooth
muscle actin, but also a significant decrease of hydroxyproline in
rats with DMN-induced liver fibrosis (Hong et al., 2010). Resveratrol
exhibited in vivo hepatoprotective and antifibrogenic effects against
DMN-induced liver injury, suggesting that resveratrol could be used
to treat liver injury and fibrosis and be useful in preventing the
development of liver fibrosis and cirrhosis (Zhang et al., 2013).
2.9 Wogonin
Wogonin is a monoflavonoid isolated from Scutellaria radix L. (Fam.
Lamiaceae) which has been used for thousands of years in Asia for
inflammatory diseases and also for hepatitis (Guo et al., 2007). The

9
anti-HBV activity of wogonin demonstrates its ability to suppress
hepatitis B surface antigen (HBsAg) secretion in cell culture. Plasma
HBsAg level was significantly reduced in ducks treated with wogonin,
and an additional histopathological evaluation of their liver showed
considerable improvement. Wogonin had effective cytotoxic effects
through apoptosis induction in hepatocellular carcinoma cells SK-
HEP-1; activation of caspase-3 cascade, induction of p53 protein
and alternative expression of p21 protein were involved (Chen et al.,
2002). Furthermore, immunohistological staining of human HBV-
transgenic mouse livers confirmed the potential of wogonin in HBsAg
reduction (Zhang et al., 2013).
Wogonin
2.10 Phyllanthin and hypophyllanthin
Phyllanthin and hypophyllanthin are potent hepatoprotective
phytochemicals found in Phyllanthus sp. (Fam. Euphorbiacea).
Chemically, both phyllanthin and hypophyllanthin are lignans
(Krishnamurthi and Seshandri, 1946; Row et al., 1966). Phyllanthin
is linked through C8-C80 of phenyl propanoid units, while
hypophyllanthin is additionally linked through C2-C70 to make a
tetrahydronaphthalene ring system (Row et al., 1967).
Phyllanthin
Hypophyllanthin
In India, it is used as a single drug in the treatment of jaundice in
children (Dixit and Achar, 1983), and British researchers showed
that children treated with Phyllanthus extract for acute hepatitis
could return the liver function to normal within 5 days. Using a rat
hepatocyte primary culture, Shamasundar et al. (1985) have shown
that phyllanthin and hypophyllanthin protected cells against carbon
tetrachloride cytotoxicity. P. niruri is used as one of the components
of a multiherbal preparation for treating liver ailments (Kapur et al.,
1994). However, a hepatoprotective effect of P. niruri has not been
demonstrated in vivo. Several studies have shown that the
hepatoprotective effect is associated with antioxidant rich plant
extracts (Emmanuel et al., 2001; Harish and Shivanandappa, 2006).
Phyllanthin and hypophyllanthin compounds present in P. amarus
have been shown to have hepatoprotective effect against CCl4,
galactosamine and ethanol induced hepatotoxicity in primary cultured
rat hepatocytes and HepG2 cells (Shamsunder et al., 1985; Krithika
et al., 2009; Chirdchupunseree and Pramyothin, 2010).
2.11 Emodin
Emodin (1,3,8-trihydroxy-6-methylanthraquinone), is an active
ingredient in the root and rhizome of Rheum palmatum L. (Fam.
Polygonaceae) (Wang et al., 2011) and several other plant species
like Rheum officinale, Ventilago madraspatana, Polygonum
multiflorum, Polygonum cuspidatum, Rumex patientia, Rhamnus
catharticus, Rhamnus orbiculatus, Aloe vera, Acorus tatarinowii,
Cassia obtusifolia, Cassia occidentalis, Eriocaulon buergerianum,
etc.
O
O
O
O
O
H3C
H
H
H
Emodin
Emodin protected against acetaminophen and CCl4-induced oxidative
stress and acute liver injury in rats (Dang et al., 2008; Bhadauria,
2010). Emodin also alleviated alcohol-mediated oxidative stress and
liver steatosis in mice by down-regulating hepatic CYP2E1 expression
(Liu et al., 2014d). Emodin also ameliorated NAFLD in rats induced
with a high caloric diet by suppressing GRP78-mediated SREBP-1c
pathway in the liver and restoring reduced expression of PPAR
gene expression (Dong et al., 2005; Li et al., 2015b). In steatotic
hepatic cells, emodin down-regulated HMGCR and diacylgycerol
acyltransferase 1 (DGAT1), key enzymes in the synthesis of
cholesterol and triglycerides, while upregulating expression of
CYP7A, involved in hepatic bile acid biosynthesis (Wang et al.,
2014). Protection against CCl4-induced fibrogenesis by emodin was
mediated by the reduction of the mRNA levels of TGF-1 and
Smad4 and inhibition of myofibroblastic differentiation (Dong et al.,
2009). Another study by Lin et al. (1996) showed emodin exhibited
hepatoprotective effects on CCl4 as well as D-galactosamine induced
liver damage. The histopathological examination also clearly showed
that emodin reduced lymphocyte cells, Kupffer cells, ballooning
degeneration, cell necrosis and hyaline degeneration on CCl4 and
D-galactosamine induced tests.

10
2.12 Thymoquinone
Thymoquinone, a monoterpenoid quinone, the major active
compound derived from the Nigella sativa L. (Fam. Ranunculaceae)
seeds, has been reported to protect experimental animals against
oxidative hepatic injury by improving hepatic antioxidant status
(Sayed-Ahmed et al., 2010; Prabhakar et al., 2014). In addition,
thymoquinone treatment has been shown to significantly suppress
CYP1A2, CYP3A4 but not CYP2E1 activity in rabbits (Elbarbry et
al., 2012). Chemically induced hepatic fibrosis and inflammation in
mice were attenuated by thymoquinone through suppression of
protein and mRNA expression of collagen I and TIMP-1 and
reduction of ECM accumulation (Bai et al., 2014; Ghazwani et al.,
2014). Thymoquinone down-regulated the expression of TLR4 and
decreased proinflammatory cytokine levels (Bai et al., 2014). In
addition, it also inhibited PI3K phosphorylation, enhanced the
phosphorylation AMPK and liver kinase B (LKB)-1. In rats, injected
with cisplatin, thymoquinone reduced the expression of NF-B and
proinflammatory proteins TNF-, IL-1 (Al-Malki and Sayed,
2014). Investigating the mechanism of antifibrotic activity in several
HSC lines, Ghazwani et al. (2014) showed that the inhibition of
LPS-induced mRNA expression of IL-6 and MCP-1 was associated
with the inactivation of NF-B pathway and down-regulation of
mRNA expression of several fibrosis-related genes. This quinone
also showed the inhibitory potential toward TLR4 and PI3K/Akt
signaling pathways in activated HSCs and proapoptotic activity, as
shown by decreased XIAP and c-FLIP expression (Bai et al., 2013).
Moreover, thymoquinone administration in rats fed high-fat diet
(HFD) diminished metabolic syndrome by preventing reduction in
hepatic mRNA levels of PPAR- and PPAR- (Prabhakar et al.,
2014).
O
O
H3C
CH3
CH3
Thymoquinone
3. Some other reports on hepatoprotective phytochemicals
There have been several other reports regarding various
hepatoprotective agents isolated from plants: Cliv-92 (a mixture of
three structurally similar coumarinolignoids) isolated from Cleome
viscosa (Ray et al., 1985), oleanolic acid from Lantana camara
(Misra et al., 1997),  amyrin and  amyrin from Protium
heptaphyllum (Oliveira et al., 2005), anastatin A and anastatin B
from Anastatica hierochuntica (Yoshikawa et al., 2003b), genistein,
orobol and 5,7,4' trihydroxy 3' methoxyisoflavone from Erycibe
expansa (Matsuda et al., 2004),  amyrin,  amyrone, 18
hydroperoxy olean 12 en 3 one and 3 epi  amyrin from Sedum
sarmentosum (Amin et al., 1998), rutin from Artemisia scoparia
(Janbaz et al., 2002), rubiadin from Rubia cordifolia (Rao et al.,
2006), myristin from Myristica fragrans (Morita et al., 2003),
naringenin and wighteone from Cudrania cochinchinensis (Lin et al.,
2003), kaempferol and salidroside from Rhodiola sachalinensis (Song
et al., 2003), gentiopicroside and sweroside from Swertia japonica
(Hase et al., 1997a), tetrahydroswertianolin from Swertia japonica
(Hase et al., 1997b), mangiferin from Salacia reticulata (Yoshikawa
et al., 2003a), torilin and torilolone from Cnidium monnieri (Oh et
al., 2002), acanthoic acid from Acanthopanax koreanum (Park et al.,
2004), 18 glycyrrhetinic acid from Glycyrrhiza uralensis (Shim et
al., 2000), lithospermate B from Salvia miltorhiza (Hase et al., 1997b),
corilagin from Terminalia catappa (Kinoshita et al., 2007),
neoandrographolide from Andrographis paniculata (Chander et al.,
1995), scropolioside A from Scrophularia koelzii (Garg et al., 1994),
schisandrin B from Schisandra chinensis (Ip et al., 1995), kahweol
and cafestol from Coffea arabica and C. robustica (Lee et al., 2007),
quercetin from Oenothera biennis, Podophyllum spp., etc. (Molina
et al., 2003), lupeol from Crataeva nurvala (Preetha et al., 2006),
caffeic acid from Ipomoea purga, Ocimum basilicum, etc. (Janbaz
et al., 2004), bergenin from Mallotus japonicas (Kim et al., 2000),
tiliroside from Magnolia fargesii (Matsuda et al., 2002), kolaviron
from Garcinia kola (Iwu et al., 1987), thymoquinon from Nigelle
sativa (Daba and Abdel-Rahman, 1998), bupleurosides III, VI, IX,
and XIII from Bupleurum scorzonerifolium (Matsude et al., 1997),
trans-tetracos-15-enoic acid from Indigofera tinctoria (Singh et al.,
2006), gomishins, schisandrin A and wuweizisu C from Schizandra
chinensis, saikosaponins from Bupleurum falcatum, sarmentosins
fom Sedum sarmetosum, fumaric acid from Sida cordifolia (Valan
et al., 2010), helioxanthin from Taiwania cryptomerioides (Tseng
et al., 2008), matrine and oxymatrine from Sophora japonica (Zhang
et al., 2001; Ma et al., 2013), nobiletin from Citrus unshiu (Suzuki
et al., 2005; Yoshigai et al., 2013), genistein from Hydrocotyle
sibthorpioides (Huang et al., 2013), salvianic acid A from Salvia
miltiorrhiza (Zhang et al., 2012), betulin and betulinic acid from
Betula platyphylla (Szuster-Ciesielska and Kandefer-Szerszen, 2005;
Szuster-Ciesielska et al., 2011), rosmarinic acid, baicalin (Yang et al.,
2012) and paeoniflorin from Moutan cortex (Li et al., 2010; Li et al.,
2011), -caryophyllene identified in the essential oil of numerous
plants and fruits (Calleja et al., 2013), etc.
Some of the traditionally used plants for liver disorders provided
useful therapeutic agents. A large number of such plants lack the
scientific evidences supporting their effectiveness. Many groups of
researchers worldwide were involved in studying the protective
effects of plant extracts against experimentally induced liver toxicity.
These results can be a helpful guide for researchers to explore the
constituents of the most promising plants and molecular mechanisms
in liver protection in order to discover new useful natural drugs for
the management of liver disorders.
3.1 Indian systems of medicine and liver diseases
Due to the high prevalence of chronic hepatic diseases in South Asia,
Indian systems of medicine has generated extensive empirical
knowledge in their treatment over several centuries (Patel et al.,
2015). There are more than 300 preparations in the Indian systems
of medicine for the treatment of jaundice and chronic liver diseases
(Table 2) (Thyagarajan et al., 2002). In India, more than 87 medicinal
plants are used in different combinations as herbal drugs for liver
diseases (Handa et al., 1989; Sharma et al., 1991b). However, not all
the plants have been evaluated for their pharmacological and antiviral
efficacy.

11
Table 1: Clinical relevance of modern medicine
Sl. No. Mo der n med icine Disease c ondition Clinical application Ref er ence
1. Corticosteroids Reduce cytokine Most studies show no important effects. Now Kashaw et al., 2011
produ ction -a-days, it is considered that corticosteroids
Ant ifibrotic have a poor futu re in the treatment of liver
diseases.
2. Interferons Antiv iral Effective in hepatitis B and C Not tested Muriel and Rivera-
Ant ifibrotic directly as antifibrotic in humans. Several Espinoza , 2008
side effects attherapeutic doses includes as
depression, anxiety, agita tion, suicidal
ideation and even suicide.
3. Lamivudine Hepatitis B a nd Continuous usage leads to emergence of Yun-Fan et al., 2004
cirrhosis a resistant hepatitis B virus mutant.
4. Propylthioura cil Alcoholic hepatic Render metabolically-compromised patients Arteel et al., 2003
diseases hypothyroid.
5. Colchicine Against gout No beneficial properties were recently Muriel and Rivera-
Ant ifibrotic demonstrated. Very toxic at high doses. Espinoza, 200 8
6. Pentox ifyl line Severe alcoholic Protective effects against hepatorenal http://li vertox .nih.gov/
hepatitis syndrome and its excellent safety profile.
Patients with xanthine hypersensitivity
should avoid use of pentoxifylline.
7. Ursodeoxycholic acid Non-alcoholic fatty Improves hepatic enzymes and hepatic Federico et al., 2006
hepatic disease histology in patients with various
hepatobiliary diseases and improves
oxidative stress.
In human pa tients that taurine depletion may
be potentiated by chronic treatment with
ursodeoxycholic acid.
8. Rosiglitazone Non-alcoholic fatty Increase risk of heart attack. Xiao et al., 2013
hepatic disease
Table 2 : Herbal formulations approved by Indian medicinal practitioner’s co-operative pharmacy and stores
Sl No. Ayur vedic preparatio n Siddha pre paration Unani prepar ations
1. Bhringarajasava Arumuga chendooram Jawarish-e-Amilasada
2. Chandraprabhavati Annabedhi chendooram no. 1 and 2 Jawarish-e-Amila luluvi
3. Drakahadi rasayam Ayaka ntha chendooram Jawarish-e-Tabashir
4. Guduchi satwam Mandooradi kudineer Kurs-e-gul
5. Jambeeradi panak am Ayabringaraja karpam Rue-e-amila
6. Panchatiktakwatha churnam Karisala i lehyam Sherbeth-e-anarshreen
7. Dhathri loham Kantha chendoo ram Sherbeth-e-deenar
8. Tapyadi loha m Loha mandooram Muffa rah-e-Ahmedi
9. Pipilyadi loham Gul-e-Nilofer
10 . Saptamiruda loham Bhoi-Am la
4. Conclusion
Liver diseases are one of the foremost health troubles worldwide,
with liver cirrhosis and drug induced liver injury accounting to ninth
leading cause of death in Western and developing countries. There
are numerous plants and traditional formulations available for the
treatment of liver diseases. About 600 commercial herbal
formulations with claimed hepatoprotective activity are being sold
all over the world. In India, more than 93 medicinal plants are used in
different combinations in the preparations of 40 patented herbal
formulations. However, only a small proportion of hepatoprotective
plants as well as formulations used in traditional medicine are
pharmacologically evaluated for their safety and efficacy.
Development of standardized, safe and effective herbal formulations

12
with proven scientific evidence can augment the existing arsenal of
herbal drugs to combat liver diseases. A regulated research policy to
highlight the advantages of hepatoprotective herbal medicine with
respect to their safety and efficacy could result in a better utilisation
of these complementary systems of medicine. Thus, plants have the
potential to serve as a source of new therapeutic agents for the
development of future drugs in the treatment of various hepatic
diseases.
Conflicts of interest
We declare that we have no conflict of interest.
Acknowledgement
The authors express their sincere thanks to Dr. Ashok K. Chauhan,
Founder President, Ritnand Balved Education Foundation (RBEF)
and Amity Grou p of Institutions for constant support and
encouragement and to Dr. Atul Chauhan, President, RBEF and
Chancellor, AUUP, Noida for facilitating this work. The authors are
also thankful to Mrs. M A Chithra and Ms. A J Bincy for assistance
in manuscript preparation.
References
Aggarwal, B.B.; Bhardwaj, A.; Aggarwal, R.S.; Seeram, N.P.; Shishoda, S. and
Takada, Y. (2004). Role of resveratrol in prevention and therapy of
cancer: preclinical and clinical studies. Anticancer Res., 24:2783-
2840.
Alexander, G.; Singh, B.; Sahoo, A. and Bhat, T.K. (2008). In vitro screening of
plant extra cts to enhance the efficiency of utilization of energy
and nitrogen in ruminant diets. Animal Feed Sci. and Tech., 145:229-
244.
Allain, H.; Schuck, S.; Lebreton, S.; Strenge-Hesse, A.; Braun, W.; Gandon, J.M.
and Brissot, P. (1999). Aminotransferase levels and silymarin in de
novo tacrine-treated patients with Alzheimer’s disease. Dement.
Geriatr. Cogn. Disord., 10:181-185.
Al- Malki , A.L. an d Saye d, A.A. ( 201 4). Thymoqu inone atten uates
cisplatininduced hepatotoxicity via nuclear factor kappa-beta.
BMC Complement. Altern. Med., 14:282.
Amin , H.; Ming shi, W.; Hong , Y.H.; Deche ng, Z. and Lee, K.H. (19 98).
Hepatoprote ctive triterpenes from Sed um sa rmentosum.
Phytochem., 49:2607-2610.
Ansari, R.A.; Aswal, B.S.; Chander, R.; Dhawan, B.N. and Sharma, S.K. (1988).
Hepatoprotective activity of Kutkin, the iridoid glycoside mixture
of Picrorrhiza kurroa. Indian J. Med. Res., 87:401-404.
Arteel, G.; Marsano, L.; M endez, C.; B entley, F. and McClain, C.J. (2003).
Advances in alcoholic liver disease. Best Practice and Resea rch
Clinical Gastroenterology, 17(4):625-647.
Bai, T.; Lian, L.H.; Wu, Y.L.; Wan, Y. and Nan, J.X. (2013). Thymoquinone
attenuates liver fibrosis via PI3K and TLR4 signaling pathways in
activated hepatic stellate cells. Int. Immunopharmacol., 15:275-
281.
Bai, T.; Yang, Y.; Wu, Y.L.; Jiang, S.; Lee, J.J.; Lian, L.H. and Nan, J.X. (2014).
Thymoquinone alleviates thioacetamide-induced hepatic fibrosis
and inflammation by activating LKB1-AMPK signaling pathway
in mice. Int. Immunopharmacol., 19:351-357.
Bhadauria, M. (2010 ). Dose-dependent hepatoprotective effect of emodin
against acetaminophen-induced acute damage in rats, Experimental
and Toxicologic Pathology, 62(6):627-635.
Bhattacharya, A.; Ramanathan, M.; Ghosal, S. and Bhat-tacharya, S.K. (2 000).
Effect of Withania somnifera glycowithanolides on iron induced
heopatotoxicity in rats. Phytother. Res., 14:568-70.
Bisht, S.; K han, M.A.; Bekhit, M.; Bai, H.; Cornish, T.; Mizuma, M.; Rudek, M.A.;
Zhao, M.; Maitra, A.; Ray, B.; Lahiri, D.; Maitra, A. and Anders, R.A. (2011 ).
A polymeric nanoparticle formulation of curcumin (NanoCurc)
ameliorates CCl4-i nduc ed hepa tic injury and fibrosis through
reduction of proinfl amma tory cytokines and stella te cell
activation. Lab Invest., 91(9):1383-1395.
Biswas, J.; Sinha, D.; Mukherjee, S.; Roy, S.; Siddiqi, M. and Roy, M. (20 10).
Curcumin protects DNA damage in a chronically arsenic-exposed
population of West Bengal. Hum. Exp. Toxicol., 29:513-524.
Calleja, M.A.; Vieites, J.M.; Montero-Meterdez, T.; Torres, M.I.; Faus, M.J.; Gil,
A. and Suárez, A. (2013). The antioxidant effect of beta-caryophyllene
protects rat liver from carbon tetra chloride-induced fibrosis by
inhibiting hepatic stellate cell activation. Br. J. Nutr., 109(3):394-
401.
Carducci, R.; Armellino, M.F.; Volpe, C.; Basile, G.; Caso, N.; Apicella, A. and
Basi le, V. (19 96) . Silibinina e intossicazione acuta da Amanita
phalloides. Minerva Anestesiol., 62:187-193.
Chan, C.C.; Cheng, L.Y.; Lin, C.L.; Huang, Y.H.; Lin, H.C. and Lee, F.Y. (2011).
Th e prot ective rol e of natu ral phytoale xin resver atrol on
inflammation, fibrosis and regeneration in cholestatic liver injury.
Mol. Nutr. Food. Res., 55(12):1841-1849.
Chander, R.; Kapoor, N.K. and Dhawan, B.N. (1992). Effect of picroliv on
glutathione metabolism in liver and brain of Mastomys natalensis
infected with Plasmo dium berg hei. Ind. J. Exp. Biol., 30:711-
714.
Chan der, R. ; Sr ivas tava, V.; Tand on, J.S . and Kapoor, N.K . (1995 ).
Antihepatotoxic activity of diterpenes of Andrographis paniculata
(Kalmegh) against Plasmodium berghei induced hepatic damage
in Masto mys natalensis. Int. J. Pharmacogn., 33:135-138.
Chatuphonprasert, W.; Jarukamjorn, K.; Kondo, S. and Nemoto, N. (2009) .
Synergistic increases of metabolism and oxidation reduction genes
on their expression after combined treatment with a CYP1A inducer
and andrographolide. Chemico-Biological Interactions, 182(2-
3):233-238.
Chatuphonprasert, W.; Remsungnen, T.; Nemoto, N. and Jarukamjorn, K. (2011).
Different AhR binding sites of diterpenoid ligands from
Andrographis paniculata caused differential CYP1A1 induction
in primary culture in mou se hepatocytes. Toxicology in vitro,
25(8):1757-1763.
Chen, Y.C.; Shen, S.C.; Lee, W.R.; Lin, H.Y.; Ko, C.H.; Shih, C.M. and Yang, L.L.
(2002). Wogonin and fisetin indu ction of apoptosis through
activation of caspase 3 cascade and alternative expression of p21
protein in hepatocellular carcinoma cells SKHEP- 1. Arch. Toxicol.,
76(5 and 6):351-359.
Chen, M.H.; Lee, M.Y.; Chuang, J.J.; Li, Y.Z.; Ning, S.T.; Chen, J.C. and Liu, Y.W.
(2012). Curcumin inhibits HCV replication by induction of heme
oxygenase-1 and suppression of AKT. Int. J. Mol. Med., 30:1021-
1028.
Chen, N.; Geng, Q.; Zheng, J.; He, S.; Huo, X. and Sun, X. (2014). Suppression of
the TGF-beta/ Smad signaling pathway and inhibition of hepatic
stellate cell proliferation play a role in the hepatoprotective effects
of curcumin against alcohol-induced hepatic fibrosis. Int. J. Mol.
Med., 34:1110-1116.
Chirdchupunseree, H. and Pramyothi n, P. (20 10). Protective activity of
phyllanthin in ethanol-treated primary culture of rat hepatocytes.
J. Ethnopharmacol., 128:172-176.
Daba, M.H. and Abdel-Rahman, M.S. (1998). Hepatoprotective activity of
thymoquinone in isola ted rat hepa tocytes. Toxicol. Lett., 95:23-
29.
Dang, S.S.; Zhang, X.; Jia, X.L., Cheng, Y.A.; Song, P.; Liu, E.Q.; He, Q. and Li, Z.F.
(2008). Protective effects of emodin and Astragalus polysaccharides
on chronic hepatic injury in rats. Chin. Med. J., 121:1010-1014.
Datta, S.; Sinha, S. and Bhattacharya, P. (1999). Hepatoprotective activity
of an herbal protein CI-1, purified from Cajan us indicus against
galactosamine HCl toxicity in isolated rat hepatocytes. Phtother.
Res., 13:508-512.
Dehmlow, C.; Eahard, J. and Goot, H.D. (19 96). Inhibition of Kupffer cells as
an explanation for the hepatoprotective properties of silibinin.
Hepatology, 23:749-754.

13
Diwedi, Y.; Rastogi, R.; C hander, R.; Sharma, S.K.; Kapoor, N.K.; Garg, N.K. and
Dhawan, B.N. (199 0). Hepatoprotective activity of Picroliv against
carbon tetrachloride induced liver damage in rats. Ind. J. Med.
Res., 92:195-200.
Dixit, S.P. and Achar, M.P. (1983). Bhunyamlaki (Phyllanthus niruri) and
jaundice in children. J. Natl. Integ. Med. Ass., 25:269-272.
Domi trovic, R.; Jakovac, H. and Blagojevic, G (201 1). Hepatoprotective
activity of berberine is mediated by inhibition of TNF-alpha, COX-
2, and iNOS expression in CCl4-intoxicated mice. Toxicology,
280:33-43.
Domitrovic, R.; Jakovac, H.; Marchesi, V.V. and Blazekovic, B. (2013). Resolution
of liver fi brosis by isoqu inol ine alkaloid ber berine in CC l4-
intoxicated mice is media ted by suppression of oxida tive stress
and upregulation of MMP-2 expression. J. Med. Food., 16:518-
528.
Domitrovic, R. and Potocnjak, I. (20 15). A comprehensive overview of
hepatoprotective natura l compounds: mechanism of action and
clinical perspectives. Arch. Toxicol., 1-41 [Epub ahead of print].
Dong, Z. (2003). Molecular mechanisms of the chemopreventive effect
of resveratrol. Mutat. Res., 523:145-150.
Dong, H.; Lu, F.E.; Gao, Z.Q.; Xu, L.J.; Wang, K.F. and Zou, X. (2005) . Effects of
emodin on treating murine nonalcoholic fatty liver induced by
high caloric laboratory chaw. World J. Gastroenterol., 11:1339-
1344.
Dong, M.X.; Jia, Y.; Zhang, Y.B.; Li, C.C.; Geng, Y.T.; Zhou, L.; Li, X.Y.; Liu, J.C.
and Niu, Y.C. (2009 ). Emodin protects rat liver from CCl4-induced
fibrogenesis via inhibition of hepatic stellate cells activation. World
J. Gastroenterol., 15:4753-4762.
Duv oux, C. (2001) . Liver transplantation: which indications? Which
results? Presse Med., 30:711-716.
EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS); Sci-
entific Opinion on the reevaluation of curcumin (E 100) as a food
additive. EFSA Journal 2010; 8(9):1679 , pp.46.
Elbarbry, F.; Ragheb, A.; Marfleet, T. and Shoker, A. (2012). Modulation of
hepatic drug meta bolizi ng enzymes by dietary doses of
thymoquinone in female New Zealand White rabbits. Phytother.
Res., 26:1726-1730.
Emmanuel, S.; Amalaraj, T. And Ignacimuthu, S. (2001). Hepatoprotective
effect o f coumestans isolated from the lea ves of Wedelia
calandulaceae in paracetamol induced liver damage. Indian Journal
of Experimental Biology, 39:1305-1307.
Federico, A.; Trappoliere, M. and Loguercio, C. (2006). Treatment of patients
with non-alcoholic fatty liver disea se: cu rrent views and
perspectives. Digestive and Liver Disease, 38(11): 789-801.
Feher, I.; Deak, G. and Muzes, G. (1989). Liver protective action of silymarin
therapy in chronic alcoholic liver diseases. Orv Hetil., 130: 2723-
2727.
Ferenci, P.; Dragosics, B.; Dittrich, H.; Frank, H.; Benda, L.; Lochs, H.; Meryn, S.;
Base, W. and Schneider, B. (1 989). Randomized controlled trial of
silymarin trea tment in patient s with ci rrhosi s of the liver. J.
Hepatol., 9(1):105-113.
Fremont, L. (2000). Biological effects of resveratrol. Life Sci., 66:663-
673.
Fujioka, T.; Kondou, T.; Fukuhara, A.; Tounou, S.; Mine, M.; Mataki, N.; Hanada,
K.; Ozaka, M.; Mitani, K.; Nakaya, T.; Iwai, T. and Miyakawa, H. (2003).
Efficacy of a glycyrrhizin suppository for the treatment of chronic
hepatitis C: a pilot study. Hepatol. Res., 26:10-14.
Garg, H.S.; Bhandari, S.P.; Tripathi, S.C.; Patnaik, G.K.; P uri, A.; Saxena, R. and
Saxena, R.P. (1994). Antihepatotoxic and immunostimulant properties
of iridoid glycosides of Scrophularia koelzii. Phytother. Res., 8:224-
228.
Ghazwani, M.; Zhang, Y.; Gao, X.; Fan, J.; Li, J. and Li, S. (2014). Antifibrotic
effect of thymoquinone on hepatic stellate cells. Phytomedicine,
21:254-260.
Guo, Q.; Zhao, L.; You, Q.; Yang, Y.; Gu, H.; Song, G.; Lu, N. and Xin, J. (2007).
Anti-hepatitis B virus activity of wogonin in vitro and in vivo .
Antiviral. Res., 74(1):16-24.
Gupta, S.C.; Kismali, G. and Aggarwal, B.B. (2013). Curcumin, a component
of turmeric: from farm to pharmacy. Biofactors, 39:2-13.
Handa, S.S.; Sharma, A. and Chakraborthi, K.K . ( 1986). Natural products and
plants as liver protecting drugs. Fitoterapia, 58:307-351.
Handa, S.S.; Sharma, A. and Chakraborty, K.K. (1989). Natural products and
plants as liver protecting drugs. Fitoterapia, 57:307-51.
Harish , R. and Shivan andapp a, T. (2 006) . Antioxidant acti vity and
hepatoprotective potential of Phyllanthus niruri, Food Chemistry,
95(2):180-185.
Hase, K.; Li, J.; Basnet, P.; Xiong, Q.; Takamura, S.; Namba, T. and Kadota, S.
(1997a). Hepatoprotect ive principles of Swe rtia japo nicaon D
galactosamine/ lipopolysaccharide induced liver injury in mice.
Chem. Pharm. Bull., 45 :1823-1827.
Hase, K.; Kasimu, R.; Basnet, P.; Kadota, S. and Namba, T. (1997b). Preventive
effect of lithospermate B from Salvia miltorhizaon experimental
hepatitis induced by ca rbon tetrachloride or D-gala ctosamine/
lipopolysaccharide. Planta Med., 63:22-26.
Hi dalgo, M.A.; Hanke, J.L .; Bertogl io, J. C. and Burgos, R.A. (20 13) .
Andrographolide a new potential drug for long term treatment of
rheumatoid arthriti s disea se. In: Ma tsuno H, (Ed.) Innovative
Rheumatology. Croatia: Intech., pp.247-270.
Hong, S.W.; Jung, K .H.; Zheng, H.M.; Lee, H.S.; Suh, J.K.; Park, I.S.; Lee, D.H. and
Hong , S.S. (20 10). The protective effect of resveratrol on dimethyl
nitrosamineinduced liver fibrosi s in rats. Arch. Pharm. Res.,
33(4):601-609.
Ip, S.P.; Poom, M.K.; Wu, S.S.; Choe, C.T.; Ng, K.H.; Kong, Y.C. and Ko, K.M.
(1995). Effect of schisandrin B on hepatic glutathione antioxidant
system in mice: protection against carbon tetrachloride toxicity.
Planta Med., 61:398-401.
Iwu, M.M.; Igboko, O.A.; Onwuchekwa, U.A. and Okunji, C.O. (1987). Evaluation
of the antihepatotoxic activity of the biflavonoids of Garcinia
kola seed. J. Ethnopharmacol., 21:127-138.
Jacobs, P.B.; Dennehy, C.; Ramirez, G.; Sapp, J. and Lawrence, V.A. (2002). Milk
thistle for the treatment of liver disease: A systematic review and
meta-ana lysis. Am. J. Med., 113:506-515.
Janbaz, K.H.; Saeed, S.A. and Gilani, A.H. ( 2002). Protective effect of rutin
on paracetam ol and CCl4 indu ced he patotoxicity in rodents.
Fitoterapia, 73:557-563.
Janbaz, K .H.; Saeed, S.A. and Gilani, A.H. (2004). Studies on the protective
effects of caffeic acid and quercetin o n chemi cal-in duced
hepatotoxicity in rodents. Phytomed., 11:424-430.
Jaruchotikamol, A.; Kanokwan, J.; Wanna, S.T.S.; Yuki, K. and Nobuo, N. (2007).
Strong s ynergi stic i nduction of CYP1A1 expre ssion by
andrographolide plu s typical CYP1A inducers in mouse
hepatocytes. Toxicology and Applied Pharmacology, 224(2):156-
162.
Jarukamjorn, K.; Don-in, K.; Makejaruskul, C.; Laha, T.; Daodee, S.; Pearaksa,
P. and Sripanidkulchai, B. (2006). Impact of Andrographis paniculata
crude extract on mouse hepatic cytochrome P450 enzymes. Journal
of Ethnopharmacology, 105(3):464-467.
Jarukamjorn, K.; Kondo, S.; Chatuphonprasert, W.; Sakuma, T.; Kawasaki, Y.
and Nemoto, N. (2010) . Gender associated modulation of inducible
CYP1A1 expression by Andrographolide in mouse liver. European
Journal of Pharmaceutica l Sciences, 39(5): 394-40 1.
Jia, Y.; Kim, S.; Kim, J., Kim, B.; Wu, C.; Lee, J.H.; Jun, H.J.; Kim, N.; Lee, D. and
Lee, S.J. (2015). Ursolic acid improves lipid and glucose metabolism
in high-fat-fed C5 7BL/6 J mice by activating peroxisome
proliferator-activated receptor alpha and hepatic autophagy. Mol.
Nutr. Food Res., 59(2):344-354.
Kapur, V.; Pillai, K.K.; Hussain, S.Z. and Balani, D.K . (1994). Hepatoprotective
activity of jigrine on liver damage caused by alcohol, carbon
tetrachlori de and pa racetamol in rat s. Indian Journal of
Pharmacology, 26:35-40.

14
Kashaw, V.; Nem a, A.K . an d Agar wal, A. (20 11) . Hepa toprotection
prospective of herbal drugs and their vesicular carriers: a review.
International Journal of Research in Pharmaceutical and Biomedical
Science, 2(2):360-374.
Kh an, M.H.; Farrell,G.C.; Byth , K. ; Lin, R.; Weltman, M.; George , J.;
Samarasinghe, D.; Kench, J.; K aba, S.; Crewe, E. and Liddle, C. (2000). Which
patients with hepatitis C develops liver complications? Hepatology,
31:513-20.
Kim, H.S.; Lim, H.K.; Chung, M.W. and Kim, Y.C. (2000). Antihepatotoxic
activity of bergenin, the major constituent of Mallotus japonicus,
on carbon tetrachloride-intoxicated hepatocytes. J.
Ethnopharmacol., 72 :469-474.
Kim, K.; Kim, K.H.; Kim, H.Y.; Cho, H.K.; Sakamoto, N. and Cheong, J. (2010).
Curcumin inhibits hepatitis C virus replication via suppressing the
Akt-SREBP-1 pathway. FEBS Lett., 584:707-712.
Kimura, M.; Inoue, H.; Hirabayashi, K.; Natsume, H. and Ogihara, M. (2001).
Glycyrrhizin and some analogues induce growth of primary cultured
adult rat hepatocytes via epidermal growth factor receptors. Eur.
J. Pharmacol., 431:151-161.
Kinoshita, S.; Inoue,Y.; Nakama, S.; Ichiba, T. and Aniya, Y. ( 2007). Antioxidant
and hepatoprotective actions of medicinal herb Terminalia catappa
L. from Okinawa Island and its tannin corilagin. Phytomedicine,
14:755-762.
Kondo, S.; Chatuphonprasert, W.; Jaruchotikamol, A.; Sakuma, T. and Nemoto,
N. (2011 ). Cellular glutathione content modulates the effect of
Andrographolide on -naphtho-flavone Induced CYP1A1 mRNA
expression in mouse hepatocytes. Toxicology, 280(1-2):18-23.
Kosina, P.; Kren, V.; Gebhardt, R.; Grambal, F.; Ulrichova, J. and Walterova, D.
(2002). Antioxidant properties of silybin glycosides. Phytother.
Res., 16:S33-39.
Krishnamurthi, G.V. and Seshadri, T.R. (19 46). Phyllanthin from plant
Phyllanthus. Proc. Indian Acad. Sci., 24:357-362.
Krithika, R.; Mohankumar, R.; Verma, R.J.; Shrivastav, P.S.; Mohamad, I.L.;
Gunasekaran, P. and Narasimhan, S. (2 009). Isolation, characterization
and antioxidat ive effect of phyll anthin against CCl4-induced
toxicity in HepG2 cell line. Chem. Biol. Interact., 181(3):351-
358.
Kumar, R.N.V. and Kuttan, R. (2000). Inhibition of hepatocarcinogenesis
by picroliv. J. Pharmacol., 32:135-137.
Lee, D.Y.W. and Liu, Y. (2003). Molecular structure and stereochemistry of
silybin A, silybin B, isosilybin A, and isosilybin B, isolated from
Silybum marianum (Milk thistle). Journal of Natural Products,
66:1171-1174.
Lee, K .J.; Choi, J.H. and Jeong , H.G. (20 07) . Hepatoprotective and
antioxidant effects of the coffee diterpenes kahweol and cafestol
on carbon tetrachloride-induced liver damage in mice. Food Chem.
Toxicol., 45:2118-2125.
Lee, H.I.; McGregor, R.A.; Choi, M.S.; Seo, K.I.; Jung, U.J.; Yeo, J.; Kim, M.J. and
Lee, M.K. (2013) . Low doses of curcumin protect alcohol-induced
liver dama ge by modulation of the alcohol metabolic pathway,
CYP2E1 and AMPK. Life Sci., 93:693-699.
Lemley, C.O. and Wilson, M.E. (2010 ). Effect of cytochrome P450 and
al doketo redu ctase inhibitors on progesterone inactivation in
primary bovine hepatic cell cultures. J. Dairy Sci., 93:4613-4624.
Li, J.; Pan, Y.; K an, M.; Xiao, X.; Wang, Y.; Guan, F.; Zhang, X. and Chen, L.
(2014 a). Hepatoprotective effects of berberine on liver fibrosis via
activation of AMP-activated protein kinase. Life Sci., 98:24-30.
Li, R.; Guo, W.; Fu, Z.; Ding, G.; Zou, Y. and Wang, Z. (2011). Hepatoprotective
action of Radix, Paeoniae, Rubra, aqueous extract against CCl4-
induced hepatic damage. Molecules, 16(10):8684-8693.
Li, X.; Shen, J.; Zhong, Z.; Peng, J.; Wen, H.; Li, J.; Luo, Q. and Wei, W. (2010).
Paeoniflorin ameliorates schistosomiasis liver fibrosis through
regulating IL-13 and its signalling molecules in mice. Parasitology,
137(8):1213-1225.
Li, J.; Pan, Y.; Kan, M.; Xiao, X.; Wang, Y.; Guan, F.; Zhang, X. and Chen, L. (2014).
Hepatoprotective effects of berberine on liver fibrosis via activation
of AMP-activated protein kinase. Life Sci., 98:24-30.
Li, J.S.; Wang, W.J.; Sun, Y.; Zhang, Y.H. and Zheng, L. (2015a). Ursolic acid
inhibits the development of nonalcoholic fatty liver disease by
attenuating endopla smic reticu lum stress. Food Funct., 6:1643-
1651.
Li, X.; Xu, Z.; Wang, S.; Guo, H.; Dong, S.; Wang, T.; Zhang, L. and Jiang, Z.
(2015b). Emodin ameliorates hepatic steatosis through endoplasmic
reticulum stress-sterol regu lator y element binding protein 1 c
pathway in liquid-fructose feeding rats. Hepatol. Res., [Epub ahead
of prin t].
Lian, N.; Jiang, Y.; Zhang, F.; Jin, H.; Lu, C.; Wu, X.; Lu, Y. and Zheng, S. (2015).
Curcumin regulates cell fate and metabolism by inhibiting hedgehog
signaling in hepatic stellate cells. Lab. Invest., 95:790-803.
Lim, J.C.; Chan, T.K.; Ng, D.S.; Sagineedu, S.R.; Stanslas, J. and Wong, W.S.
(2012). Andrographolide and its ana logues: versatile bioa ctive
mol ecul es for comba ting inflammation and cancer. Clin. Exp.
Pharmacol. Physiol., 39:300-310.
Lin, C.C.; Chang , C.H.; Yang, J.J.; Namba, T. and Hat tori, M. (1996 ).
Hepatoprotective effects of emodin fro m Ventila go le iocar pa.
Journal of Ethnopharmacology, 52 (2):107-111.
Lin, C.C.; Lee, H.Y.; Chang, C.H.; Namba, T. and Hattori, M. (2003). Evaluation
of the liver protect ive principles from the r oot of Cudrania
cochinchinensis var. gerontogea. Phytother. Res., 10:13-17.
Luper, S. (1998). A review of plants used in the treatment of liver diseases:
Part 1: Altern. Med. Rev., 3:410-421.
Ma, Z.J.; Li, Q.; Wang, J.B.; Zhao, Y.L.; Zhong, Y.W.; Bai, Y.F.; Wang, R.L.; Li,
J.Y.; Yang, H.Y.; Zeng, L.N.; Pu, S.B.; Liu, F.F.; Xiao, DK.; Xia, X.H. and Xiao,
X.H . (201 3). Combining oxymatrine or matrine with lamivudine
increased its antireplication effect against the hepatitis B virus in
vitro. Evid. Based Complement Altern. Med., pp:186-573
Ma, J.Q.; Ding, J.; Zhang, L. and Liu, C.M. (2015). Protective effects of ursolic
acid in an experimental model of liver fibrosis through Nrf2/ARE
pathway. Clin. Res. Hepatol. Gastroenterol., 39:188-197.
Manns, M.P.; Wedemeyer, H.; Singer, A.; Khomutjanskaja, N.; Dienes, H.P.;
Roskams, T.; Goldin, R.; Hehnke, U.; Inoue, H. and European SNMC Study
Group . (20 12) . G lycyrrhizin in patients who failed previous
interferon alpha-based therapies: biochemical and histologica l
effects after 52 weeks. J. Viral Hepat., 19(8):537-546.
Matsuda, H.; Morikawa, T.; Xu, F.; Ninomiya, K. and Yoshikawa M. (2004). New
isoflavones and pterocarpane with hepatoprotec-tive activity from
the stems of Erycibe expansa. Planta Med., 70:1201-1209.
Mats uda, H. ; Nino miya, K .; Shi moda, H. and Yosh ikawa , M. (2 002 ).
Hepatoprotective principles from the flowers of Tilia argentea
(Linden): structure requirements of tiliroside and mechanisms of
action. Bioorg. Med. Chem., 10:707-712.
Matsude, H.; Murakami, T.; Ninomiya, K.; Inadzuki, M. and Yoshikawa, M. (1997).
New hepa toprotective saponins, bupleurosides III, VI, IX, and
XIII, from Chinese Bupleuri radix: structure-requirements for the
cytoprot ective activity in primary cultured ra t hepatocytes.
Bioorg. Med. Chem. Lett., 7:2193-2198.
Matsumoto, Y.; Matsuura, T.; Aoyagi, H.; Matsuda, M.; Hmwe, S.S.; Date, T.;
Watanabe, N.; Watashi, K.; Suzuki, R.; Ichinose, S.; Wake, K.; Suzuki, T.;
Miyamura , T.; Wakita, T. and Aizaki H. (2013 ). Antiviral activity of
glycyrrhizin against hepatitis C virus in vitro. PLos. One, 8(7):689-
92.
Mishra, B.B. and Tiwari, V.K. ( 2011). Natural products: an evolving role in
future drug discovery, Eur. J. Med. Chem., 46(10):4769-4807.
Misra, L.N.; Dixit, A.K . and Sharma, R.P. (19 97). High concentration of
hepatoprotective oleanolic acid and its derivatives in Lantana
camara roots. Planta Med., 63(6):582.
Mittal, G.C.; Saxena, S.; Kanchan, S.K.; Mangal, O.P. and Dandiya, P.C. (1978).
Clinical trials on bibarin in liver disorders with special reference to
infective hepatitis. India n Pract., 8:683-693.

15
Molina, M.F.; Sanchez-Reus, I.; Iglesias, I. and Benedi, J. ( 2003). Quercetin, a
flavonoi ds antioxidant, prevents and prot ects agai nst et hanol
induced oxidative stress in mouse liver. Biol. Pharm. Bull., 26:1398-
1402.
Morita, T.; Jinno, K.; Kawagishi, H.; Arimoto, Y.; Suganuma, H.; Inakuma, T.
and Sugiyama, K. (2003). Hepatoprotective effect of myristin from
nutmeg (Myristica fragrans) on lipopolysaccharide/ d galactosamine
induced liver injury. J. Agric. Food Chem., 51:1560-1565.
Moro, T.; Shimoyama, Y.; Kushida, M.; Hong, Y.Y.; Nakao, S.; Higashiyama, R.;
Sugioka, Y.; Inoue, H.; Okazaki, I. and Inagaki, Y. (2008). Glycyrrhizin and
its metabol ite inhibit Sma d3-mediated type I collagen gene
transcription and suppress experimental murine liver fibrosis. Life
Sci., 83:531-539.
Munte r, K.; Maye r, D. and Faulst ich, H. (198 6). Characterization of a
tra nsporting system in rat hepatocytes: studies with competitive
and non-competitive inhibitors of phalloidin transport. Biochem.
Biophys. Acta, 860:91-98.
Muriel, P. and Rivera-Espinoza, Y. (2008). Beneficial drugs for liver diseases.
J. Appl. Toxicol., 28:93-103.
Nabavi, S.F.; Daglia, M.; Moghaddam, A.H.; Habtemariam, S. and Nabavi, S.M.
(2014). Curcumin and liver disease: from chemistry to medicine.
Comprehensive Reviews in Food Science and Food Safety, 13(1):62-
77.
Neuman, M.G.; Cameron, R.G.; Haber, J.A.; Katz, G.G.; Malkiewicz, I.M. and
Shear, N.H. (1 999 ). Inducers of cytochrome P450 2E1 enhances
methotrexate induced hepatocyto-toxicity. Clin. Biochem., 32:519-
536.
Oh, H.; Kim, J.S.; Song, E.K.; Cho, H .; Kim, D.H.; Park, S.E.; Lee, H.S. and Kim,
Y.C. (2002 ). Sesquiterpenes with hepatoprotective activity from
Cnidium monnierion tacrine induced cytotoxicity in Hep G2 cells.
Planta Med., 68:748-749.
Oliveira, F.A.; Chaves, M.H.; Almeida, F.R.; Lima, R.C. Jr.; Silva, R.M.; Maia,
J.L.; Brito, G.A.; Santos, F.A. and Rao, V.S. (200 5). Protective effect of 
and  amyrin, a triterpene mixture from Protium heptap hyllum
(Aubl.) March. trunk wood resin, against acetaminophen induced
liver injury in mice. J. Ethnopharmacol., 98:103-108.
Orazizadeh, M.; Fakhredini, F.; Mansouri, E. and Khorsandi, L. (2014). Effect
of glycyrrhizic acid on tita nium dioxide nanoparticles-induced
hepatotoxicity in rats. Chem. Biol. Interact., 220:214-221.
Othman, M.S.; Safwat, G.; Aboulkhair, M. and Abdel Moneim, A.E. (2014). The
potentia l effect of berberine in mercury-induced hepatorenal
toxicity in albino rats. Food Chem. Toxicol., 69: 175-181.
Pandey, B.R. and Verma, P. (2 013). Therapeutic potential of Picrorrhiza
kurroa i n prevent ion and trea tment of hepatic disorders: an
overview. Interna tional Journal of Scienti fic a nd Innov ative
Research, 1(1):1-13.
Park, E.J.; Zhao, Y.Z.; Kim, Y.H.; Lee, J.J. and Sohn, D.H. (2004). Acanthoic acid
from Acanthopanax koreanumprotects against liver injury induced
by tert butyl hydroperoxide or carbon tetrachloride in vitro and in
vivo. Planta Med., 70:321-327.
Patel, M.V.; Patel, K.B.; Gupta, S.; Michalsen, A.; Stapelfeldt, E. and Kessler, C.S.
(2015). A complex multiherbal regimen based on Ayurveda medicine
for the management of hepatic cirrhosis complicated by ascites:
nonrandomized, un contro lled, single gro up, open-la bel
observationa l clinical study. Evid Based Complement Alternat.
Med., Article ID 613182.
Pekthong , D.; B lanchard, N.; Abadie, C.; Bonet, A.; Heyd, B.; Mantion, G.;
Berthelot, A.; Richert, L. and Martin, H. ( 2009). Effects of Andrographis
paniculata extract and androgra pholide on hepatic cytochrome
P450 mRNA expression and monooxygenase activities after in
vivo administration to rats and in vitro in rat and human hepatocyte
cultures. Chemico-Biological Interactions, 179(2-3):247-255.
Pekthong, D.; Martin, H.; Abadie, C.; Bonet, A.; Heyd, B.; Mantion G. and Richert,
L. ( 2008 ). Differential inhibiti on of ra t a nd hum an hepatic
cytochrome P450 by An dro gra phi s paniculata extract a nd
andrographolide. Journal of Ethnopharmacology, 115(3):432-440.
Prabhakar, P.; Reet, K.H.; Maulik, S.K.; Dinda, A.K. and Gupta, Y.K. (20 14).
Protective effect of thymoquinone against high-fructose dietinduced
metabolic syndrome in rats. Eur. J. Nutr., 54(7):1117-1127.
Pradhan S.C. and Girish, C. (20 06). Hepatoprotective herbal drug, silymarin
from experimental pharmacology to clinical medicine. Indian J.
Med. Res., 124:491-504.
Preetha, S.P.; Kanniappan, M.; Selvakumar, E.; Nagaraj, M. and Varalakshmi, P.
(2006). Lupeol ameliorates aflatoxin B1-induced peroxidative
hepatic damage in rats. Comparative Biochemistry and Physiology:
Part C. Toxicol. Pharmacol., 143: 333-339.
Qiu, F.; Hou, X.L.; Takahashi, K.; Chen, L.X.; Azuma, J. and Kang, N. (2012).
Andrographolide inhibits the expression and metabolic activity of
cytochrome P450 3A4 in the modified caco-2 cells. Journal of
Ethnopha rmacology, 141(2):709-713.
Qu, Y.; Che n, W.H.; Zong, L.; Xu, M.Y. and Lu, L.G. ( 2012). 18 alpha-
Glycyrrhizin induces apoptosis and suppresses activation of rat
hepatic stellate cells. Med. Sci. Monit., 18 :Br24-Br32.
Qu, Y.; Zong, L.; Xu, M.; Dong, Y. and Lu, L. (2015). Effects of 18alpha-
glycyrrhizin on TGF-1/Smad signaling pathway in rats with carbon
tetrachloride-induced liver fibrosis. Int. J. Cli n. Exp. Pathol.,
8:1292-1301.
Rahman , S. and Sul tana , S. ( 2006 ). Chemopreventive a ctivity of
glycyrrhizin on lead acetate mediated hepatic oxidative stress and
its hyperproliferative activity in Wistar rats. Chem. Biol. Interact.,
160:61-69.
Rajasekaran, D.; Elavarasan, J.; Sivalingam, M.; Ganapathy, E.; Kumar, A.;
Kalpana, K. and Sakthisekaran, D. (2011). Resveratrol interferes with
N-nitrosodiethylamine- induced hepatocellular carcinoma at early
and advanced stages in male Wistar rats. Mol. Med. Rep., 4(6):1211-
1217.
Rao, G.M.; Ra o, C.V.; P ushp angadan, P. and Shi rwaikar, A. (2 006) .
Hepatoprotective effects of rubiadin, a major constitu ent of Rubia
cordifolia Linn. J Ethnopharmacol., 103: 484 490.
Ray, A.B.; Chattopadhyay, S.K.; Kumar, S.; Konno, C.; Kiso, Y. and Hikino, H.
(1985). Structures of cleomiscosins, coumarino-lignoids of Cleome
viscosa seeds. Tetrahedron, 41(1):209-214.
Rechtman, M.M.; Har-Noy, O.; Bar-Yishay, I.; Fishman, S.; Adamovich, Y.; Shaul,
Y.; Halpern, Z. and Shlomai, A. (2010). Curcumin inhibits hepatitis B
virus via down-regulation of the metabolic coactivator PGC-1.
FEBS Lett., 584:2485-2490.
Renganathan, A. (1999). Pharmacodynamic properties of andrographolide
in experimental animals. M.D. thesis. Pharmacology. Pondicherry:
Ja waharlal Institute of Postgra duate Medical Edu cation a nd
Research (JIPMER), Pondicherry University.
Rivera-Espinoza, Y. and Muriel, P. (20 09). Pharmacological actions of
curcumin in liver diseases or damage. Liver Intl., 29(10):1457-
1466.
Row, L.R.; Satyanarayana, P. and Subba Rao, G.S.R. (1967 ). Crystalline
const ituents of eu phorbi aceae-IV: the synt hesis and absolute
configuration of phyllanthin. Tetrahedron, 23(4):1915-1918.
Row, L.R.; Srinivasulu, C.; Smith, M. and Subba Rao, G.S.R. (1966). New lignans
fro m Ph ylla nthus niruri Linn-the constitution of phylla nthin.
Tetrahedron, 22(8):2899-2908.
Roy, M.; Sinha, D.; Mukherjee, S. and Biswas, J. (2011a). Curcumin prevents
DNA damage and enhances the repair potential in a chronically
arsenic-exposed human population in West Bengal, India. Eur. J.
Cancer Prev., 20:123-131.
Roy, S.; Sannigrahi, S.; Majumdar, S.; Ghosh, B. and Sarkar, B. (2011 b)
Resveratrol regulates antioxidant statu s, inhibits cyt okine
expression and restricts apoptosis in carbon tetrachloride induced
rat hepatic injury, Oxid. Med. Cell. Longev., 703676.
Saliou, C.; Rihn, B.; Cillard, J.; Okamoto, T. and Packer, L. (1 998). Selective
inhibition of NF-B activation by the flavonoid hepatoprotector
silymarin in HepG2. FEBS Lett., 440:8-12.

16
Saller, R.; Meier, R. and Brignoli, R. (2001). The use of silymarin in the
treatment of liver diseases. Drugs, 61:2035-2063.
Salmi , H .A. and Sarna, S. (19 82). Effects of silymarin on chemical,
functional and morphological alterations of the liver. A double-
blind controlled study. Scand. J. Gastroenterol., 17:517-521.
Sato, H.; Goto, W.; Yamamura, J.; Kurokawa, M.; K ageyama, S.; Takahara, T.;
Watanabe, A. and Shiraki, K. (1 996). Therapeutic basis of glycyrrhizin
on chronic hepatitis B. Antivir. Res., 30:171-177.
Sayed-Ahmed, M.M.; Aleisa, A.M.; Al-R ejaie, S.S.; Al-Yahya, A.A.; Al-Shabanah,
O.A.; Hafez, M.M. and Nagi, M.N. (2010). Thymoquinone attenuates
diethylnitrosamine indu ction of hepatic carcinogenesis through
antioxidant signaling. Oxid. Med. Cell Longev., 3:254-261.
Sehgal, A.; Kumar, M.; Jain, M. and Dhawan, D.K. (2013). Modulatory effects
of curcumin in conjunction with piperine on benzo(a) pyreneme-
diated DNA adducts and biotransformation enzymes. Nutr. Cancer.,
65:885-890.
Schuppan, D.; Jia, J.; Brinkhaus, B. and Hahn, E.G. (1999) . Herbal products
for liver diseases: A therapeutic challenge for the new millennium.
Hepatology, 30: 1099-1104.
Sengupta, D.; Chowdhury, K.D.; Sarkar, A.; Paul, S. and Sadhukhan, G.C. (2014 ).
Berberine and S allyl cysteine mediated amelioration of DEN +
CCl4 induced hepatocarcinoma. Biochim. Biophys. Acta, 1840:219-
244.
Shamasundar, K .V.; Singh, B.; Thakur, R.S.; Hussain, A.; Kiso, Y. and Hikino, H.
(1985). Antihepatoprotective principles of Phyllanthus niruri herbs.
Journal of Ethnopharmacology, 14(1): 41-44.
Sharma, A.; Shing, R.T.; Sehgal, V. and Handa, S.S. (1991b). Antihepatotoxic
activity of some plants used in herbal formulations. Fitoterapia,
62:131-138.
Sheng, M.; Zhou, Y.; Yu, W.; Weng, Y.; Xu, R. and Du, H. (2015). Protective effect
of berberine pretreatment in hepatic ischemia/reperfusion injury
of rat. Transpl. Proc., 47:275-282.
Sherlock, S. and Dooley, J. (2002). Diseases of liver and biliary system. 11th
Ed. Oxford: Blackwell Scientific Publications, pp.322-356.
Shim, S.B.; Kim, N.J. and K im, D.H. (2000). Beta-glucuronidase inhibitory
activity and hepatoprotective effect of 18 beta-glycyrrhetinic
acid from the rhizomes of Glycyrrhiza u ralensis. Planta Med.,
66:40-43.
Singh, B. and Rastogi, R.P. ( 1972). Chemical examination of Picrorhiza
kurrooa Benth.: Part VI. reinvestigation of Kutkin. Ind. J. Chem.,
10:29-31.
Singh, B.; Chandan, B.K.; Sharma, N.; Bhardwaj, V.; Satti, N.K.; Gupta, V.N.;
Gup ta, B.D.; Sur i, K.A. and Suri, O.P. (200 6). Isolation, structure
elucidation and in vivo hepatoprotective potential of trans-tetracos-
15-enoic acid from Indigofera tinctoria Linn. Phytother. Res.,
20:831-839.
Singh, V.; Visen, P.K.S.; Palnaik, G.K.; K apoor, N.K. and Dhawan, B.N. (1992).
Effect of picroliv on low density lipoprotein receptor binding of
rat hepatocytes in hepatic damage induced by paracetamol. Indian.
J. Biochem. Biophys., 29:428-431.
Song, E.K.; Kim, J.H.; Kim, J.S.; Cho, H.; Nan, J.X.; Sohn, D.H.; Ko, G.I.; Oh, H.
and Kim , Y.C . ( 200 3). Hepatoprotective phenolic constituents of
Rhodiola sachalinensison tacrine induced cytotoxicity in Hep G2
cells. Phytother. Res., 17:563-565.
Sonnenbichl er, J. an d Zetl , I. ( 198 6). Bioche mical effe cts of the
flavonolignan silibinin on RNA, protein, and DNA synthesis in rat
liver. Progr. Clin. Biol. Res., 213:319-331.
Sonnenbitchler, J.; Goldberg, M.; Hane, L.; Madubunyi, I.; Vogl, S. and Zetl, I.
(1986). Stimula tory effect of silybin on the DNA synthesis in
partially hepatectomized rat livers: nonresponse in hepatoma and
other malignant cell lines. Biochem. Pharmacol., 35:538-541.
Sridar, C.; Goosen, T.; Kent, U.M.; Williams, J.A. and H ollenberg, P.F. (2004).
Silybin inactivates cytochromes P450 3A4 and 2C9 and inhibits
major hepatic glu curonosyltranferases. Drug Metab. Dispos.,
32:587-594.
Srivastava, S.; Srivastava, A.K.; Patnaik, G.K. and Dhawan, B.N. (199 6). Effect
of picroliv on liver regeneration in rats. Fitoterapia, 67:252-256.
Subr amoniam, A. a nd Pushpa ngadan, P. (1 999) . D evelop ment of
phytomedicines for liver disease. Indian Journal of Phrmaclogy,
31(3):166-175.
Suzuki, M.; Sasaki, K.; Yoshizaki, F.; Oguchi, K .; Fujisawa, M. and Cyong, J.C.
(2005). Antihepatitis C virus effect of Citrus unshiu peel and its
active ingredient nobiletin. Am. J. Chin. Med., 33(1):87-94
Szuster-Ciesielska, A. and Kandefer-Szerszen, M. (2005). Protective effects of
betulin and betulinic acid against ethanol-induced cytotoxicity in
HepG2 cells. Pharmacol. Rep., 57(5):588-595.
Szuster-Ciesielska, A.; Plewka, K.; Daniluk, J. and Kandefer-Szerszen, M. (2011).
Betulin and betulinic acid attenuate ethanol induced liver stellate
cell activation by inhib iting reactive oxygen specie s (ROS),
cytokine (TNF-alpha, TGF-beta) production and by influencing
intracellu lar signalling. Toxicology, 280(3):152-163.
Takahara, T.; Watanabe, A. and Shiraki, K. (1994). Effects of glycyrrhizin
on hepatitis B surface antigen: a biochemical and morphological
study. J. Hepatol., 21:601-609.
Tang, J.; Feng, Y.; Tsao, S.; Wang, N.; Curtain, R. and Wang, Y. (2009). Berberine
and Coptidis rhizom a as novel antineoplastic agents: a review of
traditional use and biomedical investigations. J. Ethnopharmacol.,
126:5-17.
Thyagarajan, S.P.; Jayaram, S.; Gopalakrishnan, V.; Hari, R.; Jeyakumar, P. and
Sripathi, M.S. (2002). Herbal medicines for liver diseases in India. J.
Gastroenterol. Hepatol., 17(3):370-376.
Trinchet, I.C.; Coste, T.; Levy, V.G.; Vivet, F.; Duchatelle, V.; Legendre, C.; Gotheil, C.
and B eaugrand, M. (1989). Trea tment of alcoholic hepatitis with
silymarin. A double-blind comparative study in 116 patients.
Gastroenterol. Clin. Biol., 13: 120-124.
Tseng, P.C.; Hsu, H.C.; Janmanchi, D.; Lin, C.H.; Kuo, Y.H.; Chou, C.K. and Yeh,
S.F. (2008). Helioxanthin inhibits interleukin-1 beta-induced MIP-1
beta production by reduction of c-jun expression and binding of
the c-jun/CRE B1 complex to the AP-1/C RE site of the MIP-1
beta promoter in Huh7 cells. Biochem. Pharmacol., 76(9):1121-
1133.
Tu, C.T.; Han, B.; Yao, Q.Y.; Zhang, Y.A.; Liu, H .C. and Zhang, S.C. (201 2a).
Curcumin attenuates concanavalin A-induced liver injury in mice
by inhibition of toll-l ike receptor (TLR) 2, TLR4 and TL R9
expression. Int. Immunopharmacol., 12:151-157.
Tu, C.T.; Yao, Q.Y.; Xu, B.L., Wang, J.Y.; Zhou, C.H. and Zhang, S.C. (2012b).
Protective effects of curcumin against hepatic fibrosis induced by
carbon tetrachloride: modu lation of high-mobility group box 1,
toll-like receptor 4 and 2 exp ression. Food C hem. Toxicol.,
50:3343-3351.
Tu, C.T.; Yao, Q.Y.; Xu, B.L. and Zhang, S.C. (2013). Curcumin protects against
concanavalin A-induced hepatitis in mice through inhibiting the
cytopla smic translocation and expression of high mobility group
box 1. Inflamma tion., 36:206-215.
Valan, M .F.; John, A. ; B ritt o, D.E. and Ven kata raman, R. ( 2010 ).
Phytoconstituents with hepatoprotective activity. Int. J. Chem.
Sci., 8(3):1421-1432.
Veldt, B.J.; Hansen, B.E.; Ikeda, K., Verhey, E.; Suzuki, H. and Schalm, S.W. (2006).
Long-term clinical outcome and effect of glycyrrhizin in 1093
chronic hepatitis C patient s with non-response or relapse to
interferon. Scand. J. Gastroenterol., 41:1087-1094.
Ve lussi, M .; Cernigoi, A.M.; De Monte, A.; Dapas, F.; Caffau, C. and Zilli, M.
(1997). Long-term (12 months) trea tment with an antioxidant
drug (silymarin) is effective on hyperinsulinemia, exogenous insulin
need and malondialdehyde levels in cirrhotic diabetic patients. J.
Hepatol., 26:871-879.
Vizzutti, F.; Provenzano, A.; Galastri, S.; Milani, S.; Delogu, W.; Novo, E.; Caligiuri,
A.; Zamara, E.; Arena, U.; Laffi, G.; Parola, M.; Pinzani, M. and Marra, F.
(2010). Curcumin limits the fibrogenic evolution of experimental
steatohepatitis. Lab. Invest., 90:104-115.

17
Vogel, G.; Tuchweber, B. and Trost, W. (19 84). Protection by silibinin against
Amani ta phalloide s intoxication in beagles. Toxicol. Appl.
Pharmacol., 73:355-362.
Wang, M.; Grange, L.L. and Tao, J. (199 6). Hepatoprotective properties of
Silybum marianum herba l preparation on ethanolinduced liver
damage. Fitotera pia, 67:167-171.
Wang, J.B.; Zhao, H .P.; Zhao, Y.L.; Jin, C.; Liu, D.J.; Kong, W.J.; Fang, F.; Zhang,
L.; Wan g, H.J . and Xiao, X.H . ( 2011 ). H epatotoxicity or
hepatoprotection? Pattern recognition for the paradoxical effect
of the Chinese herb Rheum palm atu m L. in treating rat liver
injury. PLos One, 6(9):244-98.
Wang, W.; He, Y.; Lin, P.; Li, Y.; Sun, R.; Gu, W.; Yu, J. and Zhao, R. (2014). In
vitro effects of active components of Polygonum multifloru m
ra dix on en zymes involved in the lipid metabolism. J.
Ethnopharma col., 153:763-770.
Wagner, H. and Seligmann, O. (1985). Liver therapeutic drugs from Silybum
marianum. In: Chang, H.M.; Yeung, H.W.; Tso, W.W. and Koo, A.
(Eds.) Advances in Chinese medicinal materials research. Singapore:
World Scientific Publ. Co.
Xiao, H.B.; Sun, Z.L.; Zhang, H.B. and Zhang, D.S. (201 2). Berberine inhibits
dyslipidemia in C57BL/6 mice with lipopolysaccharide induced
inflammation. Pharmacol. Rep., 64: 889-895 .
Xiao, J.; Guo, R.; Fung, M .L.; Liong, E.C. and Tipoe, G.L. (2013). Therapeutic
approaches to non-alcoholic fatty liver disease: past achievements
and future challenges. Hepatobiliary and Pancrea tic Diseases
International, 12(2):125-135.
Xu, D.; Hu, L.; Su, C.; Xia, X.; Zhang, P.; Fu, J.; Wang, W.; Xu, D.; Du, H.; Hu, Q.;
Song, E. and Song, Y. (201 4). Tetrachloro-p-benzoquinone indu ces
hep atic oxida tive damage an d inflamma tory response, but not
apoptosis in mouse: the prevention of curcumin. Toxicol. Appl.
Pharmacol., 280 :305-313.
Yang, M.D.; Chiang, Y.M.; Higashiyama, R.; Asahina, K.; Mann, D.A.; Mann, J.;
Wang, C.C. and Tsukamoto, H. (20 12). Rosmarinic acid and baicalin
epigenetically de repress p eroxisomal proliferator-activat ed
receptor gamma in hepatic stellate cells for their antifibrotic effect.
Hepatology, 55(4):1271-1281.
Ye, X.; Feng, Y.; Tong, Y.; Ng, K.M.; Tsao, S.W.; Lau, G.K.K.; Sze, C.W.; Zhang, Y.;
Tang, J.; Shen, J. and Kobayashi, S. (2009). Hepatoprotective effects of
Coptidis rhizoma aqueous extract on carbon tetrachloride-induced
acu te liver hepatotoxicity in rats. J. Ethnopharmacol., 124:130-
136.
Yoshigai, E.; Machida, T.; Okuyama, T.; Mori, M.; Murase, H.; Yamanishi, R.;
Okumura, T.; Ikeya, Y.; Nishino, H. and Nishizawa, M. (2013). Citrus
nobiletin suppresses inducible nitric oxide synthase gene expression
in interleukin-1beta-treated hepatocytes. Biochem. Biophys. Res.
Commun., 439(1):54-59.
Yoshikawa, M.; Ninomiya, K.; Shimoda, H.; Nishida, N. and Matsuda, H. (2003a).
Hepatoprote ctive a nd an tioxidative propert ies of Salacia
reticulata: preventive effe cts of phenoli c c onstituents on
carbontetrachloride induced liver injury in mice. Biol. Pharm. Bull.,
25:72-76.
Yoshikawa, M.; Xu, F.; Morikawa, T.; Ninomiya, K. and Matsuda, H . (2003b).
Anastatins A and B, new skeletal flavonoids with hepatoprotective
activities from the desert plant Anastatica hierochuntica. Bioorg.
Med. Chem. Lett., 13:1045-1049.
Yu, H.B.; Zhang, H.F.; Zhang, X.; Li, D.Y.; Xue, H.Z.; Pan, C.E. and Zhao, S.H. (2010).
Resveratrol inhibits VEGF expression of human hepatocellu lar
carcinoma cells through a N F-kappa B-mediated mechanism.
Hepatogastroenterology, 57(102-103): 1241-1246.
Yun-Fan, L.; Sung, J.J.; Chow, W.C.; Farrell, G.; Lee, C.Z.; Yuen, H.; Tanwandee,
T.; Tao, Q.M.; Shue, K.; Keen, N.O.; Dixon, J.S.; Gray, D.F.; Sabbat, J. and
Cirrhosis Asian Lamivudine Multicentre Study Group. (2004). Lamivudine
for patients with chronic hepatitis B and advanced liver disease.
The New England Journal of Medicine, 351(15):1521-1531.
Zhang, J.P.; Zhang, M.; Zhou, J.P.; Liu, F.T.; Zhou, B.; Xie, W.F. and Guo, C. (2001).
Antifibrotic effects of matrine on in vitro and in vivo models of
liver fibrosis in rats. Acta Pharmacologica. Sinica, 22(2):183-186.
Zhang, L.; Wu, T.; Chen, J.M.; Yang, L.L.; Song, H.Y. and Ji, G. (2012). Danshensu
inhibits acetalde hyde-induced pr olifer ation and ac tiva tion of
hepatic stellate cell-T 6. Zhong Xi. Yi. Jie. He. Xue. Bao.,
10(10):1155-1161.
Zhang, A.; Sun, H. and Wang X. (2013). Recent advances in natural products
from plants for trea tment of liver diseases. Europea n Journal of
Medicinal Chemistry, 63:570-577.
Zhang, J.; Xu, L.; Zhang, L.; Ying, Z.; Su, W. and Wan, T. (2014a). Curcumin
attenuates d-galactosamine/lipopolysa ccharide-induced liver injury
and mitochondrial dysfunction in mice. J. Nutr., 144:1211-1218.
Zhang, P.; Ma, D.; Wang, Y., Zhang, M.; Qiang, X.; Liao, M.; Liu, X.; Wu, H. and
Zhang , Y. (201 4b). Berberine protects liver from ethanol-induced
oxidative stress and steatosis in mice. Food Chem. Toxicol., 74:225-
232.
Zhao, X.; Zhang, J.J.; Wang, X.; Bu, X.Y.; Lou, Y.Q. and Zhang, G.L. (2008). Effect
of berber ine on hepatocyte prolifera tion, inducible nitric oxide
synthase expression, cytochrome P450 2E1 and 1A2 activities in
diethyln itrosa mine- and phenobarbital-trea ted ra ts. Biomed.
Pharmacother., 62:567-572.
Zhu, Y.P. (1998). Chinese Materia Medica: Chemistry, Pharmacology and
Applica tions May 28 , CRC Press Referen ce, 714 Pages ISBN
9789057022852.