International Journal of Research Studies in Medical and Health Sciences
Volume 4, Issue 7, 2019, PP 11-20
ISSN : 2456-6373

Hepatoprotective Effect of Garcinol in Acute Paracetamol
Induced and Chronic Alcohol Induced Liver Injury inExperimental Rats
Muhammed Majeed1,2, Anjali Pandey2*, Sarang Bani2, Beena Bhat2, G. Muthuraman2.
1

2

Sabinsa Corporation, 20 Lake Drive East Windsor NJ 08520, USA
Sami Labs Limited, #19/1, 19/2, I Main, II Phase, Peenya Industrial Area, Bangalore, Karnataka,
India*Corresponding Author: Anjali Pandey, Sami Labs Limited, #19/1, 19/2, I Main, II Phase, Peenya
Industrial Area, Bangalore, Karnataka, India.
ABSTRACT
Garcinol (GC), a natural extract obtained from Garcinia species mostly from Garcinia indica has been
known for its various biological effects like anti-cancer, anti-oxidant, anti-inflammatory effect. The objectiveof this study was to evaluate hepatoprotectant effect of GC in various doses in acute paracetamol induced
liver injury and chronic alcohol induced liver injury. GC showed significant effect in the pracetamol
induced cytokines, Transforming growth factor beta 1, Tumour Necrosis Factor-alpha and Intercellular
Adhesion Molecule 1 and also inhibited the alcohol induced increase in Interleukin-12, Interleukin-1beta
and Tumour Necrosis Factor-alpha. Both alcohol and paracetamol increased the serum animotransferases
levels, GC after oral administration significantly reduced the elevated liver enzymes. Also the drug induced
oxidative stress was reversed by GC in dose dependent manner. In conclusion, our study suggests that GC
exerted the significant hepatoprotective effect in experimental rodents.
Keywords: Garcinol, GC, Paracetamol, APAP, Ethyl Alcohol, liver injury, hepatoprotection.

LIST OF ABBREVIATIONSALP- Alkaline Phosphotase
ALT- Alanine Transaminase
ANOVA- Analysis of Variance
APAP – Acetaminophen (paracetamol)
AST- Aspartate Transaminase
CPSEA- Committee for the Purpose of Control
and Supervision of Experiments on Animals
CTL- Cytotoxic T Lymphocyte
DMN- Dimethylnitrosamine
ECM- Extracellular Matrix
ELISA- Enzyme Linked Immune-sorbent Assay
GC- Garcinol
GSH-Glutathione
ICAM- Intercellular Adhesion Molecule

IL- Interleukin
JNK - c-Jun N-terminal kinases
LDH- Lactate dehydrogenase
LP- Lipid Peroxidation
LPS- Lipopolysaccharide
NAPQI- N-acetyl-p-benzoquinone imine
NK- Natural Killer
ROS- Reactive Oxygen Species
SD- Standard Deviation
TGF - Transforming Growth Factor
Th- T helper cell
TLR- Toll-like Receptor
TNF- Tumor Necrosis Factor

INTRODUCTION

proteins, clotting factors, synthesises glycogenand manufactures triglycerides and cholesteroland small damage in liver can affect the entire
human body. [1]Liver disease progresses slowly and usuallyremain asymptomatic for long duration as
hepatic cells reserves high self regeneration andreparative activity. The major function of liver
is to metabolize toxins including medications
and natural products. Also liver produces bile,

Paracetamol– Acetaminophen (APAP) is themost widely used analgesic-antipyretic that issafe up to the dose of 4g/day in divided doses,

International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 201911

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats

when dose exceeds the toxic metabolites areformed by cytochrome p-450 which further
causes paracetamol to induce hepatotoxicity inabsence of or decreased glutathione andcytochrome production.[2,3,4]Nowadays, excessive intake of alcohol and useof non-steroidal anti-inflammatory drugs andanalgesics is the major cause of toxicants
induced hepatotoxicity with higher prevalence
rate. Main reason for liver related mortality
throughout the world is alcoholic liver disease
which is induced due to portal concentration of
alcohol and its metabolic consequences. [5,6] Inaverage 90% alcoholics who drinks more than
16g/day is affected by steatosis and other formsof alcoholic liver diseases are steatohepatitis,
fibrosis and even cirrhosis.[6,7] Usually thesedamages are noticeable at the later stage andbecomes difficult to control and are irreversible.
[5]
Natural products are always explored due tofewer side effects which produce the long
lasting effect with its natural way of healing
most importantly in liver disease throughinhibition of tumour growth factor andfibrogenesis, elimination of pathogens anddefending the oxidative stress. [8] Garcinol(GC) is one of the natural ingredients foundmostly in Garcinia species. It is primarily extracted
from Garcinia indica which has been used formany disease ailments since ages. GC is
demonstrated as antioxidant, anti-inflammatory,
and anticancer agent in numerous studies. [9,10]Comparatively higher level of antioxidant activityof this fruit extract has been reported. It exhibitedthe 1,1 diphenyl-2-picrylhydrazyl free radical
scavenging activity by three times greater byweight in aqueous ethanol solution than the DL-tocopherol.[9] We investigated GC as the natural
hepatoprotectant with varying doses in two
different models using paracetamol (chemical)
and alcohol(toxins) to induce hepatic damage.
Expression of the pro-inflammatory cytokine
tumour necrosis factor (TNF)- occurs in many
acute and chronic liver diseases, as well as
following exposure to hepato-toxic chemicals. It
helps influence the damage processes that occur
following these insults by regulating additional
mediators. [11]Secretion of interleukin (IL)-1β and TNF-α byhepatic macrophages, which are accumulated in
the liver during chronic hepatic inflammation,
has been reported. [12] Increased hepatic andsystemic injury is related with a high production
12of pro-inflammatory cytokines such as TNF-α,
Interleukin-2, Interleukin-4, as well as growth
factors viz. transforming growth factor (TGF)-βand intercellular adhesion molecule (ICAM) 1
Toll-like Receptor (TLR)-4 signalling in hepatic
stellate cells participate to the development of
alcoholic fibrosis by enhancing TGF-βsignalling. During liver disease progression,both growth factors/cytokines and theExtracellular matrix (ECM) alter the TGF-β1
signals which stimulates the increase in ECM
accumulation leading to fibrosis. [13]Interleukin (IL)-12, a proinflammatory cytokine
produced by antigen-presenting cells upon
stimulation by various stimuli enhances
cytotoxic activity of NK cells and CTL and also
plays a role of growth factor for NK, T and
NKT cells promoting the development of Th1
cells. [14] IL-12 levels have been demonstrated
to increase in chronic alcoholism. Recently its
relationship with the different stages ofalcoholic liver disease along with the status ofalcoholism is reported. [15]Paracetamol absorption prolongs with theoverdose and further increases the saturation of
glucuronidation pathway of metabolism whichleads to increased production of reactive
metabolites. This toxic metabolite mediates
hepatotoxic effect of paracetamol leading to cell
injury.[16] Liver damage results in elevatedserum enzymes levels due to cellular leakage
and loss of functional integrity. [2, 3, 4]
The alcohol-induced liver disease comprises
increased gut-derived lipopolysaccharide (LPS)
entry into the liver. LPS/TLR-4 activates
Kupffer cells and produce TNF-α and various
other cytokines and growth factors, acts on
alcohol exposed hepatocytes and induce
apoptosis. [6,12]

MATERIALS AND METHODS
Garcinol
Garcinol (GC) (C38H50O6), polyisoprenylated
benzophenone derivative was extracted from
Garcinia indica fruit rind.[9] It has themolecular weight of 602.39252 and melting
point of 122 °. As indicated by molecular
formula and absorption spectral data GC is
probably related to the isomeric Xanthochymol
and as per optical rotation to the Cambogin. The
existence of a saturated carbonyl group (1727
cm-1) and two α, β-unsaturated carbonyl groups(1668 and 1642 cm-1) are shown by Infrared(IR) spectrum of the trimethyl ether,accountable for all the oxygen atoms.[17]International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 2019

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats

As mentioned in our previous paper
dried Garcinia indica fruit rind was extractedwith hexane andfractionatedbycolumn chromatography. Hexane extract wascompletely crystallized in ethanol and vacuum
dried. Thus, obtained residue of GC was
dissolved in cold hexane and re-crystallized atroom temperature to obtain as pale yellow
needle like crystals. The acquired GC from theabove process was standardized withmicrocrystalline cellulose powder. [18]Chemicals
The entire chemicals used were of analyticalgrade. The chemicals and reagents used werepurchased from Sigma Aldrich (St. Louis, MO,
USA). We used an enzyme-linked immunoassay
kit for cytokines from liver and blood of rats (R &D Systems Inc., Minneapolis, Minnesota, USA).
Animals
Male Wistar Rats of 180-200gms, housed
maximum of 6 per cage in a polypropylene cagewith maintained room temperature of 20.2- 23.5
C, relative humidity of 30 - 70% with 12hfluorescent light and 12h dark cycle were usedin the studies. Animals were fed with rodent
feed and purified water that was provided ad
libitum. Animals were kept in sterilized ricehusk beddings changed along with the cage
twice a week during acclimatization and entire
experimental study period.
Ethics
The hepatoprotectant effect of GC studies wereconducted
inaccordancewiththerecommendation of the committee for the
purpose of control and supervision ofexperiments on animals (CPCSEA) guidelines
for laboratory animal facility published in thegazette of India, December 15th 1998. The
protocols of the studies were also approved by
Institutional Animal Ethics Committee with theapproval number of ACP/IAEC/03/2009.

EXPERIMENTAL DESIGN
Acute Paracetamol Induced Hepatotoxicity
The individual freshly prepared dose of test
item, standard and toxicant were calculated as
per the body weight which was measured on day
1 of the study. The graded doses of GC (1.25,
2.50, 5.00 and 10 mg/kg, p.o), Silymarin (50mg/kg, p.o)) were administered. Experimental
animals orally received paracetamol (400 mg/kg
body weight) for seven days. Six rats each inseven groups were used in this study. Out ofremaining two groups one was given the same

dose of paracetamol which served as toxin
control group and to the other the proportionate
volume of vehicle was given which served as
vehicle control. Blood and liver samples werecollected in humanly manner, 2h after the lasttreatment for different estimations.
Chronic Alcohol Induced Hepatotoxicity
Seven groups with six rats each were used inthis study. The graded doses of GC (1.25, 2.50,
5.00 and 10 mg/kg, p.o), Silymarin (50 mg/kg,p.o)) were administered. Experimental animals
orally received alcohol (400 mg/kg bodyweight) for seven days. Out of remaining two
groups one was given the same dose of alcohol
which served as toxin control group and to theother the proportionate volume of vehicle wasgiven which served as vehicle control. The doseof the test item, standard and toxicants were
estimated according to the individual bodyweight of rats measured at day 1 of the study.
Blood and liver samples were collected 2h after
the last treatment for different estimations inchronic alcohol induced liver toxicity model.
Blood Biochemistry
Blood samples were collected in glass tubes
from orbital sinus to obtain haemalysis free
clear serum for the analysis of Alaninetransaminase (ALT) & Aspartate Transaminase(AST) [19], Alkaline Phosphotase (ALP) [20],and bilirubin [21] by standard methods in boththe studies.
Measurement of Oxidative Stress Markers
from Liver Homogenate
All the animals were sacrificed and livers werequickly excised freed from any adhering tissues,
washed and perfused with chilled Normal saline,
minced and homogenized in ice bath using
homogenizer (1100 rpm for 2 minutes) inchilled 10mM Tris-HCl buffer (pH 7.4) toobtain 10% liver homogenate for the estimationofglutathione(GSH)
[22]
and
lipid
peroxidation(LP) [23], by using standard
methods in both acute paracetamol induced
hepatotoxicity and chronic alcohol induced liver
toxicity model studies.
Measurement of Cytokines from Serum andLiver Homogenate
All the cytokines (TGF-β1, ICAM-1, TNF-,
IL-12, IL-1β) from Liver homogenate and serum
were analysed using Enzyme linked Immunosorbent Assay (ELISA) adhering to the user
manual of the manufacturers.

International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 201913

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats

STATISTICAL ANALYSISRESULTSRaw data was analysed using the statistical
Graphpad software. The data of each groupwere analyzed by analysis of variance(ANOVA) and expressed as mean ± standard
deviation (SD). T-test was used to compare thedifference between the treated and control
groups and treated with standard group. The
statistical significance of the differences
between groups was determined by one-way
ANOVA. All analyses and comparisons were
evaluated at a probability level of 10% (p ≤0.01). Percentage change was assessed for
categorical data.

TGF-β1 expression in liver homogenate of
Paracetamol treated rats
TGF-β1 in the liver homogenate was measured
to evaluate the effect of GC in paracetamol
treated rats comparative to Silymarin (figure1).
There was significantly high expression of TGFβ1 in paracetamol alone treated group ascompared to control as well as other groups
treated with GC or Silymarin. GC at the dose of
5 & 10mg/kg/day showed the better effect than
1.25, & 2.5mg/kg/day dose groups which wascomparative to Silymarin treated group.

Figure1. Effect of different doses of GC on TGF-β1 expression in liver homogenate of Paracetamol treated rats

ICAM-1expression in liver homogenate of
Paracetamol treated rats
Increased ICAM-1 in liver homogenate due toparacetamol induced liver damage wassuppressed by various doses of GC (figure2). 5& 10 mg/kg/day showed higher effect thanlower doses of GC but were slightly lower than
Silymarin.

Figure2. Effect of different doses of GC on ICAM-1expression in liver homogenate of Paracetamol treated rats

Effect of GC on TNF- in paracetamol treatedrats.
GC in various doses inhibited the serum TNF-
expression in the paracetamol induced hepatic
14

damage (figure3). Effect of GC wassignificantly increased according to dose
increment but 5mg/kg p.o dose group showed
better effect than 10 mg/kg p.o dose which wascomparative to the Silymarin treated group.

International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 2019

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats

Figure3. Flowcytometry histogram plot showing one representative GC effect on TNF- of paracetamol treatedrats.

Effect of GC on biochemical parameters ofparacetamol treated rats.
Serum biochemical parameters of paracetamol
treated rats are as shown in (table 1). The
activity of Aspartate Aminotransferase, Alanine
Aminotransferase and Alkaline phosphotase wassignificantly increased in paracetamol only

treated group as compared to control. Further,
GC from the dose of 2.5mg/kg showed thesignificant effect increased activity of AST,
ALT and ALP. There was lower percentagechange in ALP but was significant in the dosesof 5mg/kg p.o. and 10mg/kg p.o GC treatedgroup.

Table1. Effect of GC (GC) against oxidative stress parameters of Paracetamol (APAP) induced liver damage inrats
Hepatic parameters
Treatments
Dose mg/kg GSH µmoleGSH/g
LP µmoleMDA/g liv.
Average Protection%
9.54±0.12
40.88±2.48
Vehicle5.24±0.46
72.20±2.40
Vehicle + APAP
1.25
5.96±0.56 (13.74)
66.50±4.20 (7.89)
10.81
GC+APAP2.5
6.32±0.26* (20.61)
60.24±2.40 (16.56)
18.58
GC+APAP5.0
6.88±0.42** (31.29)
52.24±2.60 (27.64)
29.46
GC+APAP10.0
7.04±0.36** (34.35)
50.48±1.60** (30.08)
32.21
GC+APAP50
7.45±0.28** (42.17)
48.86±1.60** (35.09)
38.63
Sily + APAP
Sily: Silymarin; (Values as Mean ± SE, n = 6) ; Percent change in parenthesis;
P value *: < 0.01; ** : <0.001. (LP) Lipid peroxidation; (GSH) Glutathione reductase

Effect of GC on Oxidative parameters ofparacetamol treated rats
Reduction in glutathione reductase due toparacetamol treatment was thus improved by

GC (table 2). The percentage protection wasdose dependent; higher the dose better teprotection. Lipid peroxidation increased byparacetamol was suppressed by GC significantly
in higher dose.

Table2. Effect of GC (GC) against Paracetamol (APAP) induced biochemical changes in rats
Treatments
Vehicle

Dose
mg/kg
-

ALT µmole/min/lt AST µmole/min/lt
98.32±5.20

117.49±8.26

ALPµmolePNP/min/lt
21.42±2.04International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 2019

Average
Protection%
15

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats
1102.10±46.98
839.79±59.17
40.54±3.61862.97±53.38
761.61±43.96 (9.30) 37.21±3.44 (8.21)(21.69)13.06
2.5
808.64±38.55*
650.88±35.84*
34.28±1.98(15.44)GC+APAP(26.62)(22.49)21.51
5.0
661.67±51.40**
463.41±38.56**
30.74±2.05** (24.17)
GC+APAP(39.96)(44.81)36.31
10.0
590.22±50.98**
536.39±44.13**
33.60±1.93* (17.11)
GC+APAP(46.44)(36.12)33.22
50377.04±14.44**
379.64±23.22**
26.90±2.24** (33.64)
Sily + APAP
(65.78)(54.79)51.40
Values as Mean ± SE, n = 6); Percent change in parenthesis; P value *: < 0.01; **: <0.001. (ALT) Alaninetransaminase; (AST) Aspartate aminotransferase; (ALP) Alkaline phosphatase.
Vehicle + APAP
GC+APAP

1.25

Effect of GC on expression of TNF- and IL1β in serum of animals from Ethyl alcohol
induced liver damage
There was significant up
proinflammatory
cytokine

regulation of(IL-1β)andinflammatory cytokine (TNF-) in the serum ofethyl alcohol treated rats (figure 4). GC showed
its significant effect to decrease the serum levelof IL-1β and TNF-. The effect of GC in thedose of 5mg/kg p.o expressed higher effect incomparison to Silymarin treated group.

Figure4. Effect of GC on expression of TNF- and IL-1β in serum of animals from Ethyl alcohol induced liver
damageEffect of GC on expression of IL-12 in serumof animals from Ethyl alcohol induced liver
damageEthyl alcohol subsequently increased the levelof IL-12, GC in various doses significantly
reduced the level of IL-12 (figure 5). GC in
dose group 5mg/kg showed better reduction
than Silymarin treated group.

Figure5. Effect of GC on expression of IL-12 in serum of animals from Ethyl alcohol induced liver damage

Effect of GC in serum biochemical parameters in Ethyl Alcohol induced liver damage
Alcohol induced elevation of biochemical parameters were reduced with GC treatment in different
doses comparatively similar to Silymarin (table 3).
16

International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 2019

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats
Table 3. Effect of GC (GC) in serum biochemical parameters in Ethyl Alcohol induced liver damage
Treatments

Dose ALT µmole/min /AST
ALP µmole PNP Bilirubin
Average
mg/kg
ltrµmole/min/lt/min/lt
mg%
Protection%
Vehicle118.10±10.20
106.40±16.60
32.30±0.52
0.44±0.08
Vehicle+ ETOH
1820.08±42.80 1076.32±48.22
104.22±8.60
2.08±0.02
GC + ETOH
1.25
1320.40±52.20
858.80±32.64
88.68±8.58
1.94±0.02
17.32(27.45)*(20.20)14.91)(6.73)GC + ETOH
2.5 1080.50±48.56** 726.78±46.50* 76.12±4.88**
1.68±0.04*
29.82(40.63)(32.47)(26.96)(19.23)
GC + ETOH
5.0
876.58±76.80** 650.26±56.20** 68.32±5.60**
1.42±0.06**
39.39(51.83)(39.58)(34.44)(31.73)
GC + ETOH
10.0 870.80±48.40** 632.48±44.56** 69.00±4.82**
1.38±0.04**
40.20(52.15)(41.23)(33.79)(33.65)
Sily + ETOH
50
854.88±38.46
662.70±38.40
66.54±6.30**
1.34±0.02**
40.79(53.03)(38.44)(36.15)(35.57)Ethyl alcohol (Value Mean ± SE, n = 6); Percent change in parenthesis; P value * : < 0.01; ** : <0.001. (ALT)
Alanine transaminase; (AST) Aspartate aminotransferase; (ALP) Alkaline phosphatise.

Effect of GC against the alcohol induced
oxidative stress parameters
Glutathione reductase and lipid peroxidation
was measured in liver homogenate of ethyl

alcohol induced liver damaged rats (table 4).
GC increased the Glutathione reductase level
which was significantly decreased by ethyl
alcohol and reduced the lipid peroxidation rate.

Table4. Effect of GC (GC) against Ethyl Alcohol induced liver damage in rats
Treatments

Dose mg/kg

GSH µmoleGSH/g

LP µmoleMDA/g liv.

Average
Protection%
13.88
24.96
38.22
42.47
50.83

9.62±0.16
44.00±1.60
Vehicle4.24±0.12
94.60±4.20
Vehicle + ETOH
1.25
4.92±0.22 (16.03)
83.50±6.20 (11.73)
GC + ETOH
2.5
5.42±0.2* (27.78)
73.64±4.00* (22.15)
GC + ETOH
5.0
6.04±0.20** (42.45) 62.44±4.60** (33.99)
GC + ETOH
10.0
6.40±0.24** (50.94) 62.42±3.80** (34.01)
GC + ETOH
50
6.95±0.20** (63.91) 58.88±1.40** (37.75)
Sily + ETOH
Sily: Silymarin; EtOH : Ethyl alcohol (Values as Mean ± SE, n = 6) ; Percent change in parenthesis; P value *:< 0.01; ** : <0.001. (LP) Lipid peroxidation; (GSH) Glutathione reductase.

DISCUSSION
Garcinol is a polyisoprenylated benzophenone
derivative extracted from Garcinia indica fruit
rind. Its use in traditional and folk medicine isapparent since ancient time and recently its
various clinical benefit including anticancer,
antioxidant and anti-inflammatory activities has
been studied.[9] It is a potent hepatoprotectant
and its protection effect in dimethy
lnitrosamine (DMN) induced liver injury wasrecently explored. [24,25] Paracetamol is themost commonly used antipyretic and analgesic
with hepatoxic effect when used exessively.
Similarly extreme use of alcohol triggers thehepatic injury. So, we used paracetamol andalcohol as the toxicants and studied thehepatoprotectant effect of GC in experimental
rats.
In this study GC was found to decrease theelevated biomarkers in both acute paracetamol
induced hepatotoxicity and chronic alcohol

induced hepatotoxicity. Drug induced hepatitis
was monitored by various serum tests andcytokines test in liver homogenate.
Paracetamol is assumed to be most commonlyused medication around the globe due its
availability over the counter in various dosage
forms.[26] Davidson and Eastham reported thatparacetamol in overdose produces hepatotoxic
effect for the first time in the year 1996.[27]Paracetamol in normal dose is metabolized into
N-acetyl-p-benzoquinone imine (NAPQI) andglutathione further detoxifies to the non-toxic
metabolite (APAP-GSH) but when dose exceeds
the therapeutic level, triggers the hepatic injury
due to covalent bond between NAPQI andhepatic cells and reactions with hepatic proteins.
[28,29]TGF-β is the major profibrogenic cytokine
which enhances the damage to epithelial cells
inducing oxidative stress and myofibroblast
activation.[30] In our study Silymarin and GC

International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 201917

Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced and Chronic Alcohol Induced Liver
Injury in Experimental Rats

inhibited the TGF-β1 restoring a regenerative
reaction in acute hepatitis.
ICAM-1, a marker tissue damage is expressed
after chronic paracetamol use and controls theenhanced migration of lymphocytes into thesites of inflammation binding to the b2 integrins
lymphocyte function associated with antigen 1.[31] GC significantly reduced the increased
ICAM-1 level in dose dependent manner in
Paracetamol treated rats.
TNF-α, one of the apoptosis-inducible factors
and has possible mechanism in progression ofliver injury.[32,33] It is evidenced that TNFalpha-TNF-Rp55 axis plays major role inpathogenesis of paracetamol induced liver
damage. [34] GC significantly inhibited the
TNF- released post paracetamol ingestion in adose dependent manner.
Serum aminotransferases i;e AST, ALT, total
bilirubin and ALP concentration elevates as aresult of liver injury proportional to the severity
both in acute and chronic condition.[35,36]
Silymarin reduced the elevated serum enzymes
by almost 42% and there was comparable
reduction up to 35% in GC treated groups
probably as a result of repair and regeneration ofhepatic cells.
As a result of NAPQI protein binding
mitochondrial dysfunction occurs resulting in
the glutathione depletion and oxidative
stress.[37] GC reversed the oxidative stressparameters, thereby, suppressing the lipid
peroxidation and elevating levels of Glutathione
reductase in paracetamol induced liver disease.
Alcohol induced liver disease is highly
accountable for the alcohol related mortalities
through hepatocellular injury, fat accumulationand inflammation and even the liver cirrhosis
and carcinoma.[38] The systemic manifestationsof alcohol induced liver inflammation arecharacterized by cytokine production.[39]Kupffer cells generates ROS which activates the
JNK and enhanced secretion of chemokines andcytokine including TNF-.[40] GC in various
doses suppressed the expression of TNF-
induced by alcohol intake in rats. The
progression of several types of chronic
inflammatory diseases is triggered through, IL1β an inflammatory cytokine that signals
through IL-1 receptor 1 (IL-1R1) leading to an
inflammatorycascade.[41,42,43]
Alcohol
increased the IL-β which was significantly
reduced by GC and Silymarin in theexperimental rats.
18

IL-12 is produced by Kupffer cells inendotoxemia developed due to chronic alcohol
intake further increases the production of antiinflammatory cytokines. It also induces theexpression of interferon γ in T cells and naturalkiller cells, which leads to macrophageactivation, impairment of microcirculation andincreased
inflammation.[44,45,46]
GCsignificantly reduced the IL-12 produced byalcohol ingestion possibly by repairing the
microcirculation
furtherdecreasing
theinflammation.
As the part of liver function test, commonlyused biomarkers for liver injury are ALT, AST,
ALP and bilirubin and specifically ALT inserum indicates loss of hepatocyte membrane
integrity.[47,48] Serum level of liver enzymes
ALT, AST, ALP and bilirubin was evident post
alcohol administration in rats which was
reduced by GC. The oxidative stress and lipid
peroxidation markers increased after alcohol
intake was subsequently reduced by GC in
similar pattern to the standard Silymarin.

CONCLUSION
GC inhibited the TGF-β1, ICAM-1 and TNF-
elevated in paracetamol induced liver injury.
Also inhibited increased levels of TNF-, IL- 1β
and IL-12 induced by TLR-4 activation ofkupffer cells by LPS of gram negative bacteria
in the gut the activation and excessive growth ofwhich is due to ethyl alcohol intake. GC reduced
the hepatitis induced increased levels of AST,
ALT, ALP and Bilirubin. GC reversed theparacetamol and ethyl alcohol induced oxidative
stress, thereby, suppressing the Lipid
peroxidation and elevating levels of Glutathione
reductase. We can conclude from the above
studies GC is potent natural hepatoprotectant
which can further be explored through targetedstudies for better understanding and its exact
mechanism involved in hepatoprotection.

ACKNOWLEDGEMENT
We would like to thank Dr. Prakriti Neupane forher help during Manuscript preparation.

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Citation: Muhammed Majeed et.al., “Hepatoprotective Effect of Garcinol in Acute Paracetamol Induced
and Chronic Alcohol Induced Liver Injury in Experimental Rats”, International Journal of Research Studies
in Medical and Health Sciences. 2019; 4(7): 11-20.

Copyright: © 2019 Muhammed Majeed, This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and reproduction inany medium, provided the original author and source are credited.

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International Journal of Research Studies in Medical and Health Sciences V4 ● I7 ● 2019