Indonesian J. Pharm. Vol. 28 No.

1 : 10 – 18
ISSN-p : 2338-9427
DOI: 10.14499/indonesianjpharm28iss1pp10
Research Article

HEPATOPROTECTIVE ACTIVITY OF ETHYL ACETATE FRACTION

OF SENGGUGU’S ROOT BARK (Clerodendrum serratum L.
Moon) ON RATS INDUCED BY CARBON TETRACHLORIDE
Nasrudin1,2, Wahyono3, Mustofa4* and Ratna Asmah5

1)Student of Doc. Program in ABSTRACT

Pharmaceutical Sci, Univ Our previous study showed that ethyl acetate fraction of
Gadjah Mada, Sekip Utara, Clerodendrum serratum L. Moon (EAFCS) root bark had in vitro
Yogyakarta, 55281
2)Faculty of Teacher Training antioxidant activity. The aim of this study was to evaluate
and Education.Halu Oleo Univ, hepatoprotective effect of EAFCR in rats induced by carbon
Kendari, Southeast Sulawesi tetrachloride (CCl4). Thirty-six rats were randomly divided into 6
93232 groups. Group 1 as control was given 0.5% Na-CMC. Group 2 as
3)Dept of Pharm. Biology, Fac of positive control were given silymarin at a dose of 100mg/Kg.BW.
Pharmacy, Univ Gadjah Mada, Group 3 as negative control were induced by CCl4. Group 4-6 as
Sekip Utara, Yogyakarta, 55281 treatment groups were induced CCl4 and given EAFCR at a dose
4)Dept of Pharmacology and
of 25; 50 and 100mg/Kg BW, respectively. Biochemical and
Therapy, Fac of Medicine, Univ oxidative stress parameters in liver were determined. The results
Gadjah Mada, Sekip Utara, showed that serum glutamic oxaloacetic transaminase (SGOT),
Yogyakarta 55281
5)Dept of Pharm. Chemistry,
serum glutamic pyruvic transaminase (SGPT), alkaline
Fac of Pharmacy, Univ Gadjah phosphatase (ALP) and bilirubin were significantly lower, whereas
Mada, Sekip Utara, Yogyakarta the total protein was significantly higher after pretreatment with
55281 EAFCR at the dose of 100mg/Kg.BW (p<0.05). Moreover,
malondialdehyde (MDA) was significantly lower, whereas
Submitted: 20-10-2016 glutathione peroxidase (GPx) and catalase (CAT) were
Revised: 10-12-2016 significantly higher after pretreatment with EAFCS at the dose of
Accepted: 7-01-2017 100mg/Kg.BW (p<0.05). In conclusion, EAFCR has potent
hepatoprotective activity due to its antioxidant properties of the
*Corresponding author active compounds contained in this plant.
Mustofa
Key words: Clerodendrum serratum, antioxidant, hepatoprotective effect,
Email:
carbon tetrachloride
[email protected]

INTRODUCTION Association for the Study of the Liver (EASL),

Liver is one of the vital organs in the approximately 29 million people in the
body that plays an essential role in regulating European Union still suffer from a chronic
various physiological processes. It plays a liver condition (Blachier et al., 2013). In the US,
pivotal role in metabolism and distribution of liver disease is reported as the second leading
nutrients as well as detoxification of toxic cause of mortality amongst all digestive diseases
metabolites and xenobiotics (Chiang, 2014). It (Everhart and Ruhl, 2009). In Indonesia in
is also involved the maintenance, performance 2007, based on the Basic Health Research, the
and regulating homeostasis of the body. prevalence of clinical hepatitis varied from
Moreover, the liver is involved with almost all 0.2 and 0.9% with an average of 0.6% (National
the biochemical pathways to growth, fight Institute of Health Research and Development,
against the disease, nutrient supply, energy 2009). Liver disease is caused by various toxicants
provision and reproduction (Ward and Daily, such as certain drugs, carbon tetrachloride,
1999). Therefore, take care of a healthy liver is thioacetamide, and arsenic. It is also caused by
important for the overall prosperity of chronic alcohol consumption, viral or microbial
anybody. infections and autoimmune disorders (Adewusi
Liver disease is a major cause of illness and Afolayan, 2012; Jannu et al., 2012).
and death worldwide regardless of age, sex, In spite the remarkable advance in
region and race. According to European conventional medicine, liver disease is

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Nasrudin

challenging not only for clinician but also MATERIALS AND METHODS
researchers in drug discovery and development. Plant materials
Currently, effective drugs that stimulate liver Root bark of plant used in this study was
function that can protect the liver from injury obtained from several population of C. serratum
or regenerate liver cells are not available in the growing in Imogiri Subdistrict, Bantul District,
market (Chattopadhyay, 2003). Therefore, Yogyakarta. The species was authenticated by
the availability of alternative drugs to treat the Departement of Pharmaceutical Biology
liver diseases is needed. Some Indonesian Faculty of Pharmacy, Universitas Gadjah Mada,
medicinal plants have been used traditionally Yogyakarta. A voucher specimen had been
to treat liver diseases for a long time. Some deposited at the same department.
of them were proven to have hepatoprotective
activity such as Curcuma longa (Baxia et al., Extract preparation
2013; Singh et al., 2012; Somchit et al., 2005), The C. serratum root barks were air-dried
Curcuma xanthorrhiza (Devaraj et al., 2014; at the room temperature (25-30°C). The dried
2010), Zingiber officinale (Bardi et al., 2013; Lebda root barks were then chopped in order to
et al., 2013; Atta et al., 2010), Phyllanthus niruri obtain small size and pulverized by using
(Harish and Shivanandappa, 2006; Chatterjee Retsch Muhle brand machine before extraction
et al., 2006) and Andrographis paniculate at the Laboratory of Pharmaceutical Biology,
(Nagalekshmi et al., 2011; Rajalakshmi et al., Universitas Gadjah Mada. Powdered plant
2012). material was graded and extracted by
Clerodendrum serratum L. Moon, with local maceration method using n-hexane and ethyl
name senggugu, is one of medicinal plants that acetate. The extract of ethyl acetate was then
has been used traditionally in India, China, filtered and the filtrate was evaporated to
Thailand, Korea, Japan and Indonesia to dryness using a rotary vacuum evaporator to
treat several illness such as syphilis, typhoid, obtain ethyl acetate fractions for in vivo
cancer, jaundice, hypertension, asthma, hepatoprotective activity testing.
bronchitis, and cough (Shrivastava and Patel, Experimental animals
2007; Heyne, 1950). Senggugu has been reported Male albino Wistar rats with 150-200g
to possess several biological activities including BW and aged 12 weeks were obtained from the
anticancer, antinociceptic, anti-inflammatory, Faculty of Pharmacy, Universitas Gadjah Mada.
antipyretic (Narayanan et al., 1999; Wahyono, Rats were maintained under standard animal
2001), antifertility (Julaeha et al., 2013), husbandry conditions (25±2°C, with humidity
mucolytic (Wahyono, 1998), tracheospasmolytic 40-70%, 12h dark/12h light cycle) and allowed
(Wahyono, 2004), antioxidant and antibacterial access to standard laboratory food and water ad
(Prasad et al., 2012). libitum. The protocol of this study has been
Our previous study showed that approved by the Research Ethics Committee,
ethyl acetate fraction of C. serratum L. Moon the Integrated Research and Testing Laboratory,
(EAFCS) root bark had in vitro antioxidant Universitas Gadjah Mada, Yogyakarta (No.
activity to scavenge DPPH radical with IC50 457/KEC-LPPT/IV/2016).
of 30.968±0.686µg/mL (Nasrudin, 2015).
Furthermore, the hepatoprotective activity In vivo hepatoprotective activity testing
of the ethanol extract of C. serratum root Hepatoprotective activity test was
has also been reported (Vidya et al., 2007). performed according to the previous study
In this study, we reported that the conducted by Gomes et al. (2011). Thirty-six
hepatoprotective activity of the EAFCS rats were randomly divided into 6 groups of 6
root bark in rats induced by carbon rats in each group. Group 1 as normal control
tetrachloride (CCl4). Moreover, the effect of the was given 0.5% Na-CMC. Group 2 as negative
fraction on oxidative stress status of rats was control were induced by CCl4. Group 3 as
also reported. positive control was induced by CCl4 after given

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 Activity of Ethyl Acetate Fraction

silymarin at a dose of 100mg/Kg.BW in 0.5% used for analysis of oxidative stress parameters
Na-CMC orally. Group 4-6 as treatment groups Including MDA (malondialdehyde), GSH
were induced by CCl4 after given ethyl acetate (glutathione) and CAT (catalase) (Pareek et al.,
extract fraction at dose of 25; 50 and 2013).
100mg/Kg BW in 0.5% Na-CMC orally, Liver MDA levels were measured
respectively. The silymarin and ethyl acetate according to Singh et al. (2008). As much
extract fraction were given once daily for 7 as 0.5mL of liver supernatant was added 2.0mL
days. The CCl4 induction was performed of cold HCl (0.25N) containing 15% TCA,
intraperitoneally at dose of 1mL/Kg.BW on TBA 0.38%, and 0.5% BHT. The mixture was
day 8th. On day 9th rats were anesthetized with heated at 80°C for one hour. Once cooled, the
ketamine 60mg/Kg.BW intramuscularly and mixture was centrifuged at 3500 rpm
blood sample was drawn by retro-orbital for 10min. The absorbance of the supernatant
puncture. The blood samples were placed at was measured at 532nm. Tetraethoxypropane
room temperature for 30min and then (ETP) was used as the standard solution.
centrifuged (2000g, 10min) to separate the The activity of GPx enzyme was
serum. The serum samples were collected and determined as follows: 200µL of 10mM
stored in vacutainer vials at -4°C temperature reduced glutathione (GSH) and 200µL of
until analysis. At the end of the experiment, rats glutathione reductase enzyme (2.4 units) were
were sacrificed under deep anesthesia by incubated at 37°C for 10min and added by
inhalation of diethyl ether and then the 200µL of 1.5nM NADPH. The mixture was
abdominal incision was made. Livers were incubated again at 37°C for 3min, followed by
removed from the rats and immediately washed addition of 200µL of 1.5nM H2O2. The
with salt (0.9% sodium chloride) in cold absorbance was measured by using spectro-
conditions. The liver tissues were dried and photometer at 340nm. The enzyme activity was
weighed as much as 100 mg (10%) for analysis calculated based on following formula:
of oxidative stress parameters (Pareek et al., Abs X Vt X 2 X 1000 X 1/mg Protein
2013). M unit of GSH-Px =
6,22 X Vs

Estimation of biochemical parameters Abs = absorbance changes; Vt = total volume

Liver blood tests were conducted to (mL); 6.22 = extrinsic coefficient of NADPH;
assess liver functions including the level of 2 = 2mol of GSH that equivalent to 1mol of
SGOT (Serum Glutamic Oxaloacetic NADPH; 1000 = change into a milli unit, and
Transaminase), SGPT (Serum Glutamic Vs = sample volume.
Pyruvic Transaminase), ALP (Alkaline
Phosphatase), bilirubin, and total protein. All The activity of CAT enzyme was
parameters were measured using test kit for measured according to Aebi et al. (1984) and
blood biochemistry at Integrated Research and Jayakumar et al. (2006). A total of 0.5mL of the
Testing Laboratory, Universitas Gadjah Mada, liver supernatant was added into 2.0mL of
Yogyakarta. 50mM potassium phosphate buffer (pH 7.0)
containing 10mM of H2O2. The absorbance
Estimation of oxidative stress was measured by using spectrophotometer at
parameters 240nm and recorded every 15s for one minute.
Liver organs were homogenized using The enzyme activity was calculated using slope
homogenizer for preparing of the sample by data from the curve of absorbance of the
adding 500mL of 50mM Tris buffer (pH 7.4) sample solution (SL) and the blank solution
containing 1mM EDTA and 10µg/mL (SLb) based on following formula:
leupeptin. The homogenates were centrifuged
at 4°C temperature at 10.000rpm for 10min to (SL – SLb) 2.5
obtain supernatants. The supernatants were CAT activity (U/mg) = X
0.436 0.5

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Statistical analysis from of C. serratum roots at the dose of

Data were presented as mean ± standard 10mg/Kg.BW was more significant than its
deviation (SD). The different in biochemical ethanolic extract at the dose of 20mg/Kg.BW
and oxidative stress parameters in each group against CCl4 induced hepatotoxic in male
were analyzed by using Mann-Whitney test. A Wistar rats. Another study showed that
p-value <0.05 was considered as significantly alcoholic and aqueous extracts of C. serratum
different. leave at the dose of 200mg/Kg. BW had
hepatoprotective activity against rifampicin
RESULTS AND DISCUSSION induced hepatotoxic in male and female Swiss
Estimation of biochemical parameters albino mice (Agrawal et al., 2013).
This study was conducted to evaluate the
hepatoprotective of EAFCS root bark on CCl4 Estimation of oxidative stress
induced hepatotoxic in male albino Wistar rats. parameters
CCl4 is widely used for experimental induction Liver injury due to CCl4 induction in rats
of liver damage due to it is one of the best is caused by the formation of trichloromethyl-
models to describe the cellular mechanisms of peroxyl radicals which initiates lipid per-
oxidative damage (Basu, 2003). Hepatocellular oxidation (Shenoy et al., 2001). The hepato-
damage is thought through reactive CCl4 protective medicinal plants act through various
metabolites. CCl4 is metabolized by mechanisms including reduced in lipid
cytochrome P450 in the endoplasmic reticulum peroxidation and increase in glutathione level
and mitochondria resulting trichloromethyl (Kumar et al., 2013). In this study, the effect of
radicals and then trichloromethyl-peroxyl the ethyl acetate fraction of C. serratum L. Moon
radicals (Shenoy et al., 2001). These radicals root bark on oxidative stress status of rats
subsequently attack the cellular macromolecules induced by CCl4 was also evaluated (Table II).
such as proteins or fats resulting in lipid The MDA level of the liver of rats induced
peroxidation and cell necrosis (Zhou et al., CCl4 was significantly higher than that of
2013). normal rats not induced CCl4 (p<0.05).
Table I shows the effect of EAFCS root Malondialdehyde is one of the final products of
barks on liver functions of rats after CCl4 lipid peroxidation process. It is commonly used
induction. The liver enzymes (SGOT, SGPT, as a marker of oxidative stress. The increase of
and ALP) and serum bilirubin concentration of MDA levels after CCl4 induction indicated the
EAFCS group at the dose of 100mg/Kg.BW occurrence of liver injury due to oxidative
and silymarin at the dose of 100mg/Kg.BW stress. Furthermore, pretreatment of the
was significantly lower than those of CCl4 EAFCS root barks significantly reduced the
group at a dose of 1mL/Kg.BW, whereas their MDA level in dose dependent manner
serum total protein concentrations were (p<0.05). It was indicated that the EAFCS root
significantly higher (p<0.05). However, they barks could protect the increasing in lipid
were still significantly higher than those of Na- peroxidation process in the liver due to CCl4
CMC group as normal control (p<0.05), induction. Hence it may be possible that the
whereas their serum total proteins were not mechanism of hepatoprotection of the fraction
significantly different (p>0.05). The results is due to its antioxidant effect.
indicated that induction with CCl4 at dose In contrast, the GPx and CAT activities
1mL/Kg.BW caused hepatic damage of the rats of liver of rats induced CCl4 were significantly
and pretreatment with EAFCS at the dose of lower than that of normal rats not induced CCl4
100mg/Kg.BW protected hepatic damage. (p<0.05). Glutathione peroxidase and CAT are
The results obtained in this study were in antioxidant enzymes that found in many
agreement with the results of previous studies mammalian cells, including red blood cells. It
using extracts of different parts of C. serratum as was well reported that low activity of these
samples. Vidya et al. (2007) reported the enzymes may render the liver tissue susceptible
hepatoprotective activity of ursolic acid isolated to lipid peroxidation damage (Recknagel et al.,

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 Activity of Ethyl Acetate Fraction

Table I. The effect EAFCR root bark on liver functions of rats after CCl4 induction
SGOT SGPT ALP BRN TP
Group of treatment*
(U/L) (U/L) (U/L) (mg/dL) (g/dL)
215.06± 96.46± 206.11± 0.75± 7.29±
Na-CMC (1.0mL/Kg.BW)
188.16 192.28 116.89 0.11 0.42
716.13± 644.72± 761.26± 1.06± 5.85±
CCl4 (1.0mL/Kg.BW)
116.56 137.57 312.80 0.14 0.51
315.12± 303.66± 255.08± 0.68± 7.05±
Silymarin (100mg/Kg.BW)
190.80a 137.84a 90.92a 0.10a 0.76a,b
690.05± 665.22± 564.38± 0.91± 6.14±
EAFCR (25mg/Kg.BW)
263.17 169.85 176.58 0.07 0.43
838.42± 656.70± 426.67± 0.79± 5.95±
EAFCR (50mg/Kg.BW)
184.42 184.59 82.34 0.06 0.45
528.34± 275.71± 277.70± 0.72± 7.10±
EAFCR (100mg/Kg.BW)
154.37a 146.23a 41.28a 0.08a 0.33a,b
EAFCR: ethyl acetate fraction of C. serratum root barks; *Data was presented as mean ± SD from 5 rats of
each group (n = 5); SGOT: serum glutamic oxaloacetic; SGPT: serum glutamic pyruvic transaminase; ALP:
alkaline phosphatase; BRN: biliubin; TP: total protein. asignificantly different compared to CCl4 and Na-
CMC groups (p <0.05); bnot significantly different compared to Na-CMC group (p>0.05)

Table II. The effect of EAFCS root barks on stress oxidative status of rats after CCl4 induction
Group of treatment MDA (nmol/g) GPx (U/mg) CAT (U/mL)
Na-CMC (1.0mL/Kg.BW) 2.75±0.19 72.91±0.92 6.61±0.23
CCl4 (1.0mL/Kg.BW) 9.15±0.47 11.35±0.32 1.66±0.22
Silymarin (100mg/Kg.BW) 3.68±0.38a 57.83±0.85a 5.46±0.27a
EAFCS (25mg/Kg.BW) 7.53±0.24a 15.98±0.39a 2.43±0.09a
EAFCS (50mg/Kg.BW) 5.35±0.23a 48.71±2.23a 4.33±0.15a
EAFCS (100mg/Kg.BW) 3.39±0.14a 58.70±0.51a 5.59±0.32a
EAFCS: ethyl acetate fraction of C. serratum root barks; *Data was presented as mean ± SD from 5 rats of
each group (n = 5); MDA: malondialdehide; GPx: glutathione peroxidase; CAT: catalase; asignificantly
different compared to CCl4 and Na-CMC groups (p <0.05).

1989). The decrease of GPx and CAT after of roots bark of this plant has been proven to
CCl4 induction also indicated the occurrence of possess antioxidant activity through the DPPH
liver damage. It the present study we free radical scavenging activity with an IC50
demonstrated the effectiveness of the ethyl value of 30.968±0.686µg/mL (Nasrudin, 2015).
acetate fraction of EAFCS barks in the Bhujbal et al. (2009) reported that ethanolic
recovering reduced GPx and CAT levels and to extract of the C. serratum Linn roots possessed
prevent tissue disorders and injuries. antioxidant activity through the DPPH free
The decrease in the level of lipid radical scavenging activity, reducing power
peroxidation and the increase in GPx and CAT assay and scavenging of hydrogen peroxide.
levels might be due to the potent antioxidant The IC50 value of the ethanolic extract
activity of C. serratum L. Moon. Studies compared with ascorbic acid as control through
concerning in vitro and in vivo antioxidant the DPPH free radical scavenging activity were
activity of C. serratum L. Moon have been 175 and 137µg/mL, respectively. Acharya and
previously reported. The ethyl acetate fraction Patel (2016) investigated in vitro antioxidant

14 Volume 28 Issue 1 (2017)

Nasrudin

activity of methanolic extract and ethyl acetate, Research, Technology and Higher Education of
n-butanolic as well as aqueous fractions of C. the Republic of Indonesia for the financial
serratum roots using DPPH and ABTS radical support through BPPDN (Beasiswa Pendidikan
scavenging test. The result showed that DPPH Pascasarjana Dalam Negeri).
and ABTS radical scavenging effects of ethyl
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