Effect of Jamblang (Syzygium cumini) Seed Extract on ALT and AST

Levels in Isoniazid-induced Male Rats

Ahmad Syukur Hasibuan

, Sri Melda Br. Bangun

, Romauli Anna Teresia Marbun, Saadah Siregar,

Aminah S.

, Debi Dinha Octora

Faculty of Pharmacy, Institut Kesehatan Medistra Lubuk Pakam, Sumatera Utara, Indonesia.

Faculty of Public Health, Institut Kesehatan Medistra Lubuk Pakam, Sumatera Utara, Indonesia

Keywords: ALT, AST, Syzygium cumini, Isoniazide

Abstract: Syzygium cumini or known in Indonesia as jamblang fruit which is contain gallic acid, elagic acid, corilagin,

ellagitannin, isoquercetin, quercetin and other antioxidant. Elagic acid (EA) has a function as a free radical

scavenger that can decrease liver function marking enzymes. Use of isonazide can cause side effects such as

an increase in aminotransferase levels that occurs in 10% - 20% of patients several weeks after

consumption. This study aims to determine the effect of Syzygium cumini seed extract in the ALT and AST

values of male rats induced by isoniazid. The research subjects were 30 male white rats strain, weighing

150-200 grams and aged 2-3 months, which were divided into 5 groups. The negative control group was

given aquades, while the positive control was given isoniazid as much as 40 mg on the 12th day until the

25th day. The treatment group was given Syzygium cumini seed extract with multilevel doses (20 mg / rat,

40 mg / rat, and 80 mg / rat) from day 8 to day 25 and isoniazid 40 mg on the 12th day, on the 12

, on

day ALT and AST levels were measured. Data were analyzed using One-Way Anova.The results of the

One-Way Anova test in groups with various doses of extract of jamblang fruit extract (20 mg / rat, 40 mg /

rat, and 80 mg / rat) showed significant results in reducing ALT and AST levels in isoniazid-induced rats,

with p value <0.001 (α = 0.05).The result showed that administration of jamblang fruit extract can reduce

ALT and AST levels of isoniazid-induced mice.

1 INTRODUCTION

The World Health Organization (WHO) mentions

about one third of the world's population or around 2

trillion people with liver disease with a death toll of

1 million. Liver damage can be caused by many

things, as evidenced in previous studies by Prasetyo

(2010) and Kusuma (2010), not only diseases caused

by viruses but can also be from unhealthy lifestyles

such as consumption of foods containing excessive

cooking oil, and consumption alcohol. In addition,

drug consumption can also induce liver damage, for

example anti-tuberculosis drugs. Isoniazid (INH) is

always given to TB cases, the prevalence of TB in

Indonesia is still relatively high, the WHO report in

2010 stated that in 2009 Indonesia's ranking dropped

to fifth with the number of TB sufferers at 292,753

people (WHO, 2010). This shows a considerable

consumption of INH in Indonesia. The use of INH

can cause side effects such as an increase in

aminotransferase levels that occurs in 10% - 20% of

patients several weeks after consumption but does

not cause typical clinical symptoms (

Prasetyo, F. A.,

et a, 2010). Nonetheless 0.1% - 2% of patients

experience acute liver failure (Maddrey,2013). INH

mechanism suspected to cause liver damage can not

be proven with certainty, but hypothetically stated

that the damage was caused by toxic substances in

the form of monoacetylhydrazine (MAH) through

the mechanism of free radicals (oxidative stress)

(

Saukkonen&Jereb, 2012).

Due to its high efficacy, isoniazid (INH) remains

the drug of choice for treatment of latent

tuberculosis (TB) despite the fact that it can cause

liver failure. Although drug-induced liver injury

(DILI) caused by different drugs is somewhat

different , the clinical characteristics of INH-induced

liver injury are fairly typical for idiosyncratic DILI

and include malaise, fatigue, nausea and vomiting.

The duration of therapy before the manifestation of

jaundice can vary between 1–25 weeks with an

average of 12 weeks. Fever Affects on average 20%

Hasibuan, A., Bangun, S., Marbun, R., Siregar, S., S., A. and Octora, D.

Effect of Jamblang (Syzygium cumini) Seed Extract on ALT and AST Levels in Isoniazid-induced Male Rats.

DOI: 10.5220/0009974605430550

In Proceedings of the International Conference on Health Informatics and Medical Application Technology (ICHIMAT 2019), pages 543-550

ISBN: 978-989-758-460-2

543

of the patients and eosinophilia is present in up to

15% of the affected individuals. In most cases, liver

injury is asymptomatic and is only detected by

measuring markers of hepatocyte injury such as

alanine aminotransferase (ALT) and aspartate

aminotransferase (AST). This is especially true for

mild cases of liver injury, which occurs in up to 20%

of patients treated with the drug. However, in most

patients, liver function returns to normal despite

continued treatment with the drug, a phenomenon

referred to as' adaptation 'by hepatologists. Severe

liver injury is seen in up to 1% of the patients.

Elevations in ALT and AST can start as early as 1

week and sometimes as late as 9 months after

starting treatment with INH. However, in more than

half of the patients an ALT increase occurs between

1–6 months. The abrupt increase in ALT that leads

to liver failure is idiosyncratic in nature and is not

clearly related to the duration of treatment, the dose

of the drug, fever or eosinophil count (

Sankhari, et al,

2010).

When liver injury is identified, the first line of

treatment is to stop the drug and monitor the patient

for recovery. In most cases patients recover.

However, the challenge of patients with more severe

liver injury can result in a rapid onset of symptoms

(within hours) and is contraindicated. Histological

characteristics of severe INH-induced liver injury

including hepatocellular injury with multilobular

necrosis and a mononuclear cell infiltrate, which is

generally indistinguishable from viral hepatitis.

Steatosis is unusual in INH-induced liver injury.

However, during active TB treatment, when INH is

given in combination with other agents such as

ethambutol, pyrazinamide and rifampicin (RMP),

there have been reported cases of steatosis and

cholestatic liver injury 7-9. Prolonged treatment

with INH can also lead to a lupus-like autoimmune

reaction with the presence of antinuclear antibodies

hich occurs in up to 20% of patients (

Sankhari, et al,

2010).

INH‐induced liver injury remains a significant

clinical problem. Previous studies suggested that

bioactivation of AcHz was involved in the injury,

but more recent studies point to direct oxidation of

INH as the pathway leading to liver injury. Previous

studies had also suggested that the injury, especially

mild injury, was not immune mediated. However,

recent evidence suggests that INH‐induced liver

injury is indeed immune mediated, but most cases

are mild and resolve with immune tolerance. Severe

injury may include an autoimmune component,

which makes it difficult for patients to recover even

if the drug is stopped, often resulting in liver

transplantation or death. Understanding the

mechanism of INH‐induced liver injury may make it

possible to prevent progression of the injury after the

drug has been stopped. If the injury is immune

mediated, in particular mediated by lymphocytes as

the histology suggests, treatment with agents such as

anti‐thymocyte globulin may be effective (

Metushi &

Phillips, 2016)

However, preventive measures remain a major

concern before the occurrence of severity, including

the use of natural substances hepatoprotectorwith

less side effects. The hepatoprotector substance is

expected to prevent liver damage while reducing the

impact of damage that has already occurred. Of the

various types of medicinal plants that are known to

contain antioxidants, one of the ones that attracts

attention is Syzygium cumini fruit seeds or known in

Indonesia as jamblang fruit. Chemical content of

Syzygium cumini fruit’s seed are gallic acid, elagic

acid, corilagin, ellagitannin, isoquercetin, quercetin,

caffeine acid, ferulic acid, guaiacol,

resorcinaldimethyl ether, lignaglucoside, veratrole,

β-sitosterol, palmitic acid, etc (

Sisodia, 2009).

The plant is well known in many countries due to

its medicinal properties and fruit value. Traditionally,

various parts of the plant were utilized to treat different

ailments of humans and animals (

Thomson, 2000). The

bark has been used for the treatment of sore

throat,bronchitis, asthma, thirst, biliousness, dysentery

and ulcers (

Ayyanar&Subash-Babu, 2012). Leaf juice,

alone or in combination with herbs, goat milk and

honey is reported to be effective in treating diarrhea,

diabetes and stomach-ache (

Nikhat et al, 2008). The

literature review indicated a number of reports

regarding antioxidant activity of extracts, mainly; fruit,

peel, leaves and bark of the plant, using various

models(

Veigas, et al, 2008). The antioxidant activityof

all parts of the plant was attributed to diverse types

ofphytochemical constituents reported previously

(

Banerjee & Narendhirakannan, 2011).

In previous studies, the seeds of this plant can be

used as a drug for diabetes, metrorrhagia, anti-

inflammatory, strengthen teeth and gums and as a

treatment for non-inflamed type Tinea capitis in the

form of a sedion lotion. Elagic acid (EA) has a

function as a free radical decomposition. Elagic acid

has been reported to reduce liver function marker

enzymes on the induction of toxicity with carbon

tetrachloride (CCl4) (

Dalimartha, 2003).

Based on the background the authors wanted to

conduct research to determine the effect of jamblang

seed extract as a hepatoprotector by looking at

decreasing levels of AST and ALT in rats induced

by INH.

ICHIMAT 2019 - International Conference on Health Informatics and Medical Application Technology

544

2 EXPERIMENTAL METHODS

This research used an experimental with post test

only one control groups design.

2.1 Research Sites

Organic chemistry laboratory of the Medical

Institute of Lubuk Pakam Medistra is used for the

screening process of chemical compounds, the

Pharmaceutical Pharmacology Laboratory of the

Medical Institute of Medistra Lubuk Pakam is used

for rat blood collection and the Regional Health

Laboratory for examination of ALT and AST.

2.2 Tools and Materials

The tools used consist of animal balance (GW-

1500), electric balance (Mettler Toledo), laboratory

glassware, mortar and stamfer, surgical tools (Wells

spencer), slide glass, cover glass, parchment paper,

millimeter paper block, watch glass, oral sonde,

dropper and 1 ml syringe (Terumo), microtube,

centrifuge (Velocity 18-R) and microscope

(Olympus). The materials used in this study include

plant, animal and chemical ingredients. Plant

material used is jamblang fruit seeds. The chemicals

used are Na-CMC (sodium carboxy methyl

cellulose), distilled water, sodium chloride 0.9%

(Merck) and EDTA tube. The chemicals used unless

otherwise stated are of technical quality, namely

ethanol (distillation), acetic acid anhydride,

concentrated sulfuric acid, toluene, choral hydrate,

and concentrated hydrochloric acid.

2.3 Ethanol Extract of Jamblang Fruit

Seeds (Syzygium cumini)

The jamblang used should be ripe, with a

blackish purple color on the outside. The seeds are

taken and then dried in the sun. The extract was

obtained by jamblang seeds which were dried,

mashed, and then extracted with ethanol liquid.

Extraction was carried out by the percolation

method. The extraction result is then dissolved with

aquadest plus 0.5% carboxymethyl cellulose (CMC)

and put in a glass bottle stored in the refrigerator.

2.4 Preparation of Experimental

Animals

This research were 30 male white rats (Rattus

norvegicus) strain of Wistar male with a weight of

150-200 grams. Before being approved, the animal

experiment is conditioned for 2 weeks in a good

enclosure to adjust the environment and uniform

food. Large samples of each group are determined

using the Federer formula.

2.5 Sampling Technique

Purposive sampling technique is sampling of the

population is done intentionally according to the

required sample requirements. In purposive

sampling, the characteristics and the number of

samples taken are determined or determined in

advance. Sampling was done by purposive sampling,

with the criteria for selecting subjects based on

characteristics that have been known previously.

Experimental animals were divided into 5 groups,

each group consisting of 6 mice which were

randomly selected. Group 1 as a negative control

group (K-), group 2 as a positive control group (K

+), group 3 as a control treatment for dose 1 (P1),

group 4 as a treatment group for dose 2 (P2), and

group 5 as a treatment group for dose 3 (P3).

2.6 Dose of Jamblang Fruit Seed

Extract

Jamblang seed extract is made by percolation

method. Previously, jamblang seeds were dried,

mashed, and then extracted with 70% ethanol liquid.

The extract is obtained in the form of a solid paste.

Suspension of jamblang fruit seed extract is done by

inserting pasta into the glazing bekker then

weighing, after that it is diluted with distilled water

and added with a suspension agent (CMC 0.5%).

The solution is then homogenized with a manual

stirrer without heating until a suspension is formed.

The weight of the rat used is + 200g (150g - 220g),

then the dose of jamblang seed extract that will be

given to mice is:

a. 100mg / kg body weight / day

= (100mg × 200g) / 1000g / day

= 20 mg / rat / day

b. 200mg / kg body weight / day

= (200mg × 200g) / 1000g / day

= 40 mg / rat / day

c. 400mg / kg body weight / day

= (400mg × 200g) / 1000g / day

= 80 mg / rat / day

Jamblang fruit extract was administered orally

once a day at a dose according to Sisodia and

Bhatnagar (2009) research, 20 mg / rat for the P1

group, 40 mg / rat for the P2 group, and 80 mg / rat

for the P3 group of mice every day starting from the

day 8th to 25th day.

Effect of Jamblang (Syzygium cumini) Seed Extract on ALT and AST Levels in Isoniazid-induced Male Rats

545

2.7 Preparation of Isoniazid

Suspension

Isoniazid (INH) were given in a 300 mg tablet form.

The isoniazid drug tablet were crushed with mortar,

after that it was diluted with distilled water,

homogenized until an isoniazid solution is obtained.

Toxic dose of INH in humans is 30 mg / kg BW.

The conversion factor for humans weighing 70 kg in

mice weighing 200 g is 0.018.

a. Doses in humans weighing 70 kg 30 mg x 70 kg

= 2100 mg / human

b. Conversion in mice weighing 200 g 2100 mg x

0.018 = 37.8 mg / rat. Rounding (40 mg / rat)

2.8 Experimental Procedures

The experimental animals consisted of 30 male

white rats which were divided into 5 groups:

a. Negative control (K-): aquades 1ml / oral rat

b. Treatment 1 (P1): EEBJ 20mg / kg bw

c. Treatment 2 (P2): EEBJ 40mg / kg bw.

d. Treatment 3 (P3): EEBJ 80 mg / kg bw.

e. Positive control (K +): given INH on the 12th day

until the 25th day.

After weighing and determining the dose is

completed then on the eighth day treatment of

experimental animals began. The negative control

group was given aquabides 1 ml orally per rat,

treatment group 1 was given jamblang seed extract

20 mg / rat on the 8th day to the 25th day. Also

given INH on the 12th day until the 25th day. So

that starting on day 12 in one day the rats get

jamblang seed extract jamblang fruit seed extract is

given 1 hour before INH. Treatment group 2 was

given extract of jamblang seeds 40 mg / rat on the

8th day until the 25th day. Also given INH on the

12th day until the 25th day. Starting the 12th day,

jamblang fruit seed extract was given 1 hour before

INH. Treatment group 3 was given 80 mg jamblang

seed extract / rat on the 8th day until the 25th day.

Also given INH on the 12th day until the 25th day.

Starting the 12th day, jamblang seed extract was

given 1 hour before INH. The positive control group

was given INH on the 12th day to the 25th day.

Outside the treatment schedule the rats were given

food pellets and distilled water ad libitum

The Ethanolic Extract of Jamblang Seeds (EEJS)

was given on the 8th day until the 25th day. INH is

given on the 12th day until the 25th day, giving

jamblang seed extract is done 1 hour before INH. On

the 26th day rat blood was taken to measure ALT

and AST levels.

2.9 Measurement of ALT and AST

levels

ALT and AST levels were examined using a

spectrophotomester conducted at the North Sumatra

Provincial Health Laboratory. Blood is drawn from

the heart and arteries as much as 0.5 ml of blood is

inserted into the microtube, allowed to stand at room

temperature for 5 minutes, centrifuged for 10

minutes at a speed of 3000 rpm to produce a clear

serum. Serum was separated and AST and ALT

levels were measured.

2.10 Data Analysis

The data were analysis for normality using the

Shapiro-Wilk test because the sample size was ≤ 50.

Then the variance test was also performed using the

Levene's test. Hypotheses were tested using the One-

Way Anova (Analysis of Variance) test to find out

the existence of mean differences in the five

treatment groups.

3 DISCUSSION

3.1 The Results of Phytochemical

Screening

The results of phytochemical screening of

Jamblang seed ethanol extract showed the content of

alkaloids, flavonoids, quinones, polyphenols,

tannins, and steroids / triterpenoids groups that could

be seen in table 1.

Table 1: Phytochemical Screening Results of Ethanolic

Extract of Jamblang Seed

Compound Group Result

Alkaloids

Flavonoids

Saponin

Quinon

Polyphenols

Tanins

Steroids/ Triterpenoids

Notes:

+ :Contains the class of examination compounds

- : Did not contain the class of examination

compounds

The seeds are reported to contain jamboline,

traces of pale yellow essential oil, chlorophyll, fat,

ICHIMAT 2019 - International Conference on Health Informatics and Medical Application Technology

546

resin, albumen, tannins, phenolic compounds such

as ellagic acid, gallic acid, caffeic and ferulic acids

and their derivativesand flavonoids like rutin and

quercetin (

Charles River Laboratories, 2008). Based on

such constituents, seed extracts are expected to

possess excellent astringent and antioxidant

potential, which may be beneficial in relieving

gastroenteritis and liver inflammation.

3.2 Measurement Results of ALT

(Alanin Aminotransferase) and

AST (Aspartate Aminotransferase)

Levels

AST and ALT both are vital transaminase enzymes

and play central role in amino acid metabolism.

Both of these are found in the different body’s

organs such as liver, heart, skeletal muscle, kidneys,

brain, and red blood cells

(Agrawal, 2013). Serum

AST and ALT level, and their ratio (AST/ALT ratio)

are frequently measured clinically as biomarkers for

liver health. Their increased level has been linked

with abnormal liver functions, though these are not

very specific to liver disease. Though, the toxin

treated animals showed increased levels of these

enzymes. Conversely, extract therapies attenuated

the increased level of these enzymes in serum.

Recovery towards the normalization suggests that

these extracts caused parenchymal cell regeneration

in liver, thus protecting membrane fragility and

thereby decreasing enzyme leakage (

Achliya, et al,

2004).

The results of measurements of ALT and AST

levels could be seen on table 2 and table 3 below.

Table 2. Measurement Results of ALT

Goup

Level of

AST(IU/L) ± SD

Negative control 50,90±6,65

EEJS20mg/kg bb 50,80±6,49*

EEJS40 mg/kg bb 48,80±4,14*

EEJS 80 mg/kg bb 45.25±4.78*

Positive control 71,20±10,20

Note:

* = p< 0,05, significant difference with positive

control group

The results of statistical analysis byone way

ANOVA showed that there was a significant

difference (p <0.05) between mice given EEBJ and

an isonazide positive control group. This shows that

the administration of EEBJ has an effect of

decreasing the ALT value on isoniazid-induced test

animals. Based on Charles River Laboratories

(2008) the normal ALT value for white mice is 14-

64 IU / L.

Table 3. Measurement Results of AST

Group

Levels of

AST(IU/L) ± SD

Negative control 207,80±4,55

EEJS 20mg/kg bb 246,00±2,55*

EEJS 40 mg/kg bb 216,80±2,28*

EEJS 80 mg/kg bb 211,75±2,98*

Positive control 246,00±8,33*

The results of statistical analysis using one way

ANOVA showed that there was a significant

difference (p <0.05) between mice given EEBJ and

an isonazide positive control group. This shows that

the administration of EEBJ has an effect of

decreasing AST value on isoniazid-induced test

animals.

Based on Charles River Laboratories (2008) the

normal AST value for white rats is 64-222 IU / L.

The INH used here, is actually an antibiotic drug

but also known to cause oxidative injury particularly

in liver cells(

Achliya, et al, 2004).

INH is a hydrazide that is readily oxidized 11.

Three metabolites have been proposed to be

responsible for INH‐induced liver injury, acetyl

hydrazine (AcHz), hydrazine (Hz) and more recently

a metabolite resulting from the bioactivation of INH

itself.Experiments implicating AcHz and Hz as

hepatotoxic species were performed several decades

ago, mostly in rats where the acute liver injury

correlated with covalent binding of AcHz and with

blood levels of Hz 12. At the time, the parent drug

(INH) was not thought to contribute to liver injury

because its administration did not produce severe

liver injury. However, these experiments utilized

ring‐labelled acetylisoniazid (AcINH) (

Meng, 2015).

This conclusion was not warranted because the

drug that was administered was not INH. It was

AcINH in which the hydrazine is blocked. If

hydrolysis led to AcHz and isonicotinic acid, no

covalent binding of the pyridine ring would occur.

In addition, the characteristics of the liver toxicity in

these studies were different from that in humans. In

particular, it was an acute rather than a delayed onset

idiosyncratic liver injury. Furthermore, the

metabolism in humans may be different from that in

rats. However, the conclusion that direct

bioactivation of INH does not occur has persisted

(

Metushi, 2011). Recently, a reactive metabolite

resulting from bioactivation of INH itself has been

shown to form covalent adducts to liver

Effect of Jamblang (Syzygium cumini) Seed Extract on ALT and AST Levels in Isoniazid-induced Male Rats

547

macromolecules 13-17. Covalent binding of this

metabolite is more likely to lead to an immune

response than the reactive metabolite of AcHz which

would only acetylate proteins (Figure 1).

Figure 1. Proposed pathway for an immune mediated

reaction to INH in the liver.

Using western blots and mass spectrometry, it

has been shown that the reactive metabolite of INH

can react with multiple lysine residues on hepatic

proteins. Further characterization using mass

spectrometry revealed drug adducts on

D‐dopachrome decarboxylase, prohibitin 2 and

macrophage migration inhibitory factor 18.

Autooxidation of INH involving free radicals has

also been reported. It is unclear whether this is

significant in vivo where there are many antioxidant

systems.Moreover, INH produces hydrazine

metabolites (nitrogen free radicals) after

metabolism. These reactive free radicals act as

stimulator of lipid peroxidation resulting in cell

death and hepatic necrosis. In this investigation also,

INH treatment showed considerable liver injury.

Which was resembles with earlier investigations

(

Meng, 2015).

The administration of ethanolic extract of seeds

of the plant in two doses lowered the level of

biochemical markers, which were increased by free

radicals of INH. It is probable that the

administration of extract for 14 days increased the

antioxidant capacity of animal to scavenge the free

radicals generated by INH. The free radical

scavenging activity of the plant, under investigation,

has been attributed to the presence of flavonoids and

related compounds. The plant also contained ellagic

acid, a polyphenol having lipid peroxidation

inhibition activity.

The ethanol extracts of E. jambolana seeds

showed hepatoprotective effects in carbon

tetrachloridetreated rats. In addition, another study

has reported on the hepatoprotective and antioxidant

activity of E. jambolana seeds. Hepatoprotective

effects are attributed to its antioxidant activity,

which restores the activity of superoxide dismutase,

catalase, and glutathione peroxidase to normal

levels, and increases glutathione content and levels

of lipid peroxidation and hydroperoxides in the liver.

Seed content includes glycosides, traces of pale

yellow essential oil, fat, resin, albumin, chlorophyll,

the alkaloid jambosine, gallic acid, ellagic acid,

corilagin and related tannins, 3,6-

hexahydroxydiphenoyl glucose and its isomer 4,6-

hexahydroxydiphenoyl glucose, 1-galloyl glucose,

3-galloyl glucose, quercetin, and elements such as

zinc, chromium, vanadium, potassium, and sodium.

Unsaponifiable matter of the seed fat contains b-

sitoterol. Dried seeds of E. jambolana have been

reported, with 11.67% alcohol-soluble extractive

fiber, 3.397% inorganic fiber, 40% water-soluble

gummy fiber, and 15% water-insoluble neutral

detergent fiber. Kumar and colleagues (2009) state

that the ethyl acetate and methanol extracts of the

seeds of S. cumini show the presence of alkaloids,

amino acids, flavonoids, glycosides, phytosterols,

saponins, steroids, tannins, and triterpenoids. Since

the current worldwide morbidity and mortality due

to liver disease is increasing every year, with

corresponding increases in expenditure for drug

treatment, alternative plant therapies may be

beneficial.

Presumably, treatment with ethanolic extracts of

jamblangcan modulate liver cytochrome P-450

enzymes to enhance scavenging of hepatotoxic free

radicals and by increasing antioxidant defense

activities.

4 CONCLUSIONS

Based on the results of the study it can be

concluded that the induction of isoniazid (INH) can

increase levels of ALT and AST, giving EEBJ

20mg, 40mg and 80mg / kg bw in male white rats

which induced by isoniazid gave the effect of

decreasing ALT and AST levels. A moderate to high

dose increase (80 mg / rat / day) did not increased

the effect of increasing ALT and AST due to

INHinduction. So that the use of EEJS was expected

to be developed as an herbal hepatoprotector

product.

ICHIMAT 2019 - International Conference on Health Informatics and Medical Application Technology

548

ACKNOWLEDGEMENT

Thank you to the Medistra Foundation for the

laboratory facilities provided for this study.

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