Toxicology Mechanisms and Methods, 17:33–40, 2007
Copyright

c Informa Healthcare
ISSN: 1537-6516 print; 1537-6524 online
DOI: 10.1080/15376510600970026
Role of an Aminothiazole Derivative
on Ethanol-Induced Toxicity
Aruna Kode,
Rukkumani Rajagopalan,
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Suresh Varma Penumastha,
and Venugopal P. Menon
Department of Biochemistry,
Faculty of Science, Annamalai
University, Annamalai Nagar
608 002, Tamil Nadu, India
For personal use only.
Received 5 April 2004; accepted
27 July 2004
Address correspondence to Dr.
Venugopal P. Menon, Professor and
Head, Department of Biochemistry,
Annamalai University,
Annamalainagar - 608 002, Tamil
Nadu, India. E-mail: cmrana@sify.com
ABSTRACT The protective effect of dendrodoine analog (DA) [4-amino-
5-benzoyl-2-(4-methoxy phenylamino) thiazole] at three doses (5, 10, and
15 mg/kg body weight) was investigated on ethanol-induced hyperlipidemia.
Hepatotoxicity was induced by administering 7.9 g ethanol/kg body weight
for 45 days by intragastric intubation. Our results showed increased activity
of aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma
glutamyl transferase (GGT) and increased levels of cholesterol, triglycerides,
and phospholipids in the plasma of alcohol-given group when compared
with normal control group. The levels of tissue (liver and kidney) cholesterol
and triglycerides were increased significantly in alcohol control rats when
compared with normal control rats. The levels of phospholipids decreased
significantly in the liver and kidney of alcohol control rats when compared
with normal control rats. The activity of phospholipase A and phospholipase
C increased significantly in the liver of alcohol control rats when compared
with normal control rats. Intragastric administration of DA at 10 mg/kg body
weight effectively lowered the activity of hepatic marker enzymes (GGT,
AST, and ALP), phospholipase A, and phospholipase C, and decreased the
levels of plasma and tissue lipids. The level of tissue phospholipids increased
significantly when DA was administered at a dose of 10 mg/kg body weight
along with alcohol when compared with alcohol control group. Thus, we
propose that DA exerts a hepatoprotective effect by modulating liver marker
enzymes and lipid levels at a dosage of 10 mg/kg body weight.
KEYWORDS Aminothiazole Derivative; Dendrodoine Analog; Ethanol; Hepatic Marker
Enzymes; Hyperlipidemia; Phospholipases
INTRODUCTION
Ethanol is a powerful inducer of hyperlipidemia (Avagaro and Cazzlolatu
1975). The mechanism by which ethanol induces hyperlipidemia is complex.
The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds
via alcohol dehydrogenase. Oxidation of large amounts of alcohol results in the
release of excess hydrogen ions, which alter the NAD/NADH ratio and change
the oxidation-reduction potential of liver cells. Ethanol-induced increase in the
NAD/NADH ratio is a sign of major change in hepatic metabolism during
ethanol oxidation (Lieber and Davidson 1962). Many of the acute secondary
33
 changes in the intermediary metabolism of the liver
can be explained by the action of ethanol on the
hepatic redox state. These include the inhibition of the
tricarboxylic acid cycle and gluconeogenesis (Goedde
and Agarwal 1981). The redox-related inhibition of fatty
acid oxidation and the enhancement of triglyceride
synthesis are the main pathogenic mechanisms in the
development of alcoholic fatty liver (Aruna et al. 2002).
In addition, ethanol inhibits lipoprotein export and
increases fatty acid uptake (Galli et al. 1999).
Aminothiazoles are receiving much attention for
their wide-ranging biological activities such as anti-
tumor, antianoxic, and antioxidants (Ohkubo et al.
1995; Uchikawa et al. 1996). Dendrodoine is a marine
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alkaloid, which was isolated from Dendrodoa grossularia
(Heitz et al. 1980). It possesses a 1,2,4-thiadiazole unit,
a rarity among natural products. Though its synthesis
has been reported (Hogan and Sainsbury 1984), very
little biological studies on it or its analog have been
carried out (Fig. 1).
In this communication, we investigated the hepato-
protective and hypolipidemic effect of DA on ethanol-
induced hyperlipidemia.
For personal use only.
FIGURE 1 A) Structure of dendrodoine. B) Structure of DA [4-
amino-5- benzoyl-2-(4-methoxy phenylamino) thiazole].
A. Kode et al.
MATERIALS AND METHODS
Experimental Animals
Male albino rats Wistar strain (body weight
140–160 g) bred in the Central Animal House, Rajah
Muthiah Medical College, were used in this study.
The animals were housed in plastic cages with filter
tops under seminatural light-dark conditions and at
room temperature. The animals were fed on pellet diet
(Hindustan Lever Limited, Mumbai) and water was
given ad libitum.
Chemicals
Ethanol was purchased from E.Merck, Darmstadt,
Germany. Dendrodoine analog was synthesized as
described by Rajasekharan et al. (1987). Purity of the
compound was checked by thin layer chromatography
and structure has been confirmed by FTIR and NMR.
All other chemicals and biochemicals used for the
experiments were of analytical grade. DA was dissolved
in 1% dimethyl sulphoxide (DMSO) and administered
orally.
Experimental Design
Rats were randomized into the following groups. The
experimental period was 45 days.
Group 1 : Control rats given standard pellet diet
Group 2 : Rats given 20% ethanol (5 mL each equiv-
alent to 7.9 g ethanol/kg body weight) daily
using an intragastric tube (Rajakrishnan
et al. 1996)
Group 3 : Rats given DA (5 mg/kg body weight) + 20%
ethanol (5 mL each) (low dose)
Group 4 : Rats given DA (10 mg/kg body weight) +
20% ethanol (5 mL each) (moderate dose)
Group 5 : Rats given DA (15 mg/kg body weight) +
20% ethanol (5 mL each) (high dose)
At the end of experimental period (45 days) the
rats were given anesthesia (ketamin hydrochloride, 30
mg/kg body weight) and were sacrificed by decapita-
tion after an overnight fast. Blood was collected in
heparinized tubes and plasma was separated for various
estimations. Tissues (liver and kidney) were removed,
cleared of blood, and collected in ice cold containers
containing 0.9% NaCl for various estimations.
34
 TABLE 1 Change in body weight
Groups Initial body weight (g) Final body weight (g) Change in body weight (g)

1. Control 142.15 ± 10.22 213.46 ± 19.35 71.31 ± 5.12ad

2. Alcohol 153.74 ± 11.37 208.21 ± 18.42 54.47 ± 4.05b
3. Alc + low dose 148.35 ± 9.53 210.24 ± 20.52 61.89 ± 6.23c
4. Alc + moderate dose 160.09 ± 12.16 227.18 ± 20.52 67.09 ± 5.74d
5. Alc + high dose 151.61 ± 10.41 209.35 ±19.63 57.74 ± 5.14e
Values are mean ± SD from six rats in each group.
Values not sharing a common superscript differ significantly at p < 0.05 (DMRT).

Biochemical Estimations control rats. The average weight gain was increased in
the moderate-dose DA (10 mg/kg body weight) along
The activity of plasma gamma glutamyl transferase
with alcohol-given group when compared with alcohol
(E.C.2.3.2.2) was assayed by the method of Fiala et al.
control group. No significant changes were observed
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(1972). The activity of plasma aspartate transaminase

in low-(5 mg/kg body weight) and high-dose (15 mg/kg
(E.C.2.6.1.1) was assayed by the method of Reit-
body weight) DA along with alcohol-given groups when
man and Frankel (1957) and alkaline phosphatase
compared with alcohol control group.
(E.C.3.1.3.1) by the method of King and Armstrong
Table 2 represents the changes in the activity of
(1988) using reagent kit. Tissue lipids were extracted
hepatic marker enzymes. Alcohol treatment increased
according to the method of Folch et al. (1957).
the activity of plasma GGT, AST, and ALP when
Tissue cholesterol was estimated by using reagent kit
compared with normal control group. The activity
(Allain et al. 1974). Triglycerides were estimated by the
was decreased significantly in the group given DA
method of Foster and Dunn (1973) and phospholipids
at 10 mg/kg body weight along with alcohol when
by the method of Zilversmit and Davis (1950). The
compared with alcohol control group. The change in
For personal use only.

activity of phospholipase A (E.C. 3.1.4.1) was assayed

by the method of Rimon and Shapiro (1959) and
phospholipase C by the method of Kleiman and Lands
(1969).
Statistical Analysis
Statistical analysis was carried out using analysis
of variance (ANOVA) followed by Duncan’s multiple
range test (DMRT). The level of statistical significance
was set at p < 0.05.
RESULTS
Table 1 gives changes in the body weight of different
groups. The average weight gain by alcohol-treated rats
was significantly reduced when compared with normal
the activity was not significant in low- and high-dose
DA along with alcohol-given groups when compared
with alcohol control group.
Table 3 includes changes in the level of plasma
cholesterol, triglycerides, and phospholipids. The levels
were increased significantly in the alcohol control
group when compared with normal control group. The
level was decreased significantly in the group given
DA at 10 mg/kg body weight along with alcohol when
compared with alcohol control group.
Changes in the level of tissue lipids such as
cholesterol, triglycerides, and phospholipids are given
in Table 4. Alcohol administration to rats resulted
in a significant increase in the level of cholesterol
and triglycerides when compared with normal control

TABLE 2 Change in the activity of AST, ALP, and GGT

Groups ALP (IU/L) AST (IU/L) GGT (IU/L)

1. Control 83.26 ± 5.30ad 87.10 ± 4.72ad 0.623 ± 0.01ad

2. Alcohol 142.96 ± 10.65be 134.55 ± 6.48be 1.307 ± 0.09bce
3. Alc + low dose 125.82 ± 9.84ce 120.63 ± 9.20c 1.224 ± 0.31c
4. Alc + moderate dose 89.90 ± 4.11d 95.31 ± 7.71d 0.668 ± 0.04d
5. Alc + high dose 136.74 ± 9.70e 131.71 ± 6.93e 1.295 ± 0.12e
Values are mean ± SD from six rats in each group.
Values not sharing a common superscript differ significantly at p < 0.05 (DMRT).

35 Protective Influence of an Aminothiazole Derivative

 TABLE 3 Change in the level of plasma cholesterol, triglycerides, and phospholipids
Groups Cholesterol (mg/dL)
1. Control 92.36 ± 7.26ad
2. Alcohol 127.41 ± 8.71bce
3. Alc + low dose 118.47 ± 9.03ce
4. Alc + moderate dose 103.72 ± 6.26d
5. Alc + high dose 122.54 ± 7.60e
Values are mean ± SD from six rats in each group.
Values not sharing a common superscript differ significantly at p < 0.05 (DMRT).
group. The level was found to be decreased significantly
in the group given moderate-dose DA (10 mg/kg
body weight) along with alcohol when compared with
alcohol control group. The level of phospholipids
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decreased in alcohol-fed rats when compared with
normal control rats and found to be increased in
the group given DA at a dosage of 10 mg/kg body
weight along with alcohol when compared with alcohol
control group.
Table 5 gives changes in the activity of phospho-
lipase A and phospholipase C. Alcohol treatment
significantly increased the activity of phospholipase A
and phospholipase C in the liver when compared with
normal control group. The administration of DA at a
For personal use only.
dosage of 10 mg/kg body weight along with alcohol
resulted in marked reduction in the activity of these
enzymes. The change in the activity was not significant
in low- and high-dose DA along with alcohol-given
groups when compared with alcohol control group.
DISCUSSION
Alcohol is a toxic substance when consumed in
excess and results in a variety of pathological con-
ditions. In our study, the average weight gain by
rats during the experimental period was significantly
reduced in alcohol-treated rats compared with control
rats. Rajakrishnan et al. (1997) have also observed a
decrease in weight gain on alcohol treatment. The
weight reduction may be due to impaired function
of the cells and also due to injuries caused to various
organs (Galambos 1975). Animals given DA (10 mg/kg
body weight) along with alcohol showed near normal
pattern of weight gain, which shows the protective
effect of DA.
Damage to the liver after ethanol ingestion is a well-
known phenomenon, and the obvious sign of hepatic
injury is the leakage of cellular enzymes into plasma
(Baldi et al. 1993). Raised serum enzyme activities in
A. Kode et al.
Triglycerides (mg/dL) Phospholipids (mg/dL)
81.26 ± 5.91ad 93.73 ± 7.74ad
105.39 ± 8.71bce 140.62 ± 9.74be
100.27 ± 5.25ce 127.05 ± 8.42ce
87.13 ± 3.41d 98.96 ± 6.72d
107.42 ± 7.60e 135.43 ± 9.37e
alcohol-induced toxicity can be attributed to enhanced
hepatic generation of oxygen-derived species at various
subcellular sites due to the oxidation of ethanol (Nord-
mann et al. 1992). Ethanol also causes structural and
functional changes in the mitochondria and increases
the membrane permeability, leading to the leakage of
mitochondrial enzymes into the circulation (Devi et al.
1993). In our study we have observed raised activity
of plasma GGT, AST, and ALP in alcohol-treated rats.
In this context Akimoto et al. (1993) have reported
increased activity of AST and ALP in ethanol-fed rats.
Serum GGT level reflects excessive alcohol drinking
and might be a marker of heavy binge drinking (Anton
et al. 2000). The activity of AST, ALP, and GGT was
decreased when DA was given along with alcohol at
a dosage of 10 mg/kg body weight. The observed
decrease in plasma liver marker enzyme activity after
DA administration shows that our drug preserves the
structural integrity of the liver from the toxic effects
of alcohol. The toxicity of ethanol is primarily due
to its conversion to acetaldehyde, which can undergo
oxidation or reduction. Since it is a highly reactive toxic
molecule, it can manifest its reaction if not detoxified.
DA may form adducts with acetaldehyde, the toxic
metabolite of ethanol. This results in its removal and
hence the toxicity of acetaldehyde gets reduced.
Alcohol feeding is known to increase the biosynthe-
sis and decrease the catabolism of both fatty acids and
cholesterol, which accumulate in the liver and cause hy-
perlipidemia (Lieber 1973). Acetaldehyde, the principal
metabolite of ethanol in the liver, is often implicated
in the development of fatty liver (Joseph et al. 1991).
Our results show an increased level of triglycerides and
cholesterol in alcohol-treated group when compared
with normal control group. Excessive consumption of
alcohol leads to severe alterations of lipid metabolism,
including hyperlipemia and hypercholesterolemia
(Visioli et al. 1998). The increased cholesterol may
be due to increased β–hydroxy-methyl-glutaryl CoA
36
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TABLE 4 Changes in the level of tissue cholesterol, triglycerides, and phospholipids

Cholesterol (mg/100 g tissue) Triglycerides (mg/100 g tissue) Phospholipids (mg/100 g tissue)

Groups Liver Kidney Liver Kidney Liver Kidney

1. Control 328.09 ± 30.77ad 346.51 ± 26.58ad 371.92 ± 23.5ad 486.93 ± 32.74ad 1760.55 ±116.44ad 1461.67 ± 59.95ad
2. Alcohol 476.94 ± 23.62bce 508.32 ± 10.20bce 493.73 ± 25.77be 639.36 ± 33.57bce 1572.72 ± 111.90bce 1229.07 ± 82.84bce
3. Alc + low dose 400.31 ± 29.30ce 489.92 ± 21.90ce 421.48 ± 20.44ce 596.97 ± 26.96ce 1585.93 ± 117.53ce 1305.69 ± 99.39ce
4. Alc + moderate dose 347.25 ± 28.65d 361.91 ± 17.03d 390.79 ± 25.56d 501.88 ± 21.92d 1734.93 ± 121.09d 1395.20 ± 63.24d
5. Alc + high dose 461.65 ± 24.16e 498.92 ± 30.45e 485.82 ± 27.11e 622.43 ± 39.15e 1561.80 ± 118.41e 1276.05 ± 61.00e
Values are mean ± SD from six rats in each group.
Values not sharing a common superscript differ significantly at p < 0.05 (DMRT).

37
 TABLE 5 Changes in the activity of phospholipase A and for the decreased level of lipids in DA-given groups
phospholipase C
(Fig. 3).
Phospholipase C Phospholipids, the backbone of all cellular mem-
Phospholipase A (mmoles of phos- branes, are the primary targets of peroxidation and can
(mEq of ester phorylcholine be altered by ethanol (Yamada et al. 1985). Our results
hydrolyzed/min/ formed /min/mg
show significantly decreased level of phospholipids
Groups mg protein) protein
in the liver and kidney of alcohol-given group when
1. Control 0.031 ± 0.003ad 0.695 ± 0.03ad compared with normal control group. The decreased
2. Alcohol 0.082 ± 0.006bce 1.056 ± 0.08bce
level indicates greater phospholipid degradation (Choy
3. Alc + low dose 0.076 ± 0.003ce 1.046 ± 0.07ce
4. Alc + moderate 0.040 ± 0.004d 0.715 ± 0.06d
et al. 1989) and can result in the modification of the
dose composition, structure, and stability of cellular mem-
5. Alc + high dose 0.080 ± 0.005e 1.051 ± 0.05e branes, resulting in membrane dysfunction (Hubbell et
Values are mean ± SD from six rats in each group.
al. 1971). Rukkumani et al. (2002) have also reported
Values not sharing a common superscript differ significantly at a decrease in the phospholipid content in the liver
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p < 0.05 (DMRT). and kidney of alcohol-fed rats. DA administration at

(HMG Co A) reductase activity by ethanol, which is the
rate-limiting step in cholesterol biosynthesis (Ashaku-
mari and Vijayammal 1993). The microsomal induction
resulting from long-term alcohol consumption not
only accelerates the oxidation of ethanol, but also
increases the synthesis of triacylglycerols (Savolainen
et al. 1984). The levels of cholesterol and triglycerides
were decreased in the groups given DA at the dose of
For personal use only.
the level of 10 mg/kg body weight along with alcohol
brought the level of phospholipids to near normal,
showing the ability to repair the cellular membrane
damage caused by ethanol and its metabolic products,
thereby preserving the membrane integrity.
Intracellular phospholipases A are a diverse group
of enzymes with a growing number of members.
These enzymes hydrolyze membrane phospholipids
into fatty acid and lysophospholipid (Basavarajappa et

10 mg/kg body weight.
The amino group of DA may react with acetalde-
hyde, the toxic metabolite of ethanol, and form Schiff’s
base, which in turn prevents further conversion of
acetaldehyde to acetate (Fig. 2). This reduces the
formation of reducing equivalents and maintains the
NADH/NAD+ ratio, thereby promoting fatty acid ox-
idation. By preventing the conversion of acetaldehyde
to acetate, DA may also inhibit the formation of acetyl
CoA, the precursor of lipids. DA may also react with
acetyl CoA by acetylation to form N-acetyl derivative
and prevent lipid synthesis. This may be the reason
al. 1998). These lipid products may serve as intracellular
second messengers or can be further metabolized to
potent inflammatory mediators, such as eicosanoids
and platelet–activating factors (Farooqui et al. 1999).
Phospholipase C attacks ester bond in position 3,
liberating 1,2-diacylglycerol and a phosphoryl base.
Our result shows increased activity of phospholipase A
and C in alcohol-fed rats when compared with normal
control rats. In this context, Zhihang et al. (1996) have
found that chronic exposure to ethanol leads to a
progressive increase in membrane phospholipase A2
activity. Ethanol ingestion also induces an increase in

FIGURE 2 Schematic representation of formation of Schiff’s base.

A. Kode et al. 38
 FIGURE 3 Schematic representation of formation of N-acetyl derivative.
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microsomal phospholipase C that correlates with an
increase in the microsomal CYP 2E1 and a decrease
in microsomal 20:4. These changes are associated
with ethanol-induced liver pathology (Nanji et al.
1993a). Our earlier studies (Aruna et al. 2002) have
also shown increased activity of phospholipase A and
phospholipase C in the liver of ethanol-administered
rats. The activity of these enzymes was decreased
significantly in the group given DA at a dose of 10
mg/kg body weight along with alcohol.
For personal use only.
Thus, our study shows that DA at a dose of 10 mg/kg
body weight effectively protects the tissues against
ethanol-induced hyperlipidemia.
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