Hindawi Publishing Corporation
Journal of Biomedicine and Biotechnology
Volume 2010, Article ID 203503, 8 pages
PhysiologicalandHistopathological Investigations on
theEffectsof α-LipoicAcid inRats Exposedto Malathion
Atef M. Al-Attar
Department of Biological Sciences, Faculty of Sciences, King Abdul Aziz University, P.O. Box 139109, Jeddah 21323, Saudi Arabia
Correspondence should be addressed to Atef M. Al-Attar, atef a email@example.com
Received 16 January 2010; Accepted 7 March 2010
Academic Editor: Wen-Quan Zou
Copyright © 2010 Atef M. Al-Attar. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The present study was designed to evaluate the influence of α-lipoic acid treatment in rats exposed to malathion. Forty adult male
rats were used in this study and distributed into four groups. Animals of group 1 were untreated and served as control. Rats of
group 2 were orally given malathion at a dose level of 100mg/kg body weight (BW) for a period of one month. Experimental
animals of group 3 were orally given α-lipoic acid at a dose level of 20mg/kg BW and after 3 hours exposed to malathion at the
same dose given to group 2. Rats of group 4 were supplemented with α-lipoic acid at the same dose given to group 3. The activities
of serum glutamic oxaloacetic acid transaminase (GOT), glutamic pyruvic acid transaminase (GPT), alkaline phosphatase (ALP),
and acid phosphatase (ACP), and the values of creatinine, urea, and uric acid were statistically increased, while the values of total
protein and total albumin were significantly decreased in rats exposed to malathion. Moreover, administration of malathion for
one month resulted in damage of liver and kidney structures. Administration of α-lipoic acid before malathion exposure to rat
can prevent severe alterations of hematobiochemical parameters and disruptions of liver and kidney structures. In conclusion, this
studyobviouslydemonstratedthatpretreatmentwithα-lipoicacidsignificantlyattenuated thephysiological andhistopathological
alterations induced by malathion. Also, the present study identifies new areas of research for development of better therapeutic
agents for liver, kidney, and other organs’ dysfunctions and diseases.
Organophosphorus compounds are widely used in agricul-
ture, medicine, and industry. Organophosphorus pesticides,
in addition to their intended effects like the control of
insects or other pests, are sometimes found to affect
nontarget organisms including humans [1, 2]. Exposure to
organophosphorus pesticides is also a potential cause of
longer-term damage to the nervous system, with reports of
poor mental health and deficits in memory and concentra-
tion [3–5]. Because of the serious environmental problems
resulting from the use of pesticides in the agricultural sector,
several governments are seeking to employ biological and
other nonpolluting methods for combating pests. Several
biocides and/or their metabolites are suggested to be prior
mutagenic and/or teratogenic compounds [6–8].
Malathion (O,O-dimethyl-S-1,2-bis ethoxy carbonyl
ethyl phosphorodithionate), a pesticide in the organophos-
phate chemical family, is the most widely used throughout
the world. It is used to control the pests of agriculture
crops, ornamentals, green houses, live stocks, stored grains,
forests, buildings, and gardens. Contributing to its pop-
ularity is malathion’s low acute mammalian toxicity. But
like DDT and other pesticides that have been found to
cause irreparable damage to human and environmental
health, malathion may pose a greater risk than the product
label would lead one to believe. Shown to be mutagenic,
a possible carcinogen, implicated in vision loss, causing
myriad negative health effects in human and animal studies,
damaging nontarget organisms, and containing highly toxic
impurities, malathion has a legacy of serious problems .
The toxicity of malathion is compounded by its metabolites
and contaminants. Malaoxon, the metabolites produced by
the oxidation of malathion in mammals, insects, and plants,
is the primary source of malathion’s toxicity and it is 40
times more acutely toxic than malathion [10, 11]. Malathion
is organophosphorus pesticide extensively used to control
a wide range of sucking and chewing pests of field crops,
2 Journal of Biomedicine and Biotechnology
Figure 1: The chemical structure of α-lipoic acid.
fruits and vegetables. It has many structural similarities with
naturally occurring compounds, and their primary target of
action in insects is the nervous system; it also inhibit the
release of the acetylcholinesterase at the synaptic junction
. Acetylcholinesterase plays a key role in the control
of nerve excitability at post synaptic sites. Malathion is
found to inhibit the acetylcholinesterase. Inhibition of liver
acetylcholinesterase (AChE) activity is generally regarded as
a useful indicator of poisoning by organophophorous pes-
ticides. Additionally, several studies showed that malathion-
induced various physiological, biochemical, immunological,
and histological changes in experimental animals [13–16].
Alpha(α)-lipoic acid (also known as thioctic acid) was
discovered in 1951 as a molecule that assists in acyl-group
transfer and as a coenzyme in the Krebs cycle. α-Lipoic acid
is a natural molecule consisting of a five-membered cyclic
disulphide and hydrocarbon tail ending with a carboxylic
acid group (Figure 1). Hence, lipoic acid is a predominantly
lipophilic molecule having an amphipathic character due
to its carboxylic acid group attached to the ring structure.
Lipoic acid is present in our diet mainly in animal foods
such as meat and liver and at low or undetectable levels
in plant foods such as potato [17, 18]. However, lipoic
acid is also considered beneficial when mused as a food
supplement as its antioxidant function has been previously
reported and several studies have revealed its protective
effects in cases such as aging, diabetes mellitus, and vascular
and neurodegenerative diseases all in which free radicals
are involved [19–23]. Studies are generally dealing with the
antioxidant activities of lipoic acid and its derivatives [19,
22, 24, 25]. Data on the efficacy and biological activity of α-
lipoic acid on malathion intoxication arenot available.In the
present study, an attempt was made to elucidate the possible
protective effect of α-lipoic acid treatment on malathion-
induced physiological and histopathological alterations in
rats. Rats have been selected for present study as they have
physiological systems and responses similar to those of man.
They have also remarkable genetic similarities to human.
2.1. Animals. Forty Wistar male rats weighing 200–220g
were obtained from the Experimental Animal Unit of King
Fahd Medical Research Center, King Abdul Aziz Univer-
sity, Jeddah, Saudi Arabia. Rats were acclimatized to the
experimental room having temperature 19±1◦C, controlled
humidity conditions (65%), and 12:12 hour light: dark
cycle. The experimental animals were housed in standard
experimental procedures were approved by the Animal Care
and Use Committee of King Abdul Aziz University.
2.2. Experimental Design. After acclimatization period, rats
group as follows.
– Group 1. Rats were untreated and served as control.
– Group 2. Experimental animals were orally given
malathion at a dose level of 100mg/kg body weight
(BW), for a period of one month.
– Group 3. The animals were orally given α-lipoic acid
(Sigma Chemical Company, St. Louis, Mo, USA)
solution at a dose level of 20mg/kg BW and after 3
hours treated with malathion at the same dose given
to group 2.
– Group 4. Animals were treated with α-lipoic acid at
the same dose given to group 3.
2.3. Hematobiochemical Analysis. At the end of experimental
period, rats were anaesthetized with ether. Blood samples
were collected from orbital venous plexus in nonheparinized
tubes, centrifuged at 2000rpm for 20 minutes, and blood
sera were then collected and stored at 4◦C prior immediate
determination of glutamic oxaloacetic acid transaminase
(GOT), glutamic pyruvic acid transaminase (GPT), alkaline
phosphatase (ALP), acid phosphatase (ACP), total protein,
total albumin, creatinine, urea, and uric acid. All of these
parameters were measured using Automated Clinical Chem-
istry Analysis System, Dimension type RXL Max (Dade
Behring Delaware, DE 19714, U.S.A.).
2.4. Histopathological Examination. For light microscopic
examination, liver and kidney tissues from each groups were
fixed with 10% buffered formalin, embedded with paraffin.
After routine processing, paraffin sections of each tissue were
cut into 4μm thickness and stained with haematoxylin and
2.5. Statistical Analysis. The results of hematobiochemical
analysis were analyzed using the Statistical Package for Social
Sciences (SPSS for windows, version 12.0). Comparisons
were made between experimental groups using one-way
analysis of variance (ANOVA) followed by Dunnett’s test.
Values of less than 0.05 were regarded as statistically signif-
Table 1 shows the values of serum GOT, GPT, ALP, ACP, total
protein, total albumin, creatinine, urea and uric acid in all
experimental groups. In comparison with control values, the
levels of GOT (206.5%), GPT (185.3%), ALP (95.0%), ACP
(51.6%), creatinine (73.1%), urea (27.8%), and uric acid
(32.1%) were statistically increased, while the levels of total
Journal of Biomedicine and Biotechnology3
Table 1: Changes in values of serum GOT, GPT, ALP, ACP, total protein, total albumin, creatinine, urea, and uric acid in rats treated with
malathion, malathion plus α-lipoic acid, and α-lipoic acid. Tabulated values are means of ten determinations ± standard deviation (SD).
Malathion + α-Lipoic acid
115.30 ± 5.8a
64.30 ± 7.84a
395.30 ± 37.05a
139.30 ± 17.17a
6.64 ± 0.38
3.13 ± 0.23
0.82 ± 0.11a
25.28 ± 1.92
4.01 ± 0.36
61.80 ± 3.29
39.50 ± 3.17
324.40 ± 10.86
109.80 ± 9.25
6.75 ± 0.28
3.18 ± 0.19
0.67 ± 0.05
23.56 ± 1.77
3.71 ± 0.27
189.40 ± 13.62a,b
112.70 ± 9.99a,b
632.70 ± 29.89a,b
166.40 ± 27.69a,b
5.51 ± 0.30a,b
2.86 ± 0.20a,b
1.16 ± 0.24a,b
30.12 ± 2.45a,b
4.90 ± 0.47a,b
56.70 ± 6.52
38.20 ± 2.52
339.20 ± 20.61
114.20 ± 13.58
6.73 ± 0.28
3.24 ± 0.25
0.70 ± 0.08
22.74 ± 2.04
3.86 ± 0.26
Total protein (g 100mL−1)
Total albumin (g 100mL−1)
Creatinine (mg 100mL−1)
Urea (mg 100mL−1)
Uric acid (mg 100mL−1)
a: Indicates a significant difference between control and treated groups.
b: Indicates a significant difference between the group treated with malathion and groups treated with malathion plus α-lipoic acid and α-lipoic acid.
decreased in rats exposed to malathion, group 2. Significant
ALP (21.9%), ACP (26.9%), and creatinine (22.4%) were
observed in rats exposed to malathion plus α-lipoic acid
(group 3), while the levels of total protein, total albumin,
urea, and uric acid were statistically unchanged compared
with control values. From Table 1, it’s obviously that α-
lipoic acid notably lowered the percentage elevations of these
changes in the levels of serum hematobiochemical param-
eters were noted in rats treated with only α-lipoic acid,
Light microscopic examination of the liver of control rats
showed the normal structure in Figure 2(a). Histopathologi-
cal effects of malathion on liver of treated rats are presented
in Figures 2(b) and 2(c). Rats treated with malathion showed
many severe histopathological alterations. Administration
of malathion for one month resulted in the damage of
liver structure along with disarrangement of hepatic strands.
Several cells also show histological features of necrosis.
Moreover, an enlargement of the sinusoids and vacuole
formations in hepatocytes, leucocytic infiltrations, dilation,
and congestion of blood vessels with hemorrhage were noted
in liver of rats exposed to malathion (group 2). α-Lipoic acid
treatment brought back the cellular arrangement around
the central vein and reduced necrosis (Figure 2(d)). Also,
it helped to bring the blood vessels to normal condition.
Mild to moderate enlargement in the sinusoids, vacuole for-
mations in hepatocytes, leucocytic infiltrations, dilation and
congestion of blood vessels with hemorrhage were observed
in rats treated with malathion plus α-lipoic acid compared
with malathion treated rats and control rats. Figure 3 shows
the histology structures of the kidney in control group
(Figure 3(a)), malathion treated rats (Figures 3(b) and 3(c)),
and malathion plus α-lipoic acid treated rats (Figure 3(d)).
Areas of renal cortex containing renal corpuscles and
associated tubules showed more pronounced changes in
treated animals compared with control. Therefore, these
microscope. The normal renal corpuscle consists of a tuft of
capillaries, the glomerulus, surrounded by a double-walled
epithelial capsule called Bowman’s capsule. Between the two
layers of the capsule is the urinary or Bowman’s space
(Figure 3(a)). In one-month malathion-dosed rats, there
were pronounced changes in the structure of renal corpuscle
including swelling appearances, increasing of urinary spaces,
highly degeneration of glomeruli, Bowman’s capsules and
acid treatment reversed abnormal histology of renal cortex
areas induced by malathion intoxication (Figure 3(d)). Renal
corpuscles in this group were appeared more as normal as
shown in Figure 3(a) and the most changes were noted in
the structure of some glomeruli. Additionally, no detectable
histological differences are observed by the light microscope
between control rats and rats supplemented with only α-
lipoic acid, group 4.
The present investigation indicates that oral administration
of malathion to rats caused significant alterations in hemato-
biochemical parameters. The activities of serum GOT, GPT,
ALP, ACP, and the levels of creatinine, urea, and uric
acid were significantly increased, while the values of total
protein and total albumin were statistically decreased. These
results are in agreement with different previous researches
which indicated that the exposure to malathion and other
pesticides led to induce severe physiological and biochemical
disturbances in experimental animals, buffalo calves ,
goats , mice , cockerels , poultry , rabbits
hepatic and renal damages as shown in histopathological
examination which coupled with markedly elevated levels
of liver hemato-biochemical markers (GOT, GPT, ALP, and
ACP) and significant changes of kidney hemato-biochemical
indices including statistically increased levels of creatinine,
urea and uric acid, and decreased levels of total protein and
albumin concentrations. Tos-Luty et al.  showed that
4Journal of Biomedicine and Biotechnology
Figure 3: Renal corpuscle micrographs of control (a), malathion ((b) and (c)), and malathion plus α-lipoic acid (d) treated rats. Original
Journal of Biomedicine and Biotechnology5
malathion intoxication led to severe effects on the structures
of the liver and kidney including the presence of fine subcap-
sular infiltrations, diffused parenchymatous degeneration of
single hepatocytes, and the presence of fine foci constructed
of plasmatic cells, and histiocytes located between hepatic
plates. In the submicroscopic structure of hepatocytes, there
cell organelle and lipid vacuoles. Mitochondria were usually
swollen, showing a clearance of the matrix and destruction
covered parenchymatous degeneration of the cells of renal
tubules and hyperemia of the cortical part of the kidney,
especially of renal glomeruli, as well as infiltrations were
noted. In the ultrastructure of the cells of renal proximal
tubules, vacuoles with damaged external membrane were
observed, as well as swollen and pleomorphic mitochondria.
However, different studies showed that malathion and
other pesticides induced liver and kidney histopathological
alterations in experimental animals [16, 38, 41–43].
The present study showed that the administration of
α-lipoic acid before malathion exposure to rat can pre-
vent severe changes of hematobiochemical parameters and
disruptions of liver and kidney structures. Sandhya and
Varalakshmi  and Malarkodi et al.,  showed that
the pretreatment of rats with α-lipoic acid protected against
nephrotoxicity induced by gentamicin and adriamycin. Sun-
tres  stated that the administration of lipoic acid prior to
lipopolysaccharide challenge resulted in a significant allevia-
tion of liver injuries, evidenced by a general reversal of the
altered biochemical indices toward normal among treated
level of serum enzymes (GPT, GOT, and ALP), bilirubin,
lipids and plasma thiobarbituric acid-reactive substances
(TBARS), and hydroperoxides observed in rats treated with
chloroquine were very much reduced in rats treated with α-
lipoic acid plus chloroquine. A significant decrease in plasma
antioxidants such as reduced glutathione (GSH), vitamin
C, and vitamin E were observed in chloroquine-treated rats
acid significantly improved the levels of plasma antioxidants
GSH, vitamin C, and vitamin E in chloroquine-treated rats.
Moreover, they stated that the results revealed that α-lipoic
acid could offer protection against chloroquine-induced
hepatotoxicity. Dulundu et al.  demonstrated that serum
GPT, GOT, and lactate dehydrogenase (LDH) activities and
cytokine, TNF-alpha and IL-1beta levels were elevated in
the ischemia/reperfusion rats group, while this increase
was significantly lower in the group of animals treated
concomitantly with lipoic acid. Hepatic glutathione (GSH)
levels, significantly depressed by ischemia/reperfusion, were
elevated back to control levels in lipoic acid-treated
ischemia/reperfusion group. Furthermore, increases in tissue
luminol and lucigenin chemiluminescence (CL), malondi-
due to ischemia/reperfusion injury were reduced back to
control levels with lipoic acid treatment. Since lipoic acid
administration alleviated the ischemia/reperfusion-induced
it seems likely that lipoic acid with its antioxidant and
oxidant-scavenging properties may be of potential therapeu-
ischemia/reperfusion. Also, Abdel-Zaher etal.  reported
that the pretreatment of rats with α-lipoic acid orally pro-
tected markedly against hepatotoxicity and nephrotoxicity
induced by an acute oral toxic dose of acetaminophen as
assessed by biochemical measurements and by histopatho-
logical examinations. Sehirli et al.  showed that α-lipoic
acid treatment reversed all of examined renal biochemical
indices, as well as histopathological alterations induced
by ischaemia-reperfusion in rats. They suggested that α-
lipoic acid protects kidney tissues by inhibiting neutrophil
infiltration, balancing the oxidant-anti-oxidant status, and
regulating the generation of inflammatory mediators. Shan-
mugarajan et al.  evaluated the effect of α-lipoic acid
supplementation on acute D-galactosamine-induced oxida-
tive liver injury. Hepatotoxicity induced by D-galactosamine
was evident from increase in lipid peroxidation and serum
marker enzymes (GOT, GPT, ALP, and LDH). The decreased
activities of enzymic antioxidants (superoxide dismutase,
catalase, glutathione peroxidase, and glutathione reductase)
in D-galactosamine-induced hepatotoxicity. Pretreatment
with α-lipoic acid significantly precluded these changes and
prevents the hepatic injury induced by D-galactosamine. In
the study of Kang et al. , they showed that cisplatin-
induced decreases in renal function, measured by blood
urea nitrogen, serum creatinine level, and renal tubular
injury scores, were attenuated by α-Lipoic acid treatment.
Additionally, α-lipoic acid decreased the tissue levels of
tumour necrosis factor-α, the expression of intercellular
adhesion molecule-1 (ICAM-1), and monocyte chemoat-
tractant protein-1 (MCP-1), and suppressed the infiltration
of CD11b-positive macrophages. α-Lipoic acid also attenu-
ated the cisplatin-induced increases in the phosphorylation
and nuclear translocation of NF-B p65 subunits in kidney
Organophosphorus compounds may induce oxidative
stress leading to the generation of free radicals and
alterations in antioxidant and scavengers of oxygen-free
radicals. However, several studies showed that malathion
induced lipid peroxidation and oxidative stress in exper-
imental animals [53–57]. α-Lipoic acid taken up by the
cells where it is converted to dihydrolipoic acid (DHLA)
by glutathione reductase, thioredoxin reductase (TrxR),
and LDH and extensively metabolized by β-oxidation, in
tissue. The metabolites of α-lipoic acid and DHLA also
suggested to play a significant role in the treatment of
(ROS) and reactive nitrogen species (RNS) are produced as
byproducts of oxidative metabolism. However, high levels of
ROS and RNS have been considered to potentially damage
cellular macromolecules and have been implicated in the
pathogenesis and progression of various chronic diseases.
Several lines of evidence indicate that α-lipoic acid exerts
potent antioxidant activity in vitro and in vivo . α-Lipoic
acid acts by multiple mechanisms both physiologically and
pharmacologically. Pharmacologically, it improves glycemic
6 Journal of Biomedicine and Biotechnology
control, polyneuropathy. Physiologically as an antioxidant,
α-lipoic acid directly terminates free radicals, chelates metal
ions, and increases cytosolic glutathione and vitamin C
. However, the exact mechanism action by which α-
lipoic acid attenuates the severe influences of malathion
exposure to rats is unknown. Although the data obtained
in the present study do not allow any definite conclusions
to be drawn on the mechanism action of α-lipoic acid
in malathion-treated experimental animals, it is possible
that inhibition of malathion-induced severe physiological
and histopathological alterations in rats by α-lipoic acid
supplementation may be mediated through the modulation
of malathion metabolism. Also, it cannot be excluded that
the possibility that α-lipoic acid offers protection against
reactive oxygen species-mediated damage by enhancing
cellular antioxidant defense and reducing severe physio-
logical and histopathological alterations in rats exposed to
malathion. In conclusion, the present findings show that oral
administration of α-lipoic acid produces significant antihep-
atotoxicity and nephrotoxicity effects in malathion treated
rats. Further investigations are required to explore exactly
the mechanism action of α-lipoic acid against malathion-
induced physiological disturbances and histopathological
changes. Finally, the present study identifies new areas of
research for development of better therapeutic agents for
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