INTRODUCTION:
The clinically
important antibiotic Lincomycin (Novotna et al. , 2013), is a
systemic antibiotic, belongs to the
group of lincosamide (Rajeevkumar and Subramanian, 2012). It's first discovered
in the 1950s, derived from Streptomyces lincolnensis (a soil organism
isolated in Lincoln, NE (Hornish, 1987; Anonymous, 1993). Which has an
excellent activity against most common gram-positive bacteria, so it has been
used for treatment or prevention of
infectious disease like acne, anthrax, pneumonia as well as the
treatment of furunculosis, carbuncles, impetigo, burns and wounds (Rajee Kumar
and Subramanian, 2010). Another studies were reported that, Lincomycin also
used for the treatment of arthritis, swine, dysentery and is approved for use
at 200g/ ton for up to three weeks (Hornish, 1987; Anonymous, 1993).
It consists mainly
of methyl 6-amino-6,8-dideoxy-N-[2S,4R)-l-methyl 1-4-propyl
propyl]-l-thioerythro- 
-galacto-
octopyranoside hydrochloride monohydrate, which is inhibited cell growth and
microbial protein synthesis, by interacting with the 50 S ribosomal subunit at
mutually related sites (Indian Pharmacopoeia, 1996).
Vitamins E,C and A
are known to be antioxidant agents and these vitamins can inhibit free radicals
and mitigate their toxic effects (Kalender et al. , 2007). Vitamin E (-Tocopherol) is the
primary membrane bound, lipid soluble and chain breaking antioxidant that
protects cell membranes against lipid peroxidation (Ognjanovic et al.,
2003; Gulec et al., 2006; Soylu et al., 2006). Prior vitamin E
dietary supplementation suppresses oxidative stress and glomerulosclerosis in
rat remnant kidney (Hahn et al., 1999). Vitamin E pre-treatment has been
reported to be beneficial in preventing formaldehyde -induced tissue damage in
rats (Gurel et al., 2005, Gulec et al., 2006). Vitamin C is also
a well known natural antioxidant (Gil et al., 2002; Guo et al.,
2007). It's a low molecular antioxidant and is effective in the aqueous phase
in protecting different parts of cells against free radicals (IPCS, WHO and
ILO, 1995). L-ascorbic acid (vitamin C) is the first to become depleted on the
exposure to oxidative stress (Sies and Stahl, 1995). Normal
L-ascorbate level has a therapeutic benefit due to it's ability to reduce the
oxidative stress by reacting with superoxide and hydroxide radicals as well as
alkyl, peroxyl and alkoxyl radicals (Buettner, 1993; Sharma and Buettner, 1993). The combination of
vitamins C and E reduces lipid peroxidation and regenerates antioxidant enzyme
activity (Akturk et al., 2006). However, no pathological evaluation of
effects of vitamins E and C on the reduction of Lincomycin hepatotoxicity and
nephrotoxicity in male rats model has been done, so the present study was
undertaken.
MATERIALS AND METHODS:
1-Animals.
Adult male rats
from Sprague Dawley strain (aged 12 weeks old) weighting 223 to 250 g. They
were housed under standard laboratory conditions with a 13:12 of light-day
cycle and at 23-28
fed with rat chow
and water. They were acclimatized for one week before starting the experiments
.All experiments were performed in the morning according to current guidelines
for the care of the laboratory animals and the ethical guidelines for the
investigation of experimental pain in conscious animals (Sabir and Rocha,
2008).
2-Chemicals:
Lincomycin drug was
purchased from Pharma international Co. Amman-Jordan, vitamin C was obtained
from Roche, Turkey, and vitamin E was obtained Mefar Iiac San., Turkey.
3-Grouping of
Rats and Treatments:
Twenty rat males
were randomly divided into four groups and each group consists of 5 rats, the
first group received orally (0.9 %) of normal saline (control). The second
group was given Lincomycin (500 mg/kg) orally. The third group administrated
orally (500mg/kg) of Lincomycin plus
(500mg/kg) of vitamin C and (400mg/kg) vitamin E.The fourth group was given
(500 mg/kg) vitamin C plus vitamin E (400 mg/kg) orally. Lincomycin treatments
were started (1 day) after the first administrations of these agents and
continued for 21 day.
4-Animals
sacrificing and the collection of blood
samples.
The rats of each
group were anaesthetized with Diethyl ether, and (5 ml) of blood was collected
directly from the heart by heart puncture, then (2 ml) of blood was transferred
to the EDTA tube for the study of physiological properties of blood. The
residual 3 ml was centrifuged at 2000 g for 10 minutes to separate the serum
and kept at 40 C to assay the activities of liver enzymes and for
the study of biochemical properties of blood.
5-Body, relative
liver, kidney and spleen weight.
Body weight of each
animal was determined before treatments and before sacrifice. Liver, kidney and
spleen of each animal were dissected out and weighted.
6-Preparation of
liver samples:
The livers were rapidly
removed,( 500 mg) of each liver weighted and homogenized, using glass
homogenizer with ice-cooled saline to prepare 25% w/v homogenate, then divided
into two aliquot. The first one used for the estimation of reduced glutathione
(GSH) content according to (Baker et al., 1990), was deproteinized with
ice-cooled 12% trichloroacetic acid and the obtained supernatant, centrifuged
at 1000 xg and the resultant supernatant was used for the estimation of
malondialdehyde (MDA) level (Ohkawa et al., 1997).
7-Study of
the physiological properties of blood:
Total blood cells
count (WBC) was determined by the improved Neubauer haemocytometer method. The haemoglobin concentration was
determined by the cyanomethaemoglobin method. The packed cell volume (PVC) was
determined by the micro-haematocrit method. Six ml of blood was mixed with a
0.4 ml of tri-sodium citrate solution, then filled a Westergreen pipette to the
(O) mark and placed vertically in a Westergreen rack to determine the
erythrocytes sedimentation rate (ESR). All these physiological properties were
measured according to (Dacie and lewis, 2005).
8-Study of the biochemical properties of
blood:
The following
biochemical properties were estimated in the serum: total cholesterol and high
density lipoproteins (HDL) (Tietz, 1999), triglycerides (TG) (Fossati and
Principe, 1982), low density lipoproteins (were calculated) according to
(Friedewald et al., 1972), total
bilirubin (Steven, 1996), urea and
creatinine (Adekomi, 2010), alkaline phosohatase (ALP) (Varley, 1988), Alanine
aminotransferase (ALT) (Steven, 1996), Aspartate aminotransferase (AST)
(Shannon et al., 2010). Enzyme immunoassay used for the Quantitative
determination of testosterone concentration in the serum, was purchased from
Biocheck, Inc. Foster City.
9-Statistical
analysis:
Data were analyzed
by the using of SPSS package. Results
were expressed as mean 
Statistical
evaluations were done using the one way analysis of variance (ANOVA).
(P<0.05) level was considered a significant difference.
RESULTS:
1-The effect
of Lincomycin and vitamins
C,E on the body ,relative liver, kidney and spleen weight.
As shown in table
(1), the weights of body, liver, kidney and spleen were significantly decreased
(p<0.05) in the Lincomycin group when compared with the control, vitamins, Lincomycin
and vitamins groups.
DISCUSSION:
1-The effect of
Lincomycin and vitamin C, E on body, relative liver, kidney and spleen weight.
The present study
was showed that treatment of rats with Lincomycin caused significant decrease in the
body weight, this result was disagreement with the result of Harvey et al.(1995),
that found: final body weight, body weight gain, and feed consumption were
reduced in the aflatoxin alone, and aflatoxin plus Lincomycin, and the
aflatoxin plus Tylosin treatments when compared with the control group, but
there were no significant difference in these measurements were detected among
the Lincomycin, Tylosin, and control groups. The reduction in body weight may
be attributed to the significant decrease in the relative weights of liver,
kidney and spleen that has been recorded in the present study. Or may be due to
the gastrointestinal complications and reduction in food consumption which
resulted from the treatment with Lincomycin.
Also the reduction
in body, relative liver, kidney and spleen weights could be due to the
oxidative stress and reactive oxygen species (ROS) because of the orally
administration of Lincomycin, the ROS have been proposed as the causative
factors of the renal side-effects of some antibiotic therapy such as the
Vancomycin (Parlakpinar et al.,
2005; Oktem et al., 2005; Kadkhodaee et al., 2005), also lipid
peroxidation mediated by oxygen-free radicals is believed to be the important
cause of destruction and damage to cell membrane. Ros were caused cell death in
various models of toxic renal failure, including Vancomycin, Aminoglycosides,
Lithium and Cisplatin applications (Parlakpinar et al., 2003; Ozen et
al., 2004). In addition the Ros may produce cellular injury by numerous
mechanisms including: peroxidation of membrane lipids, protein denaturation and
DNA damage (Den et al., 1991), so Lincomycin may be caused cell damage
and, then an significant reduction in the body, relative liver, kidney and
spleen weights by the same mechanisms.
Also the reduction
in body weight can attribute to the decrease in skeletal muscle mass and
protein content that may be caused by the Lincomycin, this may lead to an
important alterations in protein turnover in skeletal muscle, which accompanied
by a severe muscle atrophy, and significant decrement in body weight. In the
contrast of that, the vitamin C plus E treated groups were revealed a
significant increase in the body, liver, kidney and spleen weights, which could
be due to their antioxidant properties, Kedziora-Kornatwska et al.(2003)
have been shown that both vitamin C and E decreased lipid peroxidation and
augmented the activity of antioxidant enzymes in the kidney of diabetic rats.
Also vitamin C and/or vitamin E have been tested for the prevention of kidney
damage induced by some drugs such as Gentamicin, Cisplatin, Sodium chromate and
Thallium, and Cydosprine (Ocak et al., 2007), so they were protected the
tissues from damage which resulted from the oxidative stress of Lincomycin and
then caused a significant increase in body, relative liver, kidney, and spleen
weights.
2-The effect
of Lincomycin and vitamins C, E on some of physiological properties (Hb, PVC,
ESR, WBC) of the blood.
The significant
decrease in Hb, PVC and WBC and increase in ESR values were disagreement with Harvey
et al. (1995), that found the treatment of growing crossbred pigs with
Lincomycin has no significant change in these parameters. The significant
decrease in haemoglobin (Hb) concentration may be attributed to the loss of
storage iron in the liver tissues that resulted from the oxidative damage of
Lincomycin antibiotic which caused by the generation of ROS, the highly
generation is toxic to the cells, particularly the cell membrane in which these
radicals interact with the lipid bilayer to produce lipid peroxides as
confirmed by Kesavulu et al.(2001), so the Hb concentration will be
significantly decreased. Or may be due to a reduction in the oxygen-carrying
capacity of blood and the amount of oxygen that delivered to the tissues
because of Lincomycin treatment, while the reduction in packed cells volume
(PVC) value which could suggest an induction of anaemia, or may be attributed
to inability of Lincomycin to stimulate the erythropoiesis process in bone
marrow tissues.
On the other hand
the decrease in white blood cell counts which probably due to damage in the
tissues that responsible for all haemopoiesis process, this damage may be
occurred also in the immune system which caused by the oxidative stress of
Lincomycin antibiotic, this can lead to a reduction in WBC counts. In contrast,
the increment in ESR value could imply a tissue damage or necrosis which may be
occurred in the liver and/or kidney in addition to the other organs due to the
Lincomycin treatment, Hadjipour et al.(2008), have been shown that
gentamycin can produce nephrotoxicity in human proximal tubular cells, which a
major site of damage in patients treated with this antibiotic or the Amikacin antibiotic,
Gentamycin binds to the wall phosphatidyl inositol which impairs cell
integrity. Another studies were confirmed that Vancomycin induced
nephrotoxicity (Celik et al., 2005) and renal dysfunction (Torbin et
al. , 2002), so the Lincomycin antibiotic may be revealed the same effects
of gentamycin and Vancomycin on the liver and kidney tissues that may lead to a
significant increase in ESR.
While the group of
Lincomycin and vitamins C, E , also vitamin C plus E group have been showed a
reduction in ESR value when compared with Lincomycin group, which could
indicate the antioxidant activities of these vitamins that may be protected the tissues of organ from the oxidative damage,
Kadkhodaee et al. (2005) have been shown that the co-supplementation of
vitamins C and E significantly reduced gentamycin-induced renal toxicity. One
of the vital roles of vitamin C is to act as an antioxidant to protect cellular
components from free radical damage as also does vitamin E (Beyer, 1994).
Also the results of
latter study revealed that vitamins A, C and E have a potent protective effects
against Diazinon-induced hepatotoxicity in rats, which may be due to the
scavenging of free radicals and increased antioxidant status (Shokrzadeh et
al. , 2012).
3-The effect of
Lincomycin and vitamins C, E on some of biochemical properties (urea, total
bilirubin, and creatinine , total cholesterol, TG, LDL and HDL) of the blood,
MDA and GSH content in liver homogenate.
The significant
increase in urea ,total bilirubin, creatinine, total cholesterol ,TG ,LDL, MDA
and decrease in HDL,GSH in Lincomycin group may be attributed to the oxidative
damage that occurred in the liver and kidney tissues which resulted from the
Lincomycin treatments, so the increment in urea concentration may be due to the
necrosis or damage in renal tubules as confirmed by Ocak et al.(2007)
that found, Vancomycin administration caused histopathologically prominent
damage in kidneys,and during the microscopic examinations tubular necrosis,
degeneration, vacuolization, interstitial oedema, tubular atrophy and
inflammatory cell infiltration were detected. Also the serum urea nitrogen is a
measure of renal function, it's level rises in some cases: heart failure,
dehydration, or a high protein diet and low urea nitrogen level can be seen in
liver and renal damage or in liver diseases (Johnson et al.,1972).
In addition to urea
concentration, a change in serum creatinine level is also an indicator of
kidney function .Therefore, the significant increase in creatinine content of
the serum after the administration of Lincomycin may be attributed to
compromise of the renal functional capacity, which may cause oxidative damage
in the renal tubules, or probably due to the effect of this chemical antibiotic
on the creatinine production rate, which leads to increase it's biosynthesis. On
the other hand the increase in serum total bilirubin, that probably indicates,
the Lincomycin ability to generate the Ros, which very toxic to the cells and
cause lipid peroxidation in the hepatocytes, this may lead to significantly
increment in serum total bilirubin. The concentration of proteins, bilirubin
and albumin in the serum can be used to differentiate between different types
of liver damage. The result of latter study revealed that, the serum bilirubin,
AST, ALT and ALP are the most sensitive biochemical markers employed in the
diagnosis of hepatic dysfunction (JohnKennedy et al. , 2010). Because the serum total bilirubin, is a
product of enzymatic breakdown of heme within the reticuloendothelium system,
so it's elevation in the blood can be adduced to over production, increased
hemolysis, decreased conjugation or impaired bilirubin transport ( Sasidharan et
al. , 2010), the increment in serum total bilirubin level in the current
study may be attributed to the increased hemolysis which confirmed by the
decrease in (Hb) concentration.
While, the
increment in the liver malondialdeyhyde (MDA) level and the decline in the
level of liver glutathione (GSH), may be suggested an enhancement in lipid
peroxidation during oxidative damage of tissues due to the fact that, MDA is
formed during oxidative degeneration and is accepted as an indicator of lipid
peroxidation (Celik et al. , 2005). Also the rise in MDA level may imply
to a failure of antioxidant defense mechanisms to inhibit the formation of
excessive free radicals, which caused more liver damage. Normally, the levels
of free radicals in the body of healthy organisms are low, because its ability
to neutralize the toxic effects of these radicals due to the presence of
scavengers, but the treatment with Lincomycin may be attenuated the activity of
these scavengers, so the level of MDA significantly increased. Glutathione
(GSH), is the main intracellular non protein sulfhydryl and it plays an
important role in the maintenance of cellular proteins and lipids in their
functional states (Kuriakose and Kurup, 2010), thus GSH depletion caused the
endogenous reactive oxygen species (Ros) to bind to cellular macromolecules
leading to initiation of processes of lipid peroxidation (Lebda et al. ,
2013). So when the level of GSH is lowered because of Lincomycin treatment, the
toxic effects of oxidative insult are exacerbated, resulting in increased
membrane breakdown and cell death that may occur in the present study. The body
of organism has an effective mechanism
to prevent and neutralize the free radical which induced a damage, this
accomplished by a group of endogenous antioxidant enzymes: SOD, CAT, GPX and
GST .
Thus the oxidative
stress occurs when the balance between production of Ros and antioxidant
defense system is lost (Kuriakose and Kurup, 2010), this unbalanced may be
happened in our study.
In addition to above
GSH provide a first line of defense mechanism against Ros as it can scavenge
free radicals and reduce H2O2 (Gumieniczek, 2005), so the
decreased level of GSH in kidney and/or liver due to Lincomycin treatment may be resulted
from GSH consumption in the conjugation and removal of peroxide.
While the
significant increment in GSH concentration at Lincomycin and vitamins C, E,
group also the group of vitamins C plus E when compared with Lincomycin group,
which probably due to the antioxidant and free radical scavenging properties of
these vitamins, that protect the tissues of liver and kidney from oxidative
damage of Lincomycin. Farombi and Onyema (2006) were showed that dietary
antioxidants such as vitamin C and vitamin E has a modulator effects on Mono-sodium
glutamate (MSG)- kidney of rats. Tawfik and Al-Badr (2012) were added that
vitamins C and E have been shown to protect and restore the liver and kidney
capabilities in several models injury via inhibiting oxidative damage.
On the other side,
rat groups which treated with Lincomycin showed a significant increase in total
cholesterol, TG and LDL and decreased in HDL concentrations, the possible
explanation of the observed hyperlipidemia might reflect the impairment of
liver cells to metabolize lipids due to decrease the activity of lipoprotein
lipase, or may be attributed to the increment in lipid peroxidation and highly
generation of Ros which induced by Lincomycin treatment. Also the increment in
serum lipids could imply to the increased hepatic synthesis. The cholesterol
molecule is a lipid may be utilized in liver to form cell membrane component or
bile acids and may be excreted in the bile. Because the liver is considered as
the only rout by which this lipid can leave the body in a significant amount
therefore, the oxidative damage and necrosis in hepatocytes which probably
resulted from Lincomycin treatment may be caused significant increase in the
serum total cholesterol.
On the other hand,
triglycerides (TG) are the main lipid in the diet, after the absorption, TG
passed into plasma as chylomicrons, while the endogenous TG are synthesized in
the liver from fatty acids and glycerol, so any disturbance in liver functions
caused significant increment in serum TG which could occur in the present study
due to the Lincomycin treatment.
Low density
lipoprotein (LDL) is often referred to as bad cholesterol because it carries
cholesterol from the liver to the cells so, the elevated serum levels increase
the risk of atherosclerosis (Edwards et al. , 1996), it's taken up by
specific receptors located on cell surface of all cells, but they are most
abundant in the liver, thus the level of these particles may be significantly
increased due to the oxidative damage and lipid peroxidation which occurred in
the liver tissues because of Lincomycin treatment.
Lincomycin
antibiotic seems to cause impairment in lipoprotein metabolism and also
alterations in cholesterol metabolism because it has deleterious effect on high
density lipoprotein (HDL) level in the serum, which is derived from liver and
intestine, these lipoprotein molecules removed the cholesterol from cells in
tissues and returning it to the liver. Numerous studies were revealed a
negative relationship between HDL level and increased risk of cardiovascular
diseases (Von Eckardstein and Assman, 2000), so the Lincomycin treatment may be
caused ischemic heart diseases and atherosclerosis. On the other hand, the significant decrement
in total cholesterol, TG, and LDL and increment in HDL levels in Lincomycin and
vitamins group also in the group of vitamins comparing to Lincomycin group, may
be attributed to the antioxidant ability of vitamins C,E which protects the
hepatocytes from oxidative damage and free radicals, also prevents serious
health problems such as liver and heart diseases.
4-The effect of
Lincomycin and vitamins C, E on the liver enzymes (ALP, AST and ALT) activity.
The significant
increment in ALP, AST and ALT activities in Lincomycin group, may be due to
lipid peroxidation and generation of Ros which caused damage in the plasma
membrane of hepatic cells, then these liver enzymes released from the cytosol
to the blood stream, so the evidence of Lincomycin-induced liver injury was the
elevation of blood levels of cellular markers (ALP, AST and ALT), because
increased levels of enzyme in the blood have been attributed to disintegration
and turnover of tissues as confirmed by Pendota et al.(2010). Also serum
levels of these enzymes are very sensitive markers employed in the diagnosis of
liver disease, thus when the hepatocellular plasma membrane is damaged, the
enzymes normally present in the cytosol are delivered to the blood (Kuriakose
and Kurup, 2010). The ALT enzyme is a
sensitive marker of liver damage due to toxic drugs, alcohol and virus, the increment
in its serum level could also be explained by free radical production which
reacts with polyunsaturated fatty acids of cell membrane leading to impairment
of mitochondrial and plasma membranes resulting in enzyme leakage as confirmed
by Poli et al.(1990).
Since the ALP is
excreted normally via bile by the liver, so the liver injury due to Lincomycin
treatment can result in defective excretion of bile by hepatocytes which
reflected as its increased level in serum, thus the serum ALT shows functional
activity of liver. On the other hand,
the activity of these enzymes have been shown significant decrement at
Lincomycin and vitamins C, E also in the group of vitamins C plus E when compared with Lincomycin group which probably indicates the
ability of vitamin C and E to protect the hepatic cell from oxidative damage
and lipid peroxidation which mediated by
oxygen – free radicals. The protective effect may be the result of
stabilization of plasma membrane thereby preserving the structural integrity of
hepatocytes . The study of Shokzadeh et al .(2012), was revealed, the
Diazinon / vitamin E,A,C group displayed significant
reduction in ALT and AST activities compared to Diazinon group . Another study
was showed that , the administration of vitamin C and E resulted a significant
reduction in the serum level of ALT enzyme at both (MSG) doses(Tawfik and
Al-Badr,2012). So these enzymes were revealed important role in the repairing
of hepatic tissue damage which caused by
Lincomycin .
Our data suggest
that , Lincomycin treatment was revealed
numerous detrimental effects on the hematological and biochemical properties of blood also liver and kidney
functions were disturbed ,these deleterious effects may be attributed to the
oxidative damage ,highly generation of ROS and lipid peroxidation were caused
by this antibiotic. Vitamin C and vitamin E exerted significant protection
against Lincomycin–induced hepatotoxicity and nephrotoxicity by their ability
to ameliorate the lipid peroxidation through the free radicals scavenging
activity and restore the liver and kidney capabilities in several models of
injury via inhibiting oxidative damage , so we recommend to use vitamin C and
vitamin E supplementation at the Lincomycin treatment to reduce the oxidative
stress on hepatic and renal functions.
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