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Advances in Environmental Biology, 8(2) February 2014, Pages: 821-824
AENSI Journals
Advances in Environmental Biology
ISSN-1995-0756
EISSN-1998-1066
Journal home page: http://www.aensiweb.com/aeb.html
Investigating Effect of Fluoxetine Drug on the Liver Enzymes ALT, AST and
ALK in Adult Female Wistar Rats
1
6
Ebrahimian Anahita, 2,3Kargar Jahromi Hossein, 4Shafiei Jahromi Nazanin, 5Bathaee Seyed Hamid,
Azhdari Sara, 6Farzam Mohammad, 5Mahmoudi Teimourabad Saeid
1
Developmental Biology, Islamic Azad University, Jahrom Brunch, Jahrom, Iran
Zoonoses research center, Jahrom University of Medical Sciences, Jahrom, Iran.
3
Young Researchers Club Elite, Jahrom Branch, Islamic Azad University, Jahrom, Iran.
4
Departmant of Nursing, Islamic Azad University, Firuzabad Brunch, Firuzabad, Iran.
5
Departmant of Science, Institution of Supreme Education and Industry of Maragheh, Iran.
6
Department of Anatomy and Embryology, International Branch, Shiraz University, Shiraz, Iran.
2
ARTICLE INFO
Article history:
Received 15 November 2013
Received in revised form 19
February 2014
Accepted 26 February 2013
Available online 20 March 2014
Key words:
Fluoxetine, ALT, AST, ALK, rat.
ABSTRACT
Introduction: Fluoxetine with the brand name of Prozac was introduced in the late
1980s. This antidepressant medication is one of the most prescribed medications in the
world and millions of people around the world are willing to pay large sums for
fluoxetine and similar drugs. Due to the heavy use of this drug and lack of attention to
the probable reaction of the drug to the liver, it can be stated that the purpose of this
study is to investigate the effects of fluoxetine drug on the liver enzymes. Method: 40
female Wistar rats were divided randomly into 5 equal groups. The first group (control
group) did not receive any medication. The second group (sham group) only injected
distilled water. Experimental group 1 received 5 mg/kg fluoxetine daily, experimental
group 2 also received 10 mg/kg fluoxetine and experimental group 3 received 20 mg/kg
fluoxetine, based on body weight, intraperitoneally. At the end of 30 days, blood
samples were taken from rats and serum concentration of ALT, AST and ALK were
measured. Data were analyzed using SPSS software version 18 and the results were
expressed as shown in the table. Results: Concentration ofALT and AST in
experimental groups 1, 2 and 3 that respectively received doses of minimum, average
and maximum of drug, showed a significant increase compared to control group. Also,
ALK concentration in experimental group 3 had significant increase compared to
control group. Conclusion: The results show that use of fluoxetine drug causes increase
of liver enzymes that indicate damage to liver tissue.
© 2014 AENSI Publisher All rights reserved.
To Cite This Article: Ebrahimian Anahita, Kargar Jahromi Hossein, Shafiei Jahromi Nazanin, Bathaee Seyed Hamid, Azhdari Sara, Farzam
Mohammad, Mahmoudi Teimourabad Saeid., Developmental Biology, Islamic Azad University, Jahrom Brunch, Jahrom, Iran. Adv.
Environ. Biol., 8(2), 821-824, 2014
INTRODUCTION
Today, unfortunately, depression is one of the most common diseases among people. In depression
diseases, the reactions are not natural, that means that humans who face adversity and defeat become too
depressed and the time duration of depression is longer than others in the same situation. Causes of disease are
heredity, brain chemistry changes, loss of parents in childhood and non pleasant life events, various physical
diseases and use of some drugs. For treatment, medication is the best way. Antidepressant drugs are a group of
drugs that are used to treat depressed patients and so the mood of depressed patients using these drugs is much
better [1]. Antidepressant drugs decrease some of the chemicals called neurotransmitters in brain. For the
normal functioning, brain needs these neurotransmitters. These drugs make these neurotransmitters available to
brain and can significantly help depressed patients. Today, several types of antidepressant medications are
made. The most common drug groups are: tricyclic antidepressant drugs (TCA), 2- Selective Seratonin
Reuptake Inhibitor (SSRI), 3- Monoaminess oxidase inhibitors (MAOIS), 4- Other drugs groups [2]. SSRI drugs
affect only a specific neurotransmitter called serotonin. These drugs are highly effective in treating depression
and in comparion with tricyclic drugs, have fewer side effects. Sedative effects of these drugs are less and do
not cause weight gain, also they do not affect heart as tricycle drugs do. Like tricyclic drugs, consumption of
these drugs in people with epilepsy should be done with caution. These medications can cause gastrointestinal
problems at the beginning of treatment. Diarrhea, nausea and vomiting can be with headaches, restlessness and
anxiety in persons who take these drugs [3]. Fluoxetine with the brand name of Prozac, introduced in the late
Corresponding Author: Ebrahimian Anahita, Islamic Azad University of Jahrom Branch, Jahrom, Iran.
Tel: +989171340979
E-mail: aebrahimian80@ yahoo.com
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Advances in Environmental Biology, 8(2) February 2014, Pages: 821-824
1980’s is the latest psychotropic medication that caused
considerable excitement in the medical
community.This antidepressant drugs is one of the most widely used in the world and millions of people around
the world are willing to pay large sums for it and similar drugs. In fact, the effect of fluoxetine is not
significantly different with tricyclic antidepressants drugs. However, from this view it is unique in that like
tricyclic drugs, it has no effect on the large range of neuronal transmitters, but only affects Serotonin and
partially dopamine [4]. Fluoxetine common side effects include headaches, nervousness, anxiety, restless insomnia, dizziness, drowsiness, fatigue, anxiety, agitation and irritability, excited state and lack of control in
speech, behavior and emotions, impaired concentration, non natural dreams, non natural facial or body
movements, dry mouth, vomiting, constipation, diarrhea, Anorexia , weight loss, abdominal pain, change in
taste, signs of low blood sugar, heart palpitations, swelling, rash, itching, back pain and joints and muscle pain ,
sexual dysfunction, urinary tract infection, frequent urination, painful menstruation, pain or natural breast
enlargement , non normal secretion of milk in women, upper respiratory tract infection, cough, dyspnea,
bronchitis, sinusitis, fever and nasal congestion. The main side effects of this drug can be hyponatremia
(syndrome of inappropriate secretion of anti- diuretic hormone), increased risk of suicide, convulsions
(especially in older people) and diffuse vasculitis involving the liver, kidney and lung that are associated with
skin rash. Also, It is known that fluoxetine causes tremors, stimulation, aggressive behavior, cramps, profuse
sweating, heart palpitations, blurred vision, hair loss and irregular periods [5]. Due to the issues mentioned
above and the unwanted side effects of this drug, the purpose of the study was to investigate the effects of
fluoxetine on the enzymes ALT, AST and ALK .
Methods:
This study was conducted in laboratory and completely randomized. All ethical principles about laboratory
animals in this research were complied with. 40 adult female Wistar rats weighing 200 ± 5% and age of 100120 days from Jahron research department were obtained. Rats were placed in the animal house of Jahrom
Medical University for 21 days under laboratory conditions including temperature of 21 ± 2°C, 12 hours light
and 12 hours dark. Rats used standard food (pellete). Also, water by special glass bottle was given. Cages were
disinfected with 70% alcohol 3 times a week. Lethal dose of the drug was 40 mg. Based on this, doses of
minimum , average and maximum were determined. In this case, maximum dose was half of lethal dose,
average dose was half of maximum dose and minimum dose was half of average dose. Fluoxetine is soluble in
water. In this study, distilled water was used as solvent. All solutions were prepared fresh every morning and the
injection was performed for 30 days. The rats were divided into 5 groups of 8 as follows:
Control group: They did not receive any medicine and all maintenance and feeding conditions were similar
to other groups.
Sham group: They received distilled water based on rat weight daily.
Experimental group 1 (C1): They received 1 capsule of fluoxetine 20 mg dissolved in 4 ml of distilled water
injected intraperitoneally.
Experimental group 2 (C2): They received 1 capsule of fluoxetine 20 mg dissolved in 2 ml of distilled water
injected intraperitoneally.
Experimental group 3 (C3): They received 1 capsule of fluoxetine 20 mg dissolved in 1 ml of distilled water
injected intraperitoneally (table 1).
Table 1: Type of animal grouping.
Time duration of blooding
21 End of days
End of days 21
End of the days 21
End of the days 21
End of the days 21
Drug type
Distilled water 1cc/kg
fluoxetine 5 mg/kg
Fluoxetine 10 mg/kg
Fluoxetine 20 mg/kg
Group classification
Control
Sham
Experimental 1
Experimental 2
Experimental 3
After the end of the 21 day period, after weighing, all groups of rats were anesthetized by ether and rats
were bled from their hearts by 5 cc syringe and after separation of blood serum, concentration of PT, OT and
ALP were measured in laboratory of Jahrom medical university. For comparison between treatments One-way
ANOVA was used followed by t-test and Duncan test for multiple comparisons between groups. Significant
level was P < 0.05. Data analysis and statistical testing was performed using SPSS software, version 18.
Results:
The results indicate that concentration of AST and ALT in experimental groups 1 , 2 and 3 which
respectively received minimum, average and maximum drug doses, have significant increase compared to
control group. Also, concentration of ALK in experimental group 3 have significant increase compared to
control group (table 2).
Table 2: Results of concentration of liver enzymes in different experimental groups.
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Advances in Environmental Biology, 8(2) February 2014, Pages: 821-824
ALK (IU/l)
122.78 ± 5.91 a
136.41 ± 19.30 a
142.54 ± 21.59 a
154.05 ± 5.55 a
276.40 ± 3.71 b
ALT (IU/l)
32.44 ± 1.82 a
39.19 ± 2.76 ab
42.93 ± 2.47 b
61.44 ± 4.16 c
84.80 ± 2.54 d
AST (IU/l)
115.42 ± 2.15 a
136.66 ± 11.43 a
175.84 ± 9.23 b
190.68 ± 16.73 b
233.4 ± 2.44 c
Groups
Control
Sham
Experimental 1
Experimental 2
Experimental 3
Discussion:
The present study was conducted to investigate the effects of fluoxetine on liver enzymes that concluded
that concentration of ALT and AST enzymes in all three experimental groups increased and in experimental
group 3, concentration of ALK enzyme increased. Many studies on the adverse effects of fluoxetine on the liver
have been done and high levels of aminotransferases [6-11] and acute hepatitis have been reported in patients
treated with fluoxetine [10,12,13]. In addition, animal studies have shown changes in liver cells. The studies
also found that fluoxetine increases metabolism energy in rats liver and is toxic in high doses. Studies have
also found that use of fluoxetine causes increase of fluorinated compounds in serum and urine of rats, and this
increase of fluoxetine metabolite is dependent on concentration [14-16]. The studies stated that concentration of
protein in serum and changes in proteins of plasma are a sign of impaired protein synthesis and liver diseases
[17,18]. In this study, significant increases in concentration of ALT and AST after use of fluoxetine was
observed, which agrees with previous findings [19, 17]. The reviews stated that the increase in concentration of
ALT and AST indicate liver injury, and increase in blood transaminase activity is an index in order to detect
damage to the cytoplasmic membrane and mitochondria [17]. Moreover, damage to the cell membrane causes an
increase in plasma enzymes. The increase in ALT in liver acute diseases and liver injury seems to be more than
concentration of AST [17]. Thus, increase in these two enzymes in the fluoxetine receiving groups indicates
harmful effects of fluoxetine. It is also stated that fluoxetine leads to significant increase in TBARS, carbonyl
groups and the concentration of uric acid in the liver tissues [20]. It has been further stated that the use of
fluoxetine causes increased uric acid in the liver which is a product of purine metabolism in the humans body
that, at high levels of uric acid, increase of ALT was observed. Uric acid is a strong absorber of oxidative stress
molecules and free radicals [21]. Therefore, one mechanism of liver damage by creating free radicals is by
fluoxetine [20], which is consistent with the present study. Also, the use of the 24 mg/ kg fluoxetine dose
increases concentration of uric acid in rat liver, indicating a product of free radicals and impaired antioxidant
and decrease of defense system [22]. In examining the effects of fluoxetine on the liver tissue, lipid peroxidation
and increased production of malondialdehyde in liver tissue has been reported followed by use of fluoxetine. In
addition, extensive damage of kidney tissue by lipid peroxidation through membrane clutter and decrease in
membrane fluidity was also caused [15,23]. The use offluoxetine has been mentioned to cause decrease of
concentration of glutathione in the kidney cells of the liver and causes impairment in antioxidant system [24].
Alkaline phosphatase is mainly derived from the liver and its value in diseases of the liver ducts, biliary and
spread of hepatic lesions increase [25]. What is certain is that the concentration of alkaline phosphatase in
experimental group 3 that received maximum dose is increased, which indicates damage to liver, probably due
to the mechanism of production of oxygen reactive species and disruption of the cells function produced by the
metabolism of fluoxetine.
Conclusion:
The study suggests that fluoxetine causes increase of AST, ALT and ALK activity. Kidney damage due to
fluoxetine is due to oxygen reactive species, and increased concentration of uric acid and increase of carbonyl
groups. Effect of this drug in this study is dose dependent, and so at the higher doses of the drug concentration
in liver enzymes has risen. Therefore, this drug should be used with caution.
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