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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 2  |  Page : 118-123

Valporic acid-induced hepatotoxicity in rats: Protective effect of selenium


1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria
2 Department of Pharmacology, Faculty of Basic Clinical Sciences, University of Port Harcourt, Rivers State, Nigeria

Date of Submission29-Sep-2020
Date of Decision10-Oct-2020
Date of Acceptance30-Nov-2020
Date of Web Publication13-Apr-2021

Correspondence Address:
Elias Adikwu
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnsm.jnsm_123_20

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  Abstract 


Background: The use of valproic acid (VPA) as therapy for epileptic and other neuropsychiatric disorders may cause hepatotoxicity. Selenium (Se), a component of selenoproteins, which performs important enzymic functions, may protect biomolecules from damage. This study assessed the protective effect of Se against VPA-induced hepatotoxicity in Wistar rats. Methods: Thirty-two adult Wistar rats of both sexes (160 ± 20 g) were divided into four groups of n = 8. Groups 1 (Control), 2, and 3 were orally administered with normal saline (0.2 mL), Se (0.1 mg/kg/day), and VPA (200 mg/kg/day) for 30 days, respectively. Group 4 was orally administered with Se (0.1 mg/kg/day) and VPA (200 mg/kg/day) for 30 days. After treatment, the rats were weighed and anesthetized. Blood samples were collected and analyzed for serum biochemical parameters. Liver samples were weighed and assessed for biochemical markers and histology. Results: Body weight was significantly (P < 0.01) decreased, whereas liver weight was significantly (P < 0.01) increased in VPA administered rats. VPA caused significant (P < 0.001) increases in serum and liver aminotransferases, alkaline phosphatase, gamma-glutamyl transferase, lactate dehydrogenase, conjugated bilirubin, total bilirubin, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and malondialdehyde levels when compared to control. VPA produced significant (P < 0.001) decreases in liver glutathione, catalase, superoxide dismutase, glutathione peroxidase and serum high density lipoprotein cholesterol levels when compared to control. Hepatocyte necrosis and fatty change were observed in VPA- administered rats. Se supplementation significantly (P < 0.01) reversed VPA-induced hepatotoxicity. Conclusion: Se seems effective against VPA-induced hepatotoxicity.

Keywords: Liver, rat, selenium, toxicity, valproic acid


How to cite this article:
Adikwu E, Liverpool E. Valporic acid-induced hepatotoxicity in rats: Protective effect of selenium. J Nat Sci Med 2021;4:118-23

How to cite this URL:
Adikwu E, Liverpool E. Valporic acid-induced hepatotoxicity in rats: Protective effect of selenium. J Nat Sci Med [serial online] 2021 [cited 2021 May 16];4:118-23. Available from: https://www.jnsmonline.org/text.asp?2021/4/2/118/313640




  Introduction Top


Valproic acid (VPA) is one of the mostly prescribed antiepileptic drugs for different types of partial and generalized epileptic seizures. It is also used for other neuropsychiatric problems including bipolar disorders, schizoaffective disorders, social phobias, and neuropathic pain.[1] It is used as an adjunctive therapy to benzodiazepines for alcohol and other sedative-hypnotic withdrawal syndromes.[2] Despite its wide therapeutic uses, it has been associated with a number of life-threatening toxicities including hepatotoxicity, which is classified as Type I and Type II.[3] Type I VPA-mediated hepatotoxicity is associated with dose-dependent changes in serum levels of liver enzymes and low plasma fibrinogen levels, which may be rectified upon VPA withdrawal. Type II VPA-mediated hepatotoxicity is considered to be rare, but often fatal. It occurs as an irreversible idiosyncratic reaction characterized by microvesicular steatosis, which may be accompanied by necrosis.[4] The speculated mechanisms by which VPA causes hepatotoxicity include hepatocyte mitochondrial dysfunction, oxidative stress, and lipid peroxidation (LPO).[5] Also, inflammation may be an essential mechanism for VPA-induced hepatotoxicity due to increased hepatic nuclear factors-κB (NF-κB), interleukin (IL-1) β, and tumor necrosis factor-alpha (TNF-α) gene expression.[6]

Selenium (Se), an essential trace element, is present in dietary sources including cereals, grains, and vegetables. It is involved in a number of biochemical processes in plants and animals.[7] Se is incorporated in selenoproteins during their translation, in the form of amino acid selenocysteine, a cysteine analog in which the sulfur-containing thiol is substituted by a seleno group.[8] Selenoproteins such as glutathione peroxidase (GPx), thioredoxin reductase (TrxR), and iodothyronine deiodinases act as important intracellular antioxidants that prevent oxidative injury.[9] Selenoproteins play significant roles in protecting cells against damage from reactive oxygen species (ROS).[9] This helps to maintain membrane integrity and prevent oxidative damage to biomolecules such as lipids, proteins, and DNA.[10] Se has anti-inflammatory effect by inhibiting NF-κB pathway and the expression of pro-inflammatory cytokines such as IL-1 β, TNFα, and interferon-gamma. It can inhibits the expression of pro-inflammatory genes[11] and increases the expression of anti-inflammatory markers such as arginase 1.[12] Preclinical studies attest to the possible therapeutic activity of Se in diseases such as cancer, diabetes, and hypertension. Se may serve as an antidote due to observed protective effects against some animal models of toxicities such as cadmium-[13] and D-galactosamine[14]-induced hepatotoxicity. In the absence of information, this study assessed the protective effect of Se against VPA-induced hepatotoxicity in Wistar rats.


  Methods Top


Drugs, chemicals, and experimental protocol

VPA (sodium valproate) was manufactured by Sanofi-Aventis, whereas Se (Se selenite) was manufactured by (Bactolac Pharm Inc 7 Oser Avenue Hauppauge, NY, USA). Thirty-two adult Wistar rats of both sexes (160 ± 20 g) were divided into four groups of eight rats each. The rats had ad libitum access to rats' chow and water and were maintained under natural conditions. The rats were obtained from the animal breeding unit of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were handled according to the recommendations of the European Parliament and the Council on the use of animals for experiments. Group 1 (Control) was administered with of 0.9% saline (0. 2 mL), whereas Group 2 was administered with Se (0.1 mg/kg/day)[15] in 0.9% saline for 30 days. Group 3 was administered with VPA (200 mg/kg/day)[16] in 0.9% saline, whereas Group 4 was supplemented with Se (0.1 mg/kg/day) before VPA (200 mg/kg/day) administration for 30 days. After treatment, the rats were anesthetized and blood samples were collected through cardiac puncture. Blood samples were allowed to clot and serum samples were extracted through centrifugation (1500 rmp for 15 min) for biochemical analyses. Liver tissues were collected via dissection and weighed. Liver tissues were used for histological assessment and biochemical evaluations. Liver tissues for biochemical evaluations were rinsed in cold 0.9% normal saline and homogenized in 0.1 mol/L phosphate buffer, pH 7.4. The homogenates were centrifuged (2000 rmp for 20 min); supernatants were collected and assessed for biochemical parameters.

Biochemical evaluation

Serum and liver tissue alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), lactate dehydrogenase, (LDH) conjugated bilrubin (CB), total bilirubin (TB), total cholesterol (CH), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) were evaluated using laboratory reagents according to the manufacturers' specifications. Low-density lipoprotein cholesterol (LDL-C) was calculated using Friedewald equation. Liver total protein was measured as reported by Gornall et al. 1949,[17] whereas malondialdehyde (MDA) was determined as reported by Buege and Aust, 1978.[18] Glutathione (GSH) was measured using the method described by Sedlak and Lindsay, 1968,[19] whereas superoxide dismutase (SOD) was assayed using the method reported by Sun and Zigman, 1978.[20] Glutathione peroxidase (GPx) was evaluated as reported by Rotruck et al. 1973,[21] whereas catalase (CAT) was assayed as described by Aebi, 1984.[22]

Liver histology

Liver sections were fixed in 10% formalin saline and dehydrated in ascending degrees of ethanol concentrations. Processed liver sections were embedded in paraffin. Sections of 3–5 μm thickness were produced using a microtome and stained with hematoxylin and eosin (H and E). The stained sections were observed under a light microscope for histological changes.

Statistical analysis

The values from different groups are presented as mean ± standard deviation. Differences between the mean values were estimated using one-way analysis of variance followed by Tukey's post hoc test. The results were considered statistically significant at P < 0.05; P < 0.01 and P < 0.001.


  Results Top


Effects of selenium on body and liver weights of valporic acid-treated rats

The administration of Se did not produce significant (P > 0.05) effects on body and liver weights when compared to control. Body weight was significantly (P < 0.01) decreased, whereas liver weight was significantly (P < 0.01) increased in VPA administered rats. The increase in absolute liver weight observed in VPA administered rats was 56.9% [Table 1]. However, Se supplementation significantly (P < 0.01) increased body weight and significantly (P < 0.01) decreased liver weight when compared to VPA-administered rats [Table 1].
Table 1: Effects of selenium on body and liver weights of valporic acid-treated rats

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Effect of selenium on serum biochemical parameters of valporic acid-treated rats

In Se administered rats, serum AST, ALT, ALP, GGT, LDH, CB, and TB levels were not significantly (P > 0.05) different when compared to control. In contrast, the aforementioned parameters were significantly (P < 0.001) elevated in VPA-administered rats when compared to control [Table 2]. However, significant (P < 0.01) reductions in serum AST, ALT, ALP, GGT, LDH, CB, and TB levels were observed in Se-supplemented rats when compared to VPA [Table 2].
Table 2: Effect of selenium on serum biochemical parameters of valporic acid- treated rats

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Effect of selenium on lipid parameters of valporic acid-treated rats

Serum CH, TG, HDL-C, and LDL-C levels were normal (P > 0.05) in Se-administered rats when compared to control. In contrast, serum CH, TG, and LDL-C levels were significantly (P < 0.001) increased, whereas serum HDL-C levels were significantly (P < 0.001) decreased in VPA-administered rats when compared to control [Table 3]. However, supplementation with Se significantly (P < 0.01) decreased serum CH, TG, and LDL-C levels, but significantly (P < 0.01) increased HDL-C level when compared to VPA [Table 3].
Table 3: Effect of selenium on the lipid profile of valporic acid-treated rats

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Effect of selenium on liver tissue biochemical parameters of valporic acid-treated rats

Effects on liver tissue AST, ALT, ALP, GGT, and LDH levels were not significant (P > 0.05) in Se-administered rats when compared to control [Table 4]. On the other hand, the aforementioned parameters were significantly (P < 0.001) increased in rats administered with VPA when compared to control [Table 4]. However, liver tissue AST, ALT, ALP, GGT, and LDH levels were significantly (P < 0.01) decreased in Se-supplemented rats when compared to VPA [Table 4].
Table 4: Effect of selenium on liver tissue biochemical indices of valporic acid-treated rats

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Effects of selenium on liver oxidative stress markers of valporic acid-treated rats

CAT, GSH, GPx, SOD, and MDA levels were not significantly (P > 0.05) different in rats administered with Se when compared to control [Table 5]. On the other hand, significant (P < 0.001) decreases in liver CAT, GSH, GPx, and SOD levels with significant (P < 0.001) increases in MDA levels occurred in VPA-administered rats when compared to control. However, Se supplementation significantly (P < 0.01) increased liver CAT, GSH, GPx, and SOD levels with significant (P < 0.01) decreases in MDA levels when compared to VPA [Table 5].
Table 5: Effect of selenium on liver oxidative stress markers of valporic acid-treated rats

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Effect of selenium on liver histology of valporic acid-treated rats

The liver of the control rat [Figure 1]a and Se-administered rat [Figure 1]b showed normal hepatocytes. In contrast, the liver of VPA-administered rat showed fatty change and hepatocyte necrosis [Figure 1]c and [Figure 1]d, whereas the liver of Se-supplemented rat showed fatty change [Figure 1]e.
Figure 1: Normal hepatocytes were observed in control rats (H) (a) and Se.administered (N) (b) rats. Fatty change (F) (c) and hepatocyte necrosis (K) (d) were observed in valporic acid-administered rats. Fatty change (M) was observed in Se-supplemented rats (e). H and E ×400

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  Discussion Top


VPA used for the management of seizures and psychiatric disorders may cause hepatotoxicity characterized by hepatic necrosis, apoptosis, steatosis,[23] and irreversible fatal liver failure.[24] This study aimed at overcoming the hepatotoxic scourge associated with VPA by assessing the protective effect of Se against VPA-induced hepatotoxicity in rats. In this study, the administration of Se had no deleterious effect on body and liver weights. The administration of VPA decreased body weight and increased liver weight. However, Se supplementation restored body and liver weights. This study measured alterations in serum biochemical indices and liver histology, as are yardsticks for liver status.[25] The induction of hepatic oxidative stress by VPA was assessed by measuring the liver levels of SOD, CAT, GSH, GPx, and MDA.[26] The serum concentrations of aminotransferases (ALT and AST) are used to estimate hepatocyte injury. Serum ALP, GGT, and CB and TB concentrations are yardsticks for biliary function and cholestasis.[27] In this study, serum and liver levels of AST, ALT, ALP, GGT, LDH, CB, and TB were stable in Se-administered rats. In contrast, the aforementioned indices were elevated in VPA-administered rats. The observation in VPA-administered rats is indicative of hepatic damage which supports previous findings.[28] However, supplementation with Se offered protection by reducing serum and liver levels of AST, ALT, ALP, GGT, LDH, CB, and TB. In the current study, serum CH, TG, LDL-C and HDL-C levels were normal in Se-administered rats. On the other, VPA administration caused alterations in the aforementioned parameters characterized by elevated CH, TG, and LDL-C levels with decreased HDL-C levels. The observation in VPA-administered rats supports earlier reports.[29] However, Se supplementation restored the serum levels of the aforementioned parameters.

Furthermore, body of evidence suggested that oxidative stress plays a key role in numerous pathological conditions including hepatic injury. Oxidative stress is a process generated by excess and unregulated activities of ROS. Studies showed that excess oxidative stress incapacitates antioxidant function and depletes antioxidant levels.[30] In this study, normal hepatic antioxidants (SOD, CAT, GSH, and GPx) were observed in Se-administered rats. On the contrary, VPA administration caused notable decreases in hepatic antioxidant levels. This finding is consistent with earlier reports.[31] Interestingly, Se supplementation remarkably upregulates hepatic SOD, CAT, GSH, and GPx levels. LPO, the breakdown of unsaturated fatty acid, is one of the consequences of the excesses of ROS. It produces by-products, which stimulates cascades of reactions that are injurious to cells. In experimental settings, MDA concentration is used as a determinant of hepatic LPO.[32] In the current study, stable MDA level was observed in Se-administered rats. In contrast, increased MDA level was conspicuous in VPA-administered rats. The observation in VPA-administered rats is in unison with earlier findings.[33] This indicates that LPO is an essential process in the induction of hepatotoxicity by VPA. However, supplementation with Se reduced hepatic LPO marked by decreased MDA level. In this study, hepatocyte necrosis and fatty change occurred in the liver of VPA-administered rats which correlates with alterations observed in biochemical parameters. The observed hepatocyte necrosis and fatty change supports previous reports.[34] Interestingly, Se supplementation abrogates hepatocyte necrosis observed in VPA-administered rats.

The prolonged administration of VPA has been reported to cause hepatic assault ranging from mild hepatotoxicity to severe hepatic failure.[16] Hepatotoxicity caused by VPA has been associated with its metabolites; 4-ene VPA and 2,4-diene produced through the oxidation of VPA by cytochrome P450. These toxic metabolites then conjugate with GSH causing GSH consumption and further depletion of other endogenous antioxidants. The oxidation of VPA by Cytochrome P450 2E1 has been associated with increased ROS production leading to oxidative stress.[35],[36] VPA-induced hepatic oxidative stress can damage hepatic biomolecules (lipids, DNA, and proteins) causing hepatocyte degeneration and necrosis.[36] The decrease in body weight in VPA-administered rats may be due to decreased appetite, whereas increase in liver weight may be due to inflammation. Studies have shown that ROS and their derivative products can activate NF leading to the production of pro-inflammatory mediators such as cytokines, which can cause inflammation.[37] In the present study, Se might have protected against VPA-induced hepatotoxicity by inhibiting the oxidative activity of its metabolites (4-ene VPA and 2,4-diene). It might have prevented the metabolites of VPA from generating excess ROS, thus decreasing oxidative stress. Se is closely localized at the active site of many antioxidants including TrxR and GPx in cells.[38],[39] GPx plays a significant role in protecting cells against oxidative damage from ROS.[40],[41] Se can also prevent DNA damage by increasing the activity of DNA repair enzymes, thus safeguarding its integrity.[42]


  Conclusion Top


Se may have therapeutic use for VPA-induced hepatotoxicity.

Acknowledgments

The authors appreciate the technical assistance offered by Mr Cosmos Obi of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria.

Financial support and sponsorship

None.

Conflicts of interest

The authors declare no conflicts of interest.



 
  References Top

1.
Johannessen CU, Johannessen SI. Valproate: Past, present, and future. CNS Drug Rev 2003;9:199-216.  Back to cited text no. 1
    
2.
Löscher W. Basic pharmacology of valproate: A review after 35 years of clinical use for the treatment of epilepsy. CNS Drugs 2002;16:669-94.  Back to cited text no. 2
    
3.
Shakya R, Hoque MK, Sapkota AS, Gupta PK. Differential hepatotoxic effects of sodium valproate at different doses in albino rats. Kathmandu Univ Med J (KUMJ) 2018;16:78-82.  Back to cited text no. 3
    
4.
Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB. Valproic acid hepatic fatalities: A retrospective review. Neurology 1987;37:379-85.  Back to cited text no. 4
    
5.
Najafi N, Heidari R, Jamshidzadeh A, Fallahzadeh H, Omidi M, Abdoli N. Valproic acid-induced hepatotoxicity and the protective role of thiol reductants. Trends Pharm Sci 2017:3:63-70.  Back to cited text no. 5
    
6.
Abdelkader NA, Elyamany M, Gad AM, Assaf N, Fawzy NM, Elesawy WH. Ellagic acid attenuates liver toxicity induced by valproic acid in rats. J Pharm Sci 2020;143:23-9.  Back to cited text no. 6
    
7.
Tapiero H, Townsend HM, Tew KD. The antioxidant role of selenium and seleno-compounds. Biomed Pharm 2003;57;3-4:134-44.  Back to cited text no. 7
    
8.
Klusonova I, Horky P, Skladanka J, Kominkova M, Hynek D, Zitka O, et al. An effect of various selenium forms and doses on antioxidant pathways at clover (trifolium pratense l. Int J Electrochem Sci 2015;10:9975-87.  Back to cited text no. 8
    
9.
Tinggi U. Selenium: Its role as antioxidant in human health. Environ Health Prev Med 2008;13:102-8.  Back to cited text no. 9
    
10.
Diplock AT, Antioxidants and disease prevention. Molec Aspects Med 1994;15:293-376.  Back to cited text no. 10
    
11.
Duntas LH. Selenium and inflammation: Underlying anti-inflammatory mechanisms. Horm Metab Res 2009;41:443-47.  Back to cited text no. 11
    
12.
Kaushal N, Kudva AK, Patterson AD, Chiaro C, Kennett MJ, Desai D, et al. Crucial role of macrophage selenoproteins in experimental colitis. J Immunol 2014;193:3683-92.  Back to cited text no. 12
    
13.
Alhazza IM. Cadmium-induced hepatotoxicity and oxidative stress in rats: Protection by selenium. Res Jour Env Sci 2008;2:305-09.  Back to cited text no. 13
    
14.
Catal T, Tunali S, Bolkent S, Yanardag R. An antioxidant combination improves histopathological alterations and biochemical parameters in d-galactosamine-induced hepatotoxicity in rats. Eur J Biol 2017;76:14-9.  Back to cited text no. 14
    
15.
Adikwu E, Ebinyo NC, Odira AF. 5-Fluorouracil-Induced hepatic perturbation: Protective potential of selenium. J Integr Health Sci 2020;8:3-8.  Back to cited text no. 15
  [Full text]  
16.
Ibrahim MA, Abdel-Karim RI, Tamam HG, Mohamed AA, Wani FA. Protective effect of silymarin and ascorbic acid in valproic acid-induced hepatic toxicity in male albino Rats Mansoura J Forens Med Clin Toxicol 2017;25;2;33-49.  Back to cited text no. 16
    
17.
Gornall AG, Bardawill CJ, David MM. Determination of serum proteins by means of the biureto reaction. J Biol Chem 1949;177:751-66.  Back to cited text no. 17
    
18.
Buege JA, Aust SD. Microsomal Lipid Peroxidation. Methods Enzymol 1978;52:302-10.  Back to cited text no. 18
    
19.
Sedlak J, Lindsay R.H.Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with ellman's reagent. Anal Biochem 1968;25:1192-205.  Back to cited text no. 19
    
20.
Sun M, Zigman S. An improved spectrophotometer assay of superoxide dismutase based on epinephrine antioxidation. Anal Biochem 1978;90:81-9.  Back to cited text no. 20
    
21.
Rotruck JT, Rope AL, Ganther HF, Swason AB. Selenium: Biochemical role as a component of glutathione peroxidase. Sci 1973;179:588-90.  Back to cited text no. 21
    
22.
Aebi H. Catalase In vitro. Meth Enzymol 1984;105:121-6.  Back to cited text no. 22
    
23.
El-Mowafy AM, Abdel-Dayem MA, Abdel-Aziz A, El-Azab MF, Said SA. Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: Dynamic synergy and therapeutic utility. Biochim et Biophys Acta 2011;1811:460-67.  Back to cited text no. 23
    
24.
Dreifuss FE, Santilli N, Langer DH, Sweeney KP, Moline KA, Menander KB Valproic acid hepatic fatalities: II. US experience since 1984. Neurology 1989: 39201—40201.  Back to cited text no. 24
    
25.
Alemu P, Forsyth GW, Searcy GP. A comparison of parameters used to assess liver damage in sheep treated with carbon tetrachloride. Can J Comp Med 1977;41:420-27.  Back to cited text no. 25
    
26.
Adikwu E, Ebinyo NC, Agbadabina H. Coenzyme Q10. Abrogates flutamide-induced hepatotoxicity in albino rats. J Med Sci Health 2019;5:1-8.  Back to cited text no. 26
    
27.
Roy V, Biswas J, Saraf A. Study of liver functions parameters in diabetic patients from raipur region. IOSR J Pharm 2018;10:18-21.  Back to cited text no. 27
    
28.
Cakmak NH, Yanardag R. Edaravone, a free radical scavenger, protects liver against valproic acid induced toxicity. J Serb Chem Soc 2015;80:627-37.  Back to cited text no. 28
    
29.
Lahneche AM, Boucheham R, Boubekri N, Bensaci S, Bicha S, Bentamenne A, et al. Sodium valproate-induced hepatic dysfunction in albino rats and protective role of n-butanol extract of centaurea sphaerocephala l. Int J Pharmacog Phytochem Res 2017;9:1335-43.  Back to cited text no. 29
    
30.
Gil DC, Rodriguez J, Ward B, Vertegel A, Ivanov V, Reukov V. Antioxidant activity of SOD and catalase conjugated with nanocrystalline. Bioengine 2017;4:18;1-9.  Back to cited text no. 30
    
31.
Abdel-Dayem MA, Elmarakby AA, Abdel-Aziz AA, Pye C, Said SA, El-Mowafy AM. Valproate induced liver injury: Modulation by the omega-3 fatty acid DHA proposes a novel anticonvulsant regimen. Drugs R D 2014;14:85-94.  Back to cited text no. 31
    
32.
Adikwu E, Bokolo B. Possible hepatotoxic consequence of nevirapine use in juvenile albino rats. J Pharm Pharm Res 2017;5:217-26.  Back to cited text no. 32
    
33.
Vidya M, Perumal S. Effects of ∝-ketoglutarate on antioxidants and lipid peroxidation products in rats treated with sodium valproate. J Appl Biomed 2006;4:141-46.  Back to cited text no. 33
    
34.
Khan SK, Shakoor KA, Jan MA, Khattak AM, Shah SH. Study of histopathological changes in the liver of albino rats, induced by toxic dose of Valproic acid. Gomal J Med Sci 2005;3:15-8.  Back to cited text no. 34
    
35.
Hamza AA, El Hodairy F, Badawi AM. Safranal ameliorates Sodium Valproate-induced liver toxicity in rats by targeting gene expression, oxidative stress and apoptosis. J Biomed Pharm Res 2015;4:46-60.  Back to cited text no. 35
    
36.
Pourahmad J, Eskandar MR, Kaghazi A, Shaki F, Shahraki J, Fard JK. A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membraneleakiness and cellular proteolysis. Toxicol In Vitro 2012;26:545-51.  Back to cited text no. 36
    
37.
Marnett LJ, Riggins JN, West JD. Endogenous generation of reactive oxidants and electrophiles and their reactions with DNA and protein. J Clin Invest 2003;111:583-93.  Back to cited text no. 37
    
38.
Ozardali I, Bitiren M, Karakilcik, AZ, Zerin M, Aksoy N, Musa D. Effects of selenium on histopathological and enzymatic changes in experimental liver injury of rats. Exp Toxicol Pathol 2004;56:59-64.  Back to cited text no. 38
    
39.
Messarah M, Klibet F, Boumendjel A, Abdennour C, Bouzerna N, Boulakoud MS, et al. Hepatoprotective role and antioxidant capacity of selenium on arsenic-induced liver injury in rats. Exp Toxicol Pathol 212;64:167-74.  Back to cited text no. 39
    
40.
Klotz LO, Kroncke KD, Buchczyk DP, Sies H. Role of copper, zinc, selenium, tellurium in the cellular defense against oxidative and nitrosative stress. J Nutr 2003;133:1448S-51S.  Back to cited text no. 40
    
41.
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals, antioxidants in oxidative stress-induced cancer. Chem Biol Interact 2006;160:1-40.  Back to cited text no. 41
    
42.
Seo YR, Sweeney C, Smith ML. Selenomethionine induction of DNA repair response in human fibroblasts. Oncogene 2002;21:3663-69.  Back to cited text no. 42
    


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