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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 5  |  Issue : 3  |  Page : 50-55

Protective activity of selenium against 5-fluorouracil-induced nephrotoxicity in rats


Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria

Date of Submission19-Aug-2019
Date of Acceptance17-Sep-2019
Date of Web Publication30-Sep-2019

Correspondence Address:
Dr. 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/ctm.ctm_26_19

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  Abstract 


Background: The nephrotoxic effect of 5-fluorouracil (5-FU) involves alterations in renal function markers and kidney morphology. This study assessed the protective effect of selenium (Se) on 5-FU-induced alterations in renal function markers and kidney morphology in albino rats.
Materials and Methods: Forty adult albino rats of (n = 5) used were randomly grouped. Groups B-D received 0.125 mg/kg, 0.25 mg/kg and 0.50 mg/kg of Se intraperitoneally (ip) daily for 5 days, respectively. Group E received 20 mg/kg of 5-FU ip daily for 5 days. Groups F-H received 0.125 mg/kg, 0.25 mg/kg, and 0.5 mg/kg of Se before receiving 20 mg/kg of 5-FU ip daily for 5 days, respectively. Group A (Control) received 0.2 mL of normal saline ip daily for 5 days. Rats were sacrificed on the 6th day, and blood samples were collected and evaluated for markers of serum renal function. Kidneys were assessed for oxidative stress indices and histology.
Results: The nephrotoxic effect of 5-FU was characterized by statistically significant (P < 0.001) elevations in creatinine, urea, uric acid, and malondialdehyde levels in comparison to control. Furthermore, significant (P < 0.001) decreases in potassium, sodium, chloride, bicarbonate, glutathione (GSH), catalase, superoxide dismutase, and GSH peroxidase levels were obtained in 5-FU-treated rats in comparison to control. Necroses of kidney tubular epithelial cells and atrophic glomeruli were observed in rats administered with 5-FU. However, 5-FU-induced nephrotoxic changes were significantly downregulated in a dose-dependent fashion in rats supplemented with 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) of Se when compared to 5-FU treated rats.
Conclusion: Supplementation with Se may have clinical benefit in nephrotoxicity caused by 5-FU.

Keywords: Key words: 5-fluorouracil, kidney, rats, selenium, toxicity


How to cite this article:
Adikwu E, Ebinyo NC, Amgbare BT. Protective activity of selenium against 5-fluorouracil-induced nephrotoxicity in rats. Cancer Transl Med 2019;5:50-5

How to cite this URL:
Adikwu E, Ebinyo NC, Amgbare BT. Protective activity of selenium against 5-fluorouracil-induced nephrotoxicity in rats. Cancer Transl Med [serial online] 2019 [cited 2019 Oct 23];5:50-5. Available from: http://www.cancertm.com/text.asp?2019/5/3/50/268230




  Introduction Top


Nephrotoxicity caused by chemotherapeutic agents remains a significant complication limiting their clinical uses.[1] A variety of renal disorders can result from the clinical use of anticancer agents in the fight against malignancies.[2] 5-fluorouracil (5-FU) is one of the anticancer agents that have been associated with renal dysfunction.[3] It is a pyrimidine-fluorinated analog, classified as an antimetabolic agent that inhibits the synthesis of both DNA and RNA in normal and tumor cells.[4] It nontargeted action has resulted in RNA and DNA damage and cell death in healthy cells leading to many adverse effects.[5] In particular, renal injury is a major challenge with the use of 5-FU marked by perturbations in serum renal markers. Furthermore, severe kidney morphological alterations such as tubular necrosis, renal lesions, and atrophy of glomeruli may occur.[6] Studies have reported decreases in kidney antioxidant activities, increases in lipid peroxidation (LPO) indexes and mediators of inflammation, suggesting central roles of oxidative stress (OS) and inflammation in renal injury caused by 5-FU.[6]

Selenium (Se) is of fundamental importance to human health. It is an essential component of several major metabolic pathways, including thyroid hormone metabolism, antioxidant defense systems, and immune function.[7] It is an important component of antioxidant enzymes, such as glutathione peroxidase (GPX), thioredoxin reductase (TrxR), and iodothyronine deiodinases.[8] GPX plays a significant role in protecting cells against oxidative damage from reactive oxygen species (ROS) and reactive nitrogen species.[9],[10] TrxR which has antioxidant activity uses Trx as a substrate to maintain a Trx/TrxR system in a reduced state for the removal of harmful hydrogen peroxide.[11] It has also prevented damage caused by the actions of LPO, probably by scavenging and neutralizing lipid radicals.[12] Furthermore, experiments in animal models have shown the ability of Se to prevent nephrotoxic insults caused by xenobiotics, leading to suggestions that Se supplementation and general antioxidant therapy may be imperative in renal dysfunction.[13] In addition, low serum levels of Se have been observed in acute renal injury and chronic kidney disease.[14] The present study assessed the protective effect of Se against renal injury caused by 5-FU in albino rats.


  Materials and Methods Top


Ethical approval

The Research Ethics Committee of Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria, approved this study. The protocol for the handling of experimental animals according to the guidelines of the Canadian Council on Animal Care was used for this study.

Experimental animals

Forty adult albino rats (200–250 g) used were obtained from the Animal Breeding Facility of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were housed in wide plastic cages (five per cage) at a temperature of 25 ± 2°C and a 12-h light/dark cycle with access to standard laboratory rodent chow and water ad libitum. The rats were acclimatized for 1 week prior to the beginning of the experiment.

Experimental design

The albino rats were randomly divided into eight groups of five rats per group:

  • Group A (Control) received 0.2 mL of normal saline intraperitoneally (ip) daily for 5 days
  • Groups B-D received 0.125 mg/kg, 0.25 mg/kg, and 0.50 mg/kg of Se[15] dissolved in normal saline ip daily for 5 days, respectively
  • Group E received 20 mg/kg of 5-FU dissolved in normal saline[16] ip daily for 5 days
  • Groups F-H received 0.125 mg/kg, 0.25 mg/kg, and 0.50 mg/kg of Se ip before treatment with 20 mg/kg of 5-FU ip daily for 5 days, respectively.


Collection of blood and tissue samples

At the end of treatment, rats in the control and experimental groups were fasted overnight and sacrificed under light ether anesthesia. Blood samples were collected via the heart, centrifuged at 1500 g for 14 min and serum samples were obtained and evaluated for biochemical indexes. Kidneys were dissected, washed with ice-cold physiological saline (0.9% NaCl) buffered, and homogenized. Homogenized samples were immediately centrifuged at 10,000 g for 15 min, and the supernatant fluids were collected and analyzed for OS indexes.

Biochemical assessment

Serum samples were evaluated for creatinine, urea, uric acid, total protein, bicarbonate and albumin using appropriate diagnostic kits according to the manufacturer's specification. Serum potassium and sodium were determined using flame photometric methods,[17] whereas serum chloride was determined using titrimetric method.[18] Kidney protein was evaluated as reported by Gornall et al., 1949,[19] whereas malondialdehyde (MDA) was assessed according to Buege and Aust, 1978.[20] Catalase (CAT) was evaluated according to the method of Aebi 1984,[21] whereas superoxide dismutase (SOD) was measured according to Sun and Zigma, 1978.[22] Glutathione (GSH) was measured as reported by Sedlak and Lindsay 1968,[23] whereas glutathione peroxidase (GPX) was evaluated as reported by Rotruck et al., 1973.[24]

Histological preparations

The kidneys of rats in the control and experimental groups were fixed in aqueous Bouin's fixative for 24 h. Kidney tissues were processed routinely, dehydrated in ascending series of ethyl alcohol, cleared in xylene an embedded in paraffin, and sectioned (5 μm). Sectioned tissues were stained with hematoxylin and eosin, The stained sections were examined using a light microscope and relevant sections photographed.

Statistical analysis

Differences between groups were compared using one-way analysis of variance followed by Duncan's multiple range test. Data were statistically analyzed using SPSS soft ware (version 16, SPSS Inc Chicago, IL, USA). Differences were considered statistically significant at P < 0.05; 0.01; 0.001.


  Results Top


Effects on renal function markers

[Figure 1], [Figure 2], [Figure 3] showed significant (P < 0.001) elevations in serum creatinine, urea, and uric acid levels in rats treated with 5-FU when compared to control. These elevations represent 250%, 300%, and 400% in serum creatinine, urea, and uric acid levels, respectively. However, the aforementioned parameters were decreased in a dose-dependent fashion in rats supplemented with 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) of Se, respectively, when compared to rats treated with 5-FU. In [Figure 4] and [Figure 5], rats treated with 5-FU showed decreases in serum levels of total protein and albumin which were significantly (P < 0.001) different when compared to control. However, notable and significant increases in the aforementioned parameters in a dose-dependent fashion were obtained in rats supplemented with 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) of Se, respectively, when compared to 5-FU. Furthermore, in comparison to control, significant low (P < 0.001) levels of serum K+, Na+, Cl+, and HCO3 were obtained in rats treated with 5-FU [Table 1]. However, significant (P < 0.001) increases in a dose-dependent fashion in serum K+, Na+, Cl+, and HCO3 levels were obtained in rats supplemented with 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) of Se, respectively, when compared to 5-FU [Table 1].
Figure 1. Effect of selenium on serum urea of 5-fluorouracil-treated albino rats. Se: Selenium, 5-FU: 5-Fluorouracil. n = 5, Data expressed as mean ± standard error of the mean, *Significant (P < 0.01) difference when compared to control, *Significant (P < 0.05) difference when compared to 5-FU, **Significant (P < 0.01) difference when compared to 5-FU, ***Significant (P < 0.001) difference when compared to 5-FU

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Figure 2. Effect of selenium on serum creatinine of 5-fluorouracil-treated albino rats. Se: Selenium, 5-FU: 5-Fluorouracil. n = 5, Data expressed as mean ± standard error of the mean, *Significant (P < 0.01) difference when compared to control, *Significant (P < 0.05) difference when compared to 5-FU, **Significant (P < 0.01) difference when compared to 5-FU, ***Significant (P < 0.001) difference when compared to 5-FU

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Figure 3. Effect of selenium on serum uric acid of 5-fluorouracil-treated albino rats. Se: Selenium, 5-FU: 5-Fluorouracil. n = 5, Data expressed as mean ± standard error of the mean, *Significant (P < 0.01) difference when compared to control, *Significant (P < 0.05) difference when compared to 5-FU, **Significant (P < 0.01) difference when compared to 5-FU, ***Significant (P < 0.001) difference when compared to 5-FU

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Figure 4. Effect of selenium on serum total protein of 5-fluorouracil-treated albino rats. Se: Selenium, 5-FU: 5-Fluorouracil. n = 5, Data expressed as mean ± standard error of the mean, *Significant (P < 0.01) difference when compared to control, *Significant (P < 0.05) difference when compared to 5-FU, **Significant (P < 0.01) difference when compared to 5-FU, ***Significant (P < 0.001) difference when compared to 5-FU

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Figure 5. Effect of selenium on serum albumin of 5-fluorouracil-treated albino rats. Se: Selenium, 5-FU: 5-Fluorouracil. n = 5, Data expressed as mean ± standard error of the mean, *Significant (P < 0.01) difference when compared to control, *Significant (P < 0.05) difference when compared to 5-FU, **Significant (P < 0.01) difference when compared to 5-FU, ***Significant (P < 0.001) difference when compared to 5-FU

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Table 1: Effects of selenium on serum electrolytes of 5-fluorouracil-treated albino rats

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Effects on kidney oxidative stress markers and histology

Results in [Table 2] showed that treatment with 5-FU significantly (P < 0.001) decreased kidney SOD, CAT, GSH, and GPX levels, whereas MDA levels were significantly (P < 0.001) increased when compared to control. In contrast, SOD, CAT, GSH, and GPX levels were significantly increased, whereas MDA levels were significantly decreased in a dose-dependent fashion in rats supplemented with 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) of Se, respectively, when compared to 5-FU. Furthermore, the kidney of control rat showed normal histology [Figure 6]a, whereas the kidney of rat treated with 5-FU showed tubular necrosis and atrophic glomerulus [Figure 6]b and [Figure 6]c. The kidney of rat supplemented with 0.125 mg/kg of Se showed atrophic glomerulus [Figure 6]d. However, the kidney of rat supplemented with 0.25 mg/kg of Se showed normal histology [Figure 6]e. Furthermore, the kidney of rat supplemented with 0.50 mg/kg of Se showed normal histology [Figure 6]f.
Table 2: Effect of selenium on kidney oxidative stress parameters of 5-fluorouracil-treated albino rats

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Figure 6. The micrographs of the kidneys of rats in the control and the experiment groups are represented above (a-f). (a): Control showing normal glomerulus (NG) and normal renal tubules (RT) (b and c): Rat treated with 20 mg/kg of 5-fluorouracil showing atrophic glomerulus (AG), widen Bowman's space (BW), and tubular necrosis (TN). (d): Rat treated with 0.125 mg/kg of selenium +20 mg/kg of 5-fluorouracil showing atrophic glomerulus (AG). (e): Rat treated with 0.25 mg/kg of selenium +20 mg/kg of 5-fluorouracil showing normal glomerulus (NG). (f): Rats treated with 0.5 mg/kg of selenium +20 mg/kg of 5-fluorouracil showing normal glomerulus (NG)

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  Discussion Top


5-FU is a potent antineoplastic agent widely used for the treatment of various malignancies because of its broad antitumor activity and synergistic action with other anticancer drugs. However, its clinical use has been limited by nephrotoxicity which may involve OS.[25] In recent years, research on Se has attracted tremendous interest because of its important antioxidant activity which offers protection against OS induced by excess ROS.[26] In an attempt to surmount the nephrotoxic challenge associated with 5-FU, this study examined the potential protective benefit that could be derived from Se against a rat model of 5-FU-induced nephrotoxicity. This study observed normal levels of serum renal function markers in Se-treated rats. In contrast, impaired renal function characterized by elevated serum creatinine urea and uric acid levels occurred in rats administered with 5-FU. This is an evidence of the incapacitation of renal function caused by 5-FU which is consistent with earlier reports.[27] Furthermore, the nephrotoxic effect of 5-FU observed in this study was characterized by impairment in the regulatory ability of the kidney on serum total protein, albumin, K+, Na+, Cl+, and HCO3-leading to their low serum levels. This is probably due to increased renal wastage of the aforementioned parameters through the urine or decreases in the syntheses of protein and albumin. This observation has been reported previously as a cardinal feature of the nephrotoxic effect of 5-FU.[28] Interestingly, supplementation with Se prior to treatment with 5-FU showed marked improvement in renal function in a dose-dependent fashion. This was characterized by normal levels of the aforementioned serum renal function markers. In addition to alterations in serum renal function markers, kidney redox status was also impaired in rats treated with 5-FU. This finding was evidenced by decreases in kidney SOD, CAT, GSH, and GPX levels with increases in MDA levels. This observation is a sign of OS which is in agreement with previous studies.[29] The impaired redox status will reduce the ability of the kidney to scavenge and neutralize free radicals, especially ROS predisposing it to various forms of assaults by OS. However, kidney redox status was restored in a dose-dependent fashion in rats supplemented with Se prior to treatment with 5-FU as evidenced by increases in kidney SOD, CAT, GSH, and GPX levels with decreases in MDA levels. This study further assessed the nephrotoxic effect of 5-FU by evaluating its impact on kidney morphology. The current study observed morphological aberrations characterized by tubular necroses and atrophy of glomeruli in the kidneys of rats treated with 5-FU which parallel changes in serum renal function markers. This observation is a cardinal mark of renal damage that is consistent with previous findings.[30] Nonetheless, supplementation with Se prior to treatment with 5-FU restore kidney structure in a dose-dependent fashion. The exact mechanism by which 5FU causes renal toxicity is still been evaluated, but some studies suggest the involvement of OS via the excessive production of free radicals, especially ROS.[31] The place of OS in renal toxicity caused by 5-FU is supported by decreases in antioxidants and increase in LPO index observed in this study. OS can stimulate LPO and cause damage to lipids, proteins, and DNA in the kidney. LPO can alter lipid–lipid interactions, ion gradients, membrane fluidity, and membrane permeability in the kidney.[32] Furthermore, some studies reported increased expression of pro-inflammatory mediators and enhanced renal apoptosis as possible mechanisms involved in renal toxicity caused by 5-FU.[33] This study showed the ability of Se to abrogate the nephrotoxic effect of 5-FU in a dose-dependent fashion. This observation can be correlated with the protective effect of Se against cadmium-induced nephrotoxicity in rats reported by some authors.[34] The mechanism by which Se protected against the nephrotoxic effect of 5-FU may not be far from its antioxidant effect and ability to upregulate endogenous antioxidant function. Its ability to upregulate other antioxidant function correlates with increases in kidney activities of SOD, CAT, GSH, and GPX observed in this study. This might have increased the antioxidant defense capacity of the kidney, thereby preventing damage caused by free radicals regenerated by 5-FU. Se functions as a cofactor for enzymes such as GPX and TXR that remove ROS and enhance antioxidant functions.[35] One of the primary functions of GPX is the enzymatic reduction of hydrogen peroxide to water, thereby preventing accumulation and reducing its detrimental effect.[36] TXR is an element of the thioredoxin system that protects against OS through its disulfide reductase activity regulating protein dithiol/disulfide balance. In addition, thioredoxin system provides electrons to thiol-dependent peroxidases to remove free radicals and is involved in the repair of DNA and proteins.[37] Se can maintain intracellular redox status and as a result sustain normal physiological processes in cells.[38]


  Conclusion Top


Se may provide clinical benefit in renal toxicity caused by 5-FU.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1], [Table 2]



 

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