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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 2  |  Page : 72-77

Therapeutic benefit of resveratrol in 5-fluorouracil-induced nephrotoxicity in rats


1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria
2 Department of Biomedical Technology, School of Science Laboratory Technology, University of Port Harcourt, Rivers State, Nigeria

Date of Submission14-Aug-2019
Date of Decision07-Oct-2019
Date of Acceptance15-Oct-2019
Date of Web Publication22-Nov-2019

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


DOI: 10.4103/BMRJ.BMRJ_19_19

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  Abstract 


Background: The prevention of nephrotoxicity caused by 5-fluorouracil (5-FU) can improve patients' adherence to treatment.Aim and Objective: This study assessed the ability of resveratrol (RES) to prevent 5-FU-induced nephrotoxicity in rats. Materials and Methods: Forty adult male albino rats randomized into eight groups of n = 5 were used. Group A (control) was administered with 0.2 mL of normal saline intraperitoneally (i.p.), whereas Groups B-D were administered with 10, 20, and 40 mg/kg of RES daily for 5 days respectively. Group E was administered with 20 mg/kg of 5-FU ip daily for 5 days. Groups F-H were administered with 10 mg/kg of RES + 20 mg/kg of 5-FU, 20 mg/kg of RES + 20 mg/kg of 5-FU, and 40 mg/kg of RES + 20 mg/kg of 5-FU ip daily for 5 days, respectively. Blood samples were collected after rats were sacrificed and evaluated for serum renal function biomarkers. Kidneys were evaluated for oxidative stress markers and histology. Results: Serum creatinine, urea, and uric acid levels were significantly (P < 0.001) increased, whereas total protein, albumin, potassium, sodium, chloride, and bicarbonate levels were significantly (P < 0.001) decreased in 5-FU-treated rats when compared to control. Kidney superoxide dismutase, glutathione, glutathione peroxidase, and catalase levels were significantly (P < 0.001) decreased, whereas malondialdehyde levels were significantly increased in 5-FU-treated rats when compared to control. Furthermore, the kidneys of 5-FU-treated rats showed tubular necroses and atrophic glomeruli. The aforementioned nephrotoxic changes were significantly abrogated in rats supplemented with 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) of RES when compared to 5-FU. Conclusion: RES may have therapeutic benefit in nephrotoxicity caused by 5-FU.

Keywords: 5-fluorourcil, antioxidant, kidney, rat, toxicity


How to cite this article:
Adikwu E, Biradee I, Ogungbaike TO. Therapeutic benefit of resveratrol in 5-fluorouracil-induced nephrotoxicity in rats. Biomed Res J 2019;6:72-7

How to cite this URL:
Adikwu E, Biradee I, Ogungbaike TO. Therapeutic benefit of resveratrol in 5-fluorouracil-induced nephrotoxicity in rats. Biomed Res J [serial online] 2019 [cited 2019 Dec 16];6:72-7. Available from: http://www.brjnmims.org/text.asp?2019/6/2/72/271483




  Introduction Top


5-fluorouracil (5-FU) is a pyrimidine fluorinated analog that is classified as an antimetabolite. It is widely used for the chemotherapeutic treatment of hepatocellular carcinoma. It also has activity against many solid tumors, including breast, stomach, pancreas, esophagus, liver, head, neck and colorectal cancers.[1] 5-FU acts via the incorporation of its metabolites into RNA and DNA, thereby inhibiting thymidylate synthase. Consequently, it causes DNA damage, cell cycle termination, apoptosis, and necrosis of cancer cells.[2] The extended activity of 5-FU on RNA and DNA in normal rapidly dividing cells causing cell damage and death has been associated with its numerous toxic effects.[3] Nephrotoxicity is one of the most disturbing adverse consequences of therapy with 5-FU characterized by arrays of features which include kidney histological changes such as glomerular and tubular degeneration.[4] It is also associated with changes in serum renal biomarkers including electrolytes and acid–base balance and alteration in glomerular filtration rate.[4] Its nephrotoxic effect has been associated with its catalyzed product dihydrouracil which is cleaved to α-fluoro-β-alanine and other by-products in the liver which are injurious to the kidney. In addition, its nephrotoxic effect may involve oxidative stress (OS) through free radical production, inflammation, and the stimulation of apoptic pathways in renal tissues.[5]

Resveratrol (RES) is a polyphenolic compound distributed in particular families of plants including Vitaceae, Dipterocarpaceae, Gnetaceae, Cyperaceae, and Leguminosae, which includes both edible and nonedible plants. It has recently attracted lots of research attentions from pharmaceutical industries, cosmetics and food additive companies due to its exciting pharmacological activities.[6] It has antioxidant activity which occurs through the scavenging and neutralization of free radicals [7] and can increase the expression of enzymes such as superoxide dismutase (SOD) and catalase (CAT) responsible for maintaining oxidation–reduction balance in cells. It can inhibit lipid peroxidation (LPO) by removing lipid peroxides produced in membranes, thereby abrogating the harmful activity of lipid peroxide on biomolecules.[8] RES acts as an anti-inflammatory agent by reducing cyclooxygenase 1 enzyme (COX-1). COX-1 catalyzes the first step in the synthesis of prostaglandins which can culminate in reactions facilitating the production of free radicals.[9] Furthermore, it can inhibit the activity of pro-inflammatory cytokines thereby preventing inflammation-mediated damage. RES interacts with a large number of receptors, kinases, and other enzymes that could possibly make major contributions to its biological effects.[10] It has shown potential in the treatment of neurodegenerative diseases, diabetes, cancer, and hypertension in animal models.[11],[12] In addition, it has shown protective benefits against a number of renal injuries caused by toxic insults in animal models.[13] This study was designed to assess the protective activity of RES against the nephrotoxic effect of 5-FU in a rat model.


  Drugs, and Animals Top


5-FU injection used was manufactured by Biochem Pharmaceutical Industries Ltd, Mumbai, Maharashtra, India, whereas RES was manufactured by Swanson Health Products, Fargo, USA. Forty adult male albino rats (200–250 g) used were purchased from the animal breeding facility of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were housed in cages under controlled temperature (26°C ± 2°C) and light cycle (12 h dark/light) and had free access to food and water ad libitum. The rats were preconditioned for 1 week prior to implementing the treatment protocol. Approval was obtained from the Research Ethics Committee of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria.

Experimental design

Forty adult male albino rats used were divided into eight groups (A–H). Each group contained five rats each. Rats in group A which served as control were administered daily with normal saline (0.2 mL) intraperitoneally (ip), whereas rats in groups B to D were administered daily with 10 mg/kg, 20 mg/kg, and 40 mg/kg of RES i.p. for 5 days, respectively.[14] Rats in group E were administered daily with 20 mg/kg of 5-FU i.p. for 5 days.[15] Rats in groups F to H were administered daily with RES 10 mg/kg + 5-FU 20 mg/kg, RES 20 mg/kg + 5-FU 20 mg/kg, and RES 40 mg/kg + 5-FU 20 mg/kg i.p. for 5 days, respectively. On the 6th day, rats in all groups were sacrificed.

Biochemical analyses

Blood samples were collected from the heart under anesthesia and were centrifuged at 2000 g for 15 min, and serum samples were extracted. Serum samples were evaluated for urea, creatinine, uric acid, total protein, and albumin levels using commercial test kits (Randox Laboratories Ltd., Crumlin, UK). Serum potassium (K) and sodium (Na) were determined using flame photometric methods whereas serum chloride (Cl) and bicarbonate (HCO3) were determined using titrimetric methods. The Kidneys samples were excised and rinsed in ice cold buffered 1.15% w/v KCl solution. Kidneys were homogenized and centrifuged (2000 g for 15 min). The supernatants were decanted and evaluated for OS markers. Kidney malondialdehyde (MDA) was evaluated according to Buege and Aust,[16] whereas glutathione peroxidase (GPX) was evaluated as reported by Rotruck et al. 1973.[17] Glutathione (GSH) was assessed using the method of Sedlak and Lindsay, 1968,[18] whereas CAT was evaluated as reported by Aebi, 1984.[19] SOD was assayed according to the method of Sun and Zigman, 1978.[20]

Histological examination of the kidney

Kidney sections were fixed in 10% formal saline for 24 hours. Fixed specimens were dehydrated in ascending alcohol solutions then cleared in xylene and embedded in paraffin blocks. The processed kidney tissues were sectioned (5 μm) with the aid of a microtome and stained with hemotoxylin-eosin and were evaluated for pathological changes with the aid of a light microscope.

Statistical analysis

The values are represented as mean ± standard error of mean (SEM). The statistical analysis was performed using one-way analysis of variance followed by Tukey's multiple comparison test using GraphPad Prism 5.0 software (GraphPad Software Inc, La Jolla, CA, USA). P < 0.05, <0.01, and < 0.001 were considered statistically significant.


  Results Top


Effect on serum renal function parameters

Serum creatinine, urea, uric acid, albumin, and total protein levels were normal (P > 0.05) in rats treated with RES when compared to control. However, serum creatinine, urea, and uric acid levels were significantly (P < 0.001) increased, whereas serum albumin and total protein were significantly (P < 0.001) decreased in rats treated with 5-FU when compared to control [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]. On the other hand, supplementation with RES significantly decreased serum creatinine, urea, and uric acid levels, whereas serum albumin and total protein levels were significantly increased in a dose-dependent fashion at 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to rats treated with 5-FU [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]. Furthermore, serum K +, Na +, Cl , and HCO3 − levels were normal (P > 0.05) in rats treated with RES, but were significantly (P < 0.001) decreased in rats treated with 5-FU when compared to control [Table 1]. In contrast, serum K +, Na, Cl , and HCO3 − levels were significantly increased in a dose-dependent fashion in RES-supplemented rats at 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to rats treated with 5-FU [Table 1].
Figure 1: Effect of resveratrol on serum urea of 5-flourouracil-treated albino rats RES: Resveratrol, 5-FU: 5-Fluorouracil, Data expressed as mean ± standard error of mean, *Significant (P < 0.001) 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 resveratrol on serum creatinine of 5-flourouracil-treated albino rats RES: Resveratrol, 5-FU: 5-Fluorouraci, Data expressed as mean ± standard error of mean, *Significant (P < 0.001) difference when compared to control, *Significant (P < 0.05) ifference 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 resveratrol on serum uric acid of 5-flourouracil-treated albino rats RES: Resveratrol, 5-FU: 5-Fluorouracil, Data expressed as mean ± standard error of mean, *Significant (P < 0.001) 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 resveratrol on serum total protein of 5-flourouracil-treated albino rats RES: Resveratrol, 5-FU: 5-Fluorouracil, Data expressed as mean ± standard error of mean, *Significant (P < 0.001) 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 resveratrol on serum albumin of 5-flourouracil-treated albino rats RES: Resveratrol, 5FU: 5-Fluorouracil, Data expressed as mean ± standard error of mean, *Significant (P < 0.001) difference when compared to control, *Significant (P < 0.05) difference when compared to 5-FU ** Significant (P < 0.01) difference when compared to5-FU, *** Significant (P < 0.001) difference when compared to 5-FU

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Table 1: Effect of resveratrol on serum electrolytes of 5-fluorouracil-treated albino rats

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Effects on kidney oxidative stress indices and histology

Kidney SOD, CAT, GSH, GPX, and MDA levels were normal (P > 0.05) in rats treated with RES when compared to control. In contrast, kidney SOD, CAT, GSH, and GPX levels were significantly (P < 0.001) decreased, whereas MDA levels were significantly (P < 0.001) increased in rats treated with 5-FU when compared to control [Table 2]. However, supplementation with RES significantly increased kidney SOD, CAT, GSH, and GPX levels, whereas MDA levels were significantly decreased at 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to rats treated with 5-FU. Furthermore, normal kidney histology was observed in control rat, but tubular necrosis, enlarged Bowman's space, shrunken and atrophic glomerulus were observed in the kidney of rat treated with 5-FU [Figure 6]a, [Figure 6]b, [Figure 6]c. On the other hand, the kidney of rat supplemented with 10 mg/kg of RES showed atrophic glomerulus [Figure 6]d In addition, the kidneys of rats supplemented with 20 mg/kg of RES [Figure 6]e showed atrophic glomerulus whereas 40mg/kg of RES [Figure 6]f showed normal glomerulus respectively.
Table 2: Effect of resveratrol on kidney oxidative stress indices of 5-fluorouracil-treated albino rats

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Figure 6: (a) Kidney of control rat showing normal glomerulus (NG). (b) Kidney of rat treated with 20 mg/kg of 5-fluorouracil showing atrophic glomerulus (AG), shrunken glomerulus (SG) and enlarged bowman's space (BS). (c) Kidney of rat treated with 20 mg/kg of 5-fluorouracil showing tubular necrosis (TN). (d) Kidney of rat treated with 10 mg/kg of resveratrol + 20 mg/kg of 5-fluorouracil showing atrophic glomerulus (AG). (e) Kidney of rat treated with with 20 mg/kg of resveratrol + 20 mg/kg of 5-fluorouracil showing atrophic glomerulus (AG). (f) Kidney of rat treated with 40 mg/kg of resveratrol + 20 mg/kg of 5-fluorouracil showing normal glomerulus (NG) (400×)

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  Discussion Top


The increasing need to alleviate or prevent suffering that may arise from the nephrotoxic effect of 5-FU is imperative so as to sustain its use in cancer treatment and to facilitate patients' adherence. This study assessed the ability of RES to prevent nephrotoxicity in a rat model treated with 5-FU. Serum creatinine and uric acid levels are the most predisposed markers reflecting the appropriate function of the kidney.[21] The current study observed normal kidney function in RES-treated rats characterized by normal serum levels of creatinine, urea, uric acid, total protein, and albumin. However, the regulatory effect of the kidney on the aforementioned parameters was incapacitated in rats treated with 5-FU, which was characterized by elevated serum levels of creatinine, urea, and uric acid with decreased levels of total protein and albumin. The observed alterations in the aforementioned parameters in rats treated with 5-FU correlate with those of previous reports.[22] However, improvement in the functional capacity of the kidney was observed in rats supplemented with RES as shown by decreased levels of serum creatinine, urea, and uric acid with increased total protein and albumin in a dose-dependent fashion. Aberration in serum electrolytes is one of the cardinal marks of the nephrotoxic effect of 5-FU.[22] The regulatory effect of the kidney on serum electrolytes was normal in RES-treated rats due to normal serum levels of K +, Na +, Cl , and HCO3. In contrast, the ability of the kidney to regulate serum electrolytes was impaired in rats treated with 5-FU as evidenced by the decreased levels of K +, Na +, Cl , and HCO3. However, serum electrolytes were restored in a dose-dependent fashion in rats supplemented with RES.

Antioxidants which include GSH, SOD, CAT, and GPX abrogate the destructive effects of OS by terminating the excess activities of free radicals, especially reactive oxygen species (ROS). Excess and unregulated activities of free radicals can incapacitate antioxidant functions culminating in OS, stimulating apoptic pathways and cell death. Therefore, low antioxidant activity is often correlated with OS activity.[23] The present study observed OS in the kidneys of rats treated with 5-FU as evidenced by decreased GSH, SOD, CAT, and GPX levels. However, the levels of GSH, SOD, CAT, and GPX were upregulated in a dose-dependent fashion in RES-supplemented rats. ROS can oxidize various biomolecules, such as nucleic acids, proteins, and lipids, causing morphological and functional changes in these molecules. Lipid peroxidation (LPO) produces hydroperoxides which leads to the production of a broad range of reactive intermediates including MDA. Therefore, elevated MDA level is used in experimental settings to establish the occurrence of LPO and also, as a measure of antioxidant status.[24],[25] The present study observed increased MDA level in the kidney of rats treated with 5-FU. This observation is consistent with previous studies.[26] However, MDA levels were decreased in a dose-dependent fashion in rats supplemented with RES.

Furthermore, in addition to alterations in serum renal function biomarkers, aberrations in kidney morphology such as tubular necrosis and atrophy of glomerulus may occur as a result of the nephrotoxic effect of 5-FU.[27] The current study observed tubular necrosis, enlarged Bowman's space, shrunken and atrophic glomerulus in rats treated with 5-FU. However, the aforementioned nephrotoxic changes were abrogated in rats supplemented with RES. The observation in this study showed the ability of RES to restore the structural and functional activities of the kidneys of rats treated with 5-FU. The exact mechanism by which 5-FU induces nephrotoxicity is not clear, but it was reported that 5-FU is catabolized to dihydrouracil in the liver which is cleaved to fluoro-β-alanine and other products that are injurious to the kidney.[28] Furthermore, one possible mechanism postulated by many investigators is free radical production which induces OS-causing damage to cell membrane components. Also, free radical production can activate lysosomal enzymes, and cause cell apoptosis.[29] The involvement of OS as an essential step in the cascade of processes associated with the nephrotoxic effect of 5-FU is supported by the downregulation of the activities of SOD, CAT, GSH, and GPX observed in this study. Furthermore, LPO may be an essential process in the nephrotoxic effect of 5-FU due to elevated level of LPO index (MDA) observed in this study. Inflammation may play a significant role in the pathogenesis of 5-FU-induced nephrotoxicity because animal models have shown evidence of increased activities of pro-inflammatory mediators such as tumour necrosis factor alpha (TNF-α), interleukin-1β (IL-1β)and interleukin-6 (IL-6) in the organs of rats treated with 5-FU.[30] Inflammation and OS are inextricably associated as one starts and amplifies the other. OS can cause inflammation through the activation of nuclear factor kappa B (NF-k B) which is required for the production of pro-inflammatory chemokines and cytokines. The production of the aforementioned mediators can stimulate macrophage/leukocyte production, infiltration, and the generation of ROS, which in turn triggers OS.[31]

In this study, the protection against 5-FU-induced nephrotoxicity by RES can be due to its ability to inhibit free radical production and enhance antioxidant activity thereby preventing OS. RES is a very effective scavenger of free radicals as well as secondary organic radicals formed as a result of the reaction of biomolecules with free radicals. It can also reduce the activity of enzymes which play dominant roles in the production of free radicals.[32] RES can increase the expression of enzymes such as SOD, CAT, and GPX responsible for maintaining oxidation–reduction balance in cells.[33] Furthermore, RES can inhibit the production of pro-inflammatory cytokines such as TNF-α and IL-6.[34]


  Conclusion Top


RES may have essential therapeutic role in preventing nephrotoxicity caused by 5-FU.

Acknowledgments

The authors are grateful to Dr. Yibala Obuma of the Department of Medical Laboratory Sciences, Faculty of Basic Medical Sciences, Niger Delta University, Nigeria for histological assessment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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