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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 1  |  Page : 3-8

5-Fluorouracil-Induced hepatic perturbation: Protective potential of selenium


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

Date of Submission05-Jun-2019
Date of Decision07-Aug-2019
Date of Acceptance07-Apr-2020
Date of Web Publication30-Jun-2020

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


DOI: 10.4103/JIHS.JIHS_30_19

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  Abstract 


Background: Hepatotoxicity is a serious adverse effect that has characterized the therapeutic use of 5-fluorouracil (5-FU). Selenium (Se) has shown potential therapeutic benefits in animal models of some diseases. Aim: This study assessed the ability of Se to protect against hepatotoxicity induced by 5-FU in albino rats. Materials and Methods: Adult male albino rats (n = 40) were grouped and used. Group A (Control) was treated with normal saline (0.2 mL) intraperitoneally (i. p.) daily for 5 days. Group B (B1–B3) was treated with Se (0.125, 0.25, and 0.50 mg/kg i. p.) daily for 5 days, respectively. Group C was treated with 5-FU (20 mg/kg i. p.) daily for 5 days. Group D (D1–D3) was supplemented with Se (0.125, 0.25, and 0.50 mg/kg i. p) before treatment with 5-FU (20 mg/kg i. p.) daily for 5 days, respectively. After treatment, the rats were anesthetized; blood samples were collected for serum biochemical assessments. Liver was evaluated for biochemical parameters and histology. Results: Liver and serum aminotransferases, gamma-glutamyl transferase, lactate dehydrogenase, alkaline phosphatase, total bilirubin, and conjugated bilirubin levels were significantly (P < 0.001) increased in 5-FU-treated rats when compared to control. Liver glutathione peroxidase, superoxide dismutase, catalase, and glutathione levels were significantly (P < 0.001) decreased, whereas malondialdehyde levels were significantly (P < 0.001) increased in 5-FU-treated rats when compared to control. Hepatocyte necrosis occurred in 5-FU-treated rats. Nonetheless, 5-FU-induced alterations were significantly abrogated in a dose-dependent fashion in rats supplemented with Se 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) when compared to 5-FU-treated rats. Conclusion: Se may be effective against hepatotoxicity caused by 5-FU.

Keywords: 5-Fluorouracil, antioxidant, hepatocyte, rat, selenium, toxicity


How to cite this article:
Adikwu E, Ebinyo NC, Odira AF. 5-Fluorouracil-Induced hepatic perturbation: Protective potential of selenium. J Integr Health Sci 2020;8:3-8

How to cite this URL:
Adikwu E, Ebinyo NC, Odira AF. 5-Fluorouracil-Induced hepatic perturbation: Protective potential of selenium. J Integr Health Sci [serial online] 2020 [cited 2020 Oct 21];8:3-8. Available from: https://www.jihs.in/text.asp?2020/8/1/3/288688




  Introduction Top


Hepatotoxicity is a serious adverse consequence associated with the use of some anticancer agents. In clinical practice, liver toxicity associated with anticancer drugs can manifest in diverse pathological forms specific to the causative agent. This phenomenon can culminate in treatment modification such as dose reduction, complete drug withdrawal, or postponement of therapy schedule which may jeopardize therapeutic outcomes and consequently patients' survival. Severe cases of liver toxicity associated with anticancer agents have caused hepatic failure and death.[1] The mechanisms for the induction of hepatotoxicity by anticancer drugs are not clear, but hepatocyte injury may arise either directly as a result of the interference of drugs with intracellular function and membrane integrity or indirectly as a result of immune-mediated membrane damage.[2]

The clinical use of 5-fluorouracil (5-FU) in cancer chemotherapy has reduced mortality associated with various forms of cancer such as breast, gastric, colorectal, neck, and head cancers.[3] The anticancer activity of 5-FU has been attributed to its inhibitory effect on DNA and RNA syntheses in cancer cells.[4] A notable curative outcome has been achieved in the fight against cancer with 5-FU; however, its maximum therapeutic benefit could be jeopardized due to the frequent occurrence of hepatotoxicity in clinical practice. Hepatotoxic features including alterations in hepatocyte structure and mild or severe elevations in serum hepatic markers have been associated with 5-FU.[4] In addition, studies involving animal models have suggested that oxidative stress (OS), inflammation, and cell apoptosis are possible mechanisms of 5-FU-induced hepatotoxicity.[5]

Selenium (Se), an essential mineral, is a necessary trace element in the human body and is indispensable for maintaining normal metabolic function. It is incorporated in selenoproteins involved in the syntheses of diverse selenoenzymes such as glutathione peroxidase (GPx), thioredoxin reductases, and iodothyronine deiodinases which play important biological functions. Se performs multiphysiological functions including antioxidant activity, maintenance of immune-endocrine function, metabolic cycling, and cellular homeostasis.[6],[7] The regulatory activity of Se on the immune system may involve mechanisms such as increased T-lymphocytes proliferation, upregulation of natural killer cell activity, increased interferon-γ production, and increased antibody-producing B-cell function.[8] Furthermore, due to the involvement of Se in numerous biological functions, Se deficiency can lower the overall health status as a result of increased vulnerability to infectious diseases and can impair reproductive function.[9] In addition to its effects on physiological functions, Se supplementation has been beneficial in animal models of diseases such as hyperlipidemia, diabetes, arteriosclerosis, and hyperphenylalaninemia.[8] Se supplementations have been shown to protect against toxicities associated with drugs, heavy metals, and pesticide in animal models.[10] However, there is absolutely no study on the protective effect of Se on animal models of hepatotoxicity induced by 5-FU. The current study evaluated the ability of Se to safeguard against hepatotoxicity induced by5-FU in albino rats.


  Materials and Methods Top


Animal handling

This study was approved by the Research Ethics Committee of Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were handled according to the guidelines of the Canadian Council on Animal Care. Forty adult male albino rats (220–250 g) kept 5 per cage were used. The rats were housed in the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were kept at a standard temperature of 25°C ± 2°C and 12/12 h light-dark cycle during the experiment. The rats were fed with rat chow and were allowed to acclimatize for 2 weeks.

Animal treatment, sacrifice, and biochemical analyses

Group (A) was treated intraperitoneally (i. p.) with normal saline (0.2 mL) daily for 5 days. Group B (B1–B4) was treated with Se (0.125, 0.25, and 0.50 mg/kg i. p.) daily for 5 days, respectively.[11] Group C was treated with 5-FU (20 mg/kg i. p.) daily [12] for 5 days. Group D (D1–D3) was supplemented with Se (0.125, 0.25, and 0.50 mg/kg i. p.) before treatment with 5-FU (20 mg/kg i. p.) daily for 5 days respectively. On day 6, the rats were anesthetized with diethyl ether; blood samples were collected directly from the heart in sample containers and were allowed to clot at room temperature. Serum samples were removed by centrifugation at 3000 g for 15 min and were analyzed for biochemical parameters. The rats were dissected, and liver samples were collected and washed in cold saline and homogenized in buffered (pH: 7.4) 0.1 M Tris-HCl solution. The homogenates were centrifuged at 2000 g for 15 min, and the supernatants were collected and evaluated for biochemical indices. Serum and liver gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), conjugated bilirubin (CB), alkaline phosphatase (ALP), aspartate aminotransferase (AST), total bilirubin (TB), and alanine aminotransferase (ALT) were analyzed using standard test kits according to manufacturers protocol. Liver protein was assessed according to Gornall et al. 1949,[13] whereas catalase (CAT) was assessed according to the method of Aebi, 1984.[14] Glutathione (GSH) was analyzed using the method of Sedlak and Lindsay 1968,[15] whereas superoxide dismutase (SOD) was assayed as reported by Sun and Zigman, 1978.[16] GPx was evaluated using the method of Rotruck et al., 1973,[17] whereas malondialdehyde (MDA) was assayed using the method of Buege and Aust, 1978.[18]

Histological analysis

Liver samples were fixed in 10% buffered formalin for 24 h after which samples were dehydrated in graded concentrations of alcohol. Liver tissues were processed and embedded in paraffin, and 4 μm sections were cut and deparaffinized and fixed on slides. The fixed tissues were stained with hematoxylin and eosin and examined under a light microscope for pathology.

Statistical analysis

The results are expressed as mean ± standard error of the mean of n = 5. Differences among groups were evaluated using one-way analysis of variance (ANOVA) followed by Duncan's multiple range test. Graph Pad Prism (Version 5.0, Graph Pad Software Inc., La Jolla, California, U.S.A.) was used for the statistical analysis. P < 0.05, <0.01, and <0.001 was considered statistically significant.


  Results Top


Effects of selenium on liver tissue and serum biochemical parameters of 5-fluorouracil-treated rats

The serum and liver levels of CB, TB, GGT, AST, ALT, ALP, and LDH were normal (P > 0.05) in rats treated with Se when compared to control. In contrast, elevated (P < 0.001) levels of CB, TB, GGT, AST, ALT, ALP, and LDH were observed in 5-FU-treated rats [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] and [Table 1]. However, the above hepatic biochemical markers were decreased in a dose-dependent fashion in rats supplemented with Se 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) in relation to rats treated with 5-FU [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] and [Table 1].
Figure 1: Effect of selenium on serum aspartate aminotransferase of 5-fluorouracil-treated albino rats. AST: Aspartate aminotransferase, Se: Selenium, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Figure 2: Effect of selenium on serum alanine aminotransferase of 5- fluorouracil-treated albino rats. ALT: Alanine aminotransferase, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Figure 3: Effect of selenium on serum alkaline phosphatase of 5-fluorouracil-treated albino rats. ALP: Alkaline phosphatase, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Figure 4: Effect of selenium on gamma-glutamyl transferase of 5-fluorouracil-treated albino rats. GGT: Gamma-glutamyl transferase, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Figure 5: Effect of selenium on lactate dehydrogenase of 5-fluorouracil-treated albino rats. LDH: Lactate dehydrogenase, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Figure 6: Effect of selenium on total bilirubin of 5-fluorouracil-treated albino rats. TB: Total bilirubin, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Figure 7: Effect of selenium on conjugated bilirubin of 5-fluorouracil-treated albino rats CB: Conjugated bilirubin, 5-FU: 5-fluorouracil, n = 5, Data expressed as mean ± standard error of the mean, *P < 0.001 when compared to control, *P < 0.05 when compared to 5-FU, **P < 0.01 when compared to 5-FU, ***P < 0.001 when compared to 5-FU

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Table 1: Effect of selenium on liver biochemical parameters of 5-fluorouracil-treated rats

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Effects of selenium on oxidative stress markers and liver histology of 5-fluorouracil-treated rats

Furthermore, the liver levels of GPx, SOD, GSH, CAT, and MDA were normal (P > 0.05) in rats treated with Se when compared to control [Table 2]. On the contrary, liver GPx, SOD, GSH, and CAT levels were significantly (P < 0.001) decreased, whereas MDA levels were significantly (P < 0.001) increased in rats treated with 5-FU in relation to control [Table 2]. However, liver GPx, SOD, GSH, and CAT levels were increased, whereas MDA levels were decreased in a dose-dependent fashion in rats supplemented with Se 0.125 mg/kg (P < 0.05), 0.25 mg/kg (P < 0.01), and 0.50 mg/kg (P < 0.001) in relation to rats treated with 5-FU [Table 2]. Normal hepatocytes were observed in the liver of control rats, whereas hepatocyte necroses were observed in the liver of rats treated with 5-FU, respectively [Figure 8]a and [Figure 8]b. However, the liver of rats supplemented with Se (0.125 mg/kg) showed inflammatory cell infiltration [Figure 8]c. On the other hand, the liver of rats supplemented with Se 0.25 mg/kg [Figure 8]d and Se 0.50 mg/kg [Figure 8]e showed normal hepatocytes, respectively.
Table 2: Effects of selenium on liver oxidative stress markers parameters of 5-fluorouracil-treated rats

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Figure 8: Above are the photomicrographs (a-e) of the liver of rats in the control and the experimental groups. (a) Liver of rat in the control group showing normal hepatocytes (TC). (b) Liver of rat treated with 5-FU (20 mg/kg) showing hepatocyte necrosis (NH). (c) Liver of rat supplemented with selenium (0.125 mg/kg) showing inflammatory cell infiltration (IF). (d) Liver of rat supplemented with selenium (0.25 mg/kg) showing normal hepatocytes (TC). (e) Liver of rat supplemented with selenium (0.50 mg/kg) showing normal hepatocytes (TC)

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  Discussion Top


The therapeutic benefit that can be derived from the clinical use 5-FU can be maximized by preventing the hepatotoxic consequence that may arise in the course of therapy. The current study assessed the potential protective effect of Se on hepatotoxicity induced by 5-FU in albino rats. Serum AST, ALT, ALT, GGT, LDH, CB, and TB are essential markers used to ascertain the health status of the liver. AST is present in mitochondria and cytoplasm, whereas ALT is found in the cytoplasm. ALT is more sensitive than AST; therefore, it is the primary hepatic marker used to diagnose drug-induced liver injury. Bilirubin is often produced by the liver at a constant rate, and its level in the serum correlates with liver function. Elevation in serum aminotransferases and bilirubin can give a vivid diagnostic picture of liver injury.[19] This study observed normal serum and liver levels of AST, ALT, ALT, GGT, LDH, CB, and TB in rats treated with Se. In contrast, the aforementioned parameters were severely elevated in rats treated with 5-FU. The observation in rats treated with 5-FU attests to liver toxicity which has been previously documented.[20] However, the levels of AST, ALT, ALT, GGT, LDH, CB, and TB were restored in a dose-dependent fashion in Se-supplemented rats. This showed the ability of Se to restore and stabilized liver function following intoxication by 5-FU.

Studies have speculated that increased free radical production culminating in OS is involved in the initiation and progression of liver toxicity associated with anticancer agents.[21] The liver has an inherent detoxification mechanism fortified with antioxidants such as CAT, GSH, GPx, and SOD that detoxifies the activities of excess free radicals especially reactive oxygen species. However, with the advent of free radical accumulation, the activities of the aforementioned antioxidants can be surmounted culminating in OS, leading to hepatic biomolecular damage.[22] In the current study, normal cellular levels of CAT, GSH, GPx, and SOD were observed in the liver of Se-treated rats. On the other hand, severe depletions leading to decreases in liver CAT, GSH, GPx, and SOD levels occurred in rats treated with 5-FU. The finding in rats treated with 5-FU is a sign of OS which was reported previously.[23] Studies have reported that free radical-induced LPO is a biochemical process that has characterized most adverse effects caused by anticancer agents.[24] LPO can culminate in the formation of lipoperoxyl radicals, lipid hydroperoxides, and some secondary products including aldehydes, MDA, hexanal, and 4-hydroxynonenal. MDA is one of the primary markers for the assessment of LPO. It is a reactive aldehyde which interacts with deoxyguanosine and deoxyadenosine in DNA culminating in mutagenic DNA adducts.[25] This study observed normal MDA levels in the liver of rats treated with Se, but MDA levels were highly elevated in rats treated with 5-FU. The observation in 5-FU-treated rats showed that hepatic LPO is involved in 5-FU-induced hepatotoxicity and is consistent with previous findings.[26] On the other hand, MDA levels were normalized in rats supplemented with Se in a dose-dependent fashion.

Hepatic distortions such as liver necrosis, vacuolated cytoplasm, pyknotic nuclei, congested hepatic sinusoids, and inflammatory cell infiltration are some reported features of hepatic damage caused by 5-FU.[27] This study observed hepatocyte necroses in the liver of rats treated with 5-FU. However, hepatocyte necroses were abrogated in rats supplemented with Se. Furthermore, some hypotheses by which 5-FU causes liver toxicity include the breakdown of 5-FU to dihydrofluorouracil which forms metabolites such as fluoro-beta-alanine (FABL) which are biotransformed in the liver. FABL can remain in the liver for a very long time after discontinuation of therapy, suggesting the saturation of pathways involved. This results in reduced ability of the liver to metabolize fat and drugs leading to intracellular lipid accumulation. 5-FU can stimulate mitochondrial damage, causing impaired fatty acid oxidation and elevated levels of free radicals leading to hepatic biomolecular damage.[28] The current study observed that supplementation with Se restored hepatic function and structure of rats treated with 5-FU in a dose-dependent fashion. This can be compared with the reported ameliorative potential of Se against bisphenol A-induced hepatotoxicity in rats.[29] Furthermore, it can be correlated with the reported protective effect of Se on tebuconazole-induced hepatotoxicity in rats.[30]

This finding can be attributed to the antioxidant activity of Se in preventing 5FU-induced hepatic OS, thereby preserving the integrity of hepatocytes.[31] Se is a cofactor for antioxidants such as thioredoxin reductase and GPx.[32] GPx scavenges free radicals, prevents LPO, and maintains cellular redox balance. Thioredoxin reductase plays a significant function in protecting against OS-induced injury. It can facilitates cell growth and transformation, and inhibits cellular apoptosis.[33]


  Conclusion Top


Se may be effective against hepatotoxicity caused by 5-fluorouracil.

Acknowledgment

We appreciate Mr. Cosmos Obi of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria, for animal handling.

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], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1], [Table 2]



 

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