|Year : 2021 | Volume
| Issue : 3 | Page : 116-122
Lycopene abrogates ifosfamide-induced fanconi syndrome in albino rats
Elias Adikwu1, Bonsome Bokolo2, Dorcas Okayo Okoroafor3
1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria
2 Department of Pharmacology, Faculty of Basic Medical Sciences, Niger Delta University, Bayelsa State, Nigeria
3 Department of Biomedical Technology, School of Science Laboratory Technology, University of Port Harcourt, Port Harcourt, Nigeria
|Date of Submission||30-Apr-2020|
|Date of Decision||11-Jun-2020|
|Date of Acceptance||05-Aug-2020|
|Date of Web Publication||26-Oct-2020|
Dr. Elias Adikwu
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State
Source of Support: None, Conflict of Interest: None
Background: Treatment modalities for Fanconi syndrome caused by ifosfamide (IFO) are very limited. This study assessed the protective effect of lycopene (LYP) against IFO-induced Fanconi syndrome in albino rats. Methods: Forty adult male albino rats randomized into eight groups of n = 5 were used. Group A (Control) was treated intraperitoneally (IP) with normal saline (0.2 mL), whereas groups B–D were treated orally with LYP (10, 20, and 40 mg/kg) daily for 5 days, respectively. Group E was treated IP with IFO (80 mg/kg) daily for 5 days, whereas groups F–H were pretreated orally with LYP (10, 20, and 40 mg/kg) before IP treatment with IFO (80 mg/kg) daily for 5 days. After treatment, the rats were anesthetized; blood samples were collected and evaluated for serum biochemical biomarkers. Kidneys were excised, weighed and evaluated for oxidative stress markers and histology. Results: Significant (P < 0.001) increases in serum creatinine, urea, and uric acid levels with significant (P < 0.001) decreases in glucose, phosphate, magnesium, calcium, potassium, sodium, chloride, and bicarbonate levels were observed in IFO-treated rats when compared to control. Significant (P < 0.001) decreases occurred in kidney superoxide dismutase, catalase, glutathione (GSH), and GSH peroxidase levels with significant (P < 0.001) increases in malondialdehyde levels in IFO-treated rats in comparison to control. Glomerulus with sclerosis, lipid accumulation, and tubular necrosis were observed in the kidneys of IFO-treated rats. The aforementioned changes were significantly abrogated in rats pretreated with LYP 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to IFO-treated rats. Conclusions: LYP may be useful as treatment for Fanconi syndrome caused by IFO.
Keywords: Ifosfamide, kidney, toxicity, lycopene, protection, rat
|How to cite this article:|
Adikwu E, Bokolo B, Okoroafor DO. Lycopene abrogates ifosfamide-induced fanconi syndrome in albino rats. J Med Sci 2021;41:116-22
| Introduction|| |
Ifosfamide (IFO) is an anticancer drug that is a synthetic analog of cyclophosphamide. It is an alkylating anticancer drug with a potent clinical effect against a wide variety of blood malignancies, sarcomas, and carcinomas. It has gained clinical use in the treatment of rhabdomyosarcoma, soft-tissue sarcomas, lymphoma, neuroblastoma, Ewing's sarcoma, osteosarcoma, and Whilms' tumor in children. It has a greater antineoplastic activity in comparison to its analog cyclophosphamide. IFO has a higher therapeutic index and a greater cure rate with no cross-resistance. Despite comparative advantage over some anticancer drugs, presently, renal toxicity is the greatest challenge associated with the use of IFO. Reports have shown that about 30% of people treated with IFO could experience varying degrees of renal toxicity which may seriously impact the quality of life and the well-being of people who survived treatment. IFO renal toxicity can manifest in any segment or more segments of the nephron: glomerulus, distal tubule, or the collecting duct. The severity of renal toxicity associated with the use of IFO may differ from subclinical to severe tubular and/or glomerular damage. Chronic glomerular damage can be characterized by reduced glomerular filtration rate (GFR) and elevated serum creatinine and urea. Subclinical features may include fluctuations in electrolytes and acid–base balance. Suggestions regarding the mechanisms of IFO-induced renal toxicity have been proposed, these include toxic metabolite production locally in the kidney, generation of free radicals leading to oxidative stress (OS), and the depletion of kidney antioxidant defense mechanism.
Lycopene (LYP) is a red-pigmented linear carotenoid with 11 conjugated and 2 nonconjugated double bonds. It has a lipophilic property that makes it more soluble in organic solvents. It is an essential dietary carotenoid that is produced by plants and microorganisms. It is primarily found in tomatoes; it is also present in vegetables, red fruits, watermelon, pink guava, pink grape fruit, papaya, and apricots. It has a variety of biological activities such as antiaging, anticancer, anti-inflammatory, and antioxidant effects. Studies have reported benefits in diabetes, heart disease, and other degenerative diseases. Several in-vivo and in-vitro studies have shown that it is a potent antioxidant that scavenges and neutralizes free radicals such as singlet oxygen, nitrogen dioxide and sulfonyl radicals, superoxide anion, peroxy radicals, and hydroxyl radicals. This contributes to its inhibitory effects on lipid peroxidation (LPO) and OS, thereby preventing proteins, lipids, and DNA from damage., Furthermore, some studies have demonstrated the potential ameliorative effect of LYP against animal models of xenobiotic-induced renal damage; however, there is a lack of literature on its protective effect against animal models of IFO-induced renal toxicity. This study assessed the protective effect of LYP against a rat model of IFO-induced renal toxicity.
| Methods|| |
Animal care, treatment, and sacrifice
This study was approved by the Research Ethics Committee (REC 20-12-2019) of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Nigeria. Forty adult male albino rats (210 g ± 220 g) were obtained from the animal house of the Faculty of Pharmacy, Niger Delta University, Nigeria. The rats were randomized into eight groups of five each and were housed in well-ventilated cages with ad libitum access to a balanced laboratory diet and water. The rats were acclimated to housing conditions (12-h light/dark cycle, temperature 25°C) for 1 week before the initiation of the experiment. LYP (10, 20, and 40 mg/kg) and IFO (80 mg/kg) were used. Group A (Control) was treated intraperitoneally (IP) with normal saline (0.2 mL), whereas groups B–D were treated orally with LYP (10, 20, and 40 mg/kg) daily for 5 days, respectively. Group E was treated IP with IFO (80 mg/kg) daily for 5 days (IP), whereas groups F–H were pretreated orally with LYP (10, 20, and 40 mg/kg) before IP treatment with IFO (80 mg/kg) daily for 5 days. After overnight fast, the rats were sacrificed under anesthesia; blood samples were collected and evaluated for serum biochemical parameters. Kidney samples were isolated through dissection, weighed, and rinsed in physiological saline. Kidney samples were homogenized in 0.1 M Tris-hydrochloric acid (HCl) buffer, pH 7.4. The homogenates were centrifuged at 2000 rmp for 30 min. The resulting supernatants were decanted and used for biochemical analyses.
Measurement of biochemical parameters
Serum samples were evaluated for creatinine, urea, uric acid, total protein, albumin, sodium, magnesium, phosphorus, sodium, calcium, and bicarbonate levels using standard laboratory reagents according to the manufacturers' specifications. Blood glucose was measured using glucometer (easy touch).
Superoxide dismutase assay
Superoxide dismutase (SOD) activity was determined according to the method described by Sun and Zigman. The principle is based on the ability of SOD to inhibit auto-oxidation of epinephrine determined by the increase in absorbance at 480 nm. To initiate the reaction, kidney homogenate (0.1 mL) was allowed to react with 2.95 mL of sodium carbonate buffer (0.05 M, pH 10.2) and 0.03 mL of epinephrine in 0.005 N HCl. The reference cuvette contained 2.95 mL buffer, 0.03 mL of substrate (epinephrine), and 0.02 mL of water. Enzyme activity was calculated by measuring the change in absorbance at 480 nm for 5 min, Σ = 4020M−1 cm−1.
Reduced glutathione assay
Reduced glutathione (GSH) content of the kidney as nonprotein sulfhydryls was estimated according to the method described by Sedlak and Lindsay. To the kidney homogenate, 10% tricarboxylic acid (TCA) was added and centrifuged. The supernatant (1.0 mL) was then treated with 0.5 mL of Ellman's reagent (19.8 mg of 5,5-dithiobisnitrobenzoic acid [DTNB], in 100 mL of 0.1% sodium nitrate) and 3.0 mL of phosphate buffer (0.2 M, pH 8.0). The absorbance was read at 412 nm, Σ = 1.34 × 10 4M−1 cm−1.
Catalase (CAT) activity was assayed calorimetrically at 620 nm and expressed as micromoles of H2O2 consumed/min/mg protein at 25°C, according to the method described by Aebi. The reaction mixture (1.5 mL) contained 1.0 mL of 0.01 M phosphate buffer (pH 7.0), 0.1 mL of kidney homogenate, and 0.4 mL of 2 M H2O2. The reaction was stopped by the addition of 2.0 mL of dichromate-acetic acid reagent (5% potassium dichromate and glacial acetic acid were mixed in 1:3 ratio), Σ = 40M−1 cm−1.
Malondialdehyde (MDA) was determined using the method of Buege and Aust. Kidney homogenate (0.1 mL) was added to 2 mL mixture of 15% TCA, 0.37% thiobarbituric acid (TBA), and 0.24 N HCl reagents (0.37% TBA, 15% TCA, and 0.24 N HCl) in a 1:1:1 ratio and boiled at 100°C for 15 min and allowed to cool. Flocculent materials were removed by centrifuging at 3000 rpm for 10 min. The supernatant was then removed, and the absorbance read at 532 nm against a blank. MDA was calculated using the molar extinction coefficient for MDA-TBA complex of 1.56 × 105 M−1 cm−1.
Glutathione peroxidase assay
Glutathione peroxidase (GPx) was evaluated according to the method of Rotruck et al., 1973. 0.2 ml each of ethylenediaminetetraacetic acid, sodium azide, GSH, and hydrogen peroxide together with a suitable volume of buffer and kidney homogenate (0.1mL) were mixed together in a total incubation volume of 2 ml. Incubation was carried at 37°C, and their action was terminated at 1 min intervals by the addition of 5% TCA. A zero time was also carried out simultaneously by the addition of TCA prior to the the addition of kidney homogenate (0.1mL). To determine the residual GSH content, the contents were centrifuged and to 2 ml of the supernatant, 8 ml of phosphate solution was added followed by 1 ml of DTNB and read immediately at 412 nm using a spectrophotometer.
The kidneys were fixed in 10% neutral buffered formalin, processed, and embedded in paraffin wax. Sections (5 μm) were cut using a microtome, stained with hematoxylin and eosin, and examined under a light microscope for histological changes.
The results are presented as mean ± standard error of mean for each group. Differences among groups were analyzed using one-way analysis of variance, followed by Dunnett's post hoc test. Data was analyzed using GraphPad Prism Version 5 software (GraphPad Software Inc., La Jolla, CA, USA).
| Results|| |
Effects on body and kidney weights and serum biochemical markers
The body and kidney weights of rats administered with LYP (10 mg/kg, 20 mg/kg and 40 mg/kg) were not significantly (P > 0.05) different when compared to control. Treatment with IFO also did not produce significant (P > 0.05) effects on the body and kidney weights of rats when compared to control [Table 1]. Serum creatinine, urea, uric acid, total protein, albumin, and blood glucose levels were normal (P > 0.05) in LYP-treated rats when compared to control. However, serum creatinine, urea, and uric acid levels were significantly (P < 0.001) increased, whereas total protein, albumin, and glucose levels were significantly (P < 0.001) decreased in IFO-treated rats when compared to control [Table 2]. On the other hand, serum creatinine, urea, and uric acid levels were significantly decreased, whereas total protein, albumin, and glucose levels were significantly increased in a dose-dependent fashion in rats pretreated with LYP 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to IFO-treated rats [Table 2].
|Table 1: Effects of lycopene on body and kidney weights of ifosfamide-treated rats|
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|Table 2: Effect of lycopene on serum renal function markers of ifosfamide-treated rats|
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Effects on serum electrolytes and kidney histology
Treatment with LYP did not produce significant (P > 0.05) effects on serum sodium, magnesium, phosphorus, sodium, calcium, and bicarbonate levels when compared to control. However, significant (P < 0.001) decreases in serum levels of the aforementioned parameters were observed in IFO-treated rats in comparison to control [Table 3]. In contrast, the serum levels of sodium, magnesium, phosphorus, sodium, calcium, and bicarbonate levels were significantly increased in a dose-dependent fashion in rats pretreated with LYP 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to IFO-treated rats [Table 3]. The kidneys of control rat and rat treated with LYP (40 mg/kg) showed normal glomeruli and renal tubules [Figure 1]a and [Figure 1]b, whereas the kidney of rat treated with IFO (80 mg/kg) showed glomerulus with sclerosis, lipid accumulation, and tubular necrosis [Figure 1]c. The kidney of rat treated with of LYP (10 mg/kg) and IFO (80 mg/kg) showed normal glomerulus and mild tubular necrosis [Figure 1]d, whereas the kidney of rat treated with LYP (20 mg/kg) and IFO (80 mg/kg) showed normal glomerulus and renal tubule [Figure 1]e. The kidney of rat treated with LYP (40 mg/kg) and IFO (80 mg/kg) showed normal glomerulus and renal tubule [Figure 1]f.
|Table 3: Effect of lycopene on serum electrolytes of ifosfamide-treated rats|
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|Figure 1: (a) Control kidney shows normal glomerulus (G) and renal tubule (H). (b) Kidney of rat treated with lycopene (40 mg/kg) shows normal glomerulus (I) and renal tubule (J) (c) Kidney of rat treated with ifosfamide (80 mg/kg) shows glomerulus with sclerosis (L), lipid accumulation (M) and tubular necrosis (N). (d) Kidney of rat treated with lycopene (10 mg/kg) and ifosfamide (80 mg/kg) shows mild tubular necrosis (P) and normal glomerulus (R). (e) Kidney of rat treated with lycopene (20 mg/kg) and ifosfamide (80 mg/kg) shows normal glomerulus (S) and renal tubule (T). (f) Kidney of rat treated with lycopene (40 mg/kg) and ifosfamide (80 mg/kg) shows normal glomerulus (W) and renal tubule (V). (H and E) ×400|
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Effect on kidney oxidative stress markers
Effects were not (P > 0.05) significant on kidney SOD, CAT, GSH, GPx, and MDA levels in rats treated with LYP when compared to control [Table 4]. 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 IFO-treated rats in comparison to control [Table 4]. However, kidney SOD, CAT, GSH, and GPx levels were significantly increased, whereas MDA levels were significantly decreased in a dose-dependent fashion in rats pretreated with LYP 10 mg/kg (P < 0.05), 20 mg/kg (P < 0.01), and 40 mg/kg (P < 0.001) when compared to IFO-treated rats [Table 4].
|Table 4: Effect of lycopene on kidney oxidative stress markers of ifosfamide-treated rats|
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| Discussion|| |
Fanconi syndrome caused by IFO is a serious clinical challenge due to limited treatment options. It has been characterized by altered serum electrolytes, acid–base balance and increased serum creatinine and urea levels. Chronic episode can be accompanied by pathologic changes in kidney structure. Some studies have correlated Fanconi syndrome caused by IFO with increased biomarkers of LPO, inflammation, and OS. LYP is a carotenoid that can inhibit the nefarious activities of LPO, pro-inflammatory, and pro-oxidative mediators. The current study assessed the protective effect of LYP against IFO-induced Fanconi syndrome in albino rats. Relative organ weight assessment is used in toxicity studies in animals to ascertain the functional status of organs. The uses of drugs can initiate and sustain abnormal metabolic reactions that can impair the weights of organs. This study observed normal body and kidney weights in rats treated with LYP and IFO. Serum creatinine, urea, uric acid, albumin, and total protein are basic and vital diagnostic markers that give vivid information on the pathological status of the kidney. Abnormal alterations in the serum levels of the aforementioned diagnostic markers are signs of renal impairment. Serum creatinine, urea and uric acid, albumin, total protein, and blood glucose levels were normal in LYP-treated rats. However, IFO-treated rats showed nephrotoxic changes marked by increased serum creatinine, urea, and uric acid levels with decreased albumin, total protein, and blood glucose levels. This observation is consistent with earlier findings. Serum levels of creatinine, urea, uric acid, albumin, and total protein are regulated by GFR; a decrease in GFR is often preceded by alterations in serum levels of the aforementioned parameters. The observation in this study could be attributed to a decrease in GFR which is a cardinal feature of Fanconi syndrome caused by IFO. Interestingly, the serum levels of creatinine, urea, uric acid, albumin, total protein, and blood glucose were stabilized in a dose-related fashion in LYP-pretreated rats, probably due to its ability to stabilize the regulatory effect of GFR on the aforementioned biochemical markers. The kidney is very important for the regulation of electrolytes and acid–base balance. Studies have shown that derangements in electrolytes and acid–base balance inevitably occur with the advent of progressive loss of kidney function. In this study, serum sodium, magnesium, phosphorus, sodium, calcium, and bicarbonate levels were normal in LYP-treated rats. On the other hand, the regulatory capacity of the kidney on the aforementioned parameters was impaired in IFO-treated rats, as evidenced by decreases in their serum levels. The observation in IFO-treated rats is consistent with earlier reports. However, the serum levels of sodium, magnesium, phosphorus, sodium, calcium, and bicarbonate were restored in a dose-dependent fashion in rats pretreated with LYP. Antioxidants including SOD, CAT, GSH, and GPx are imbedded in cells to inhibit the detrimental activities of excess reactive oxygen species (ROS). Normal concentrations of ROS are essential for normal physiological functions; however, higher concentrations of ROS that surpass antioxidant regulatory capacity will culminate in OS and the progressive depletion of antioxidant repertoire. The current study observed normal kidney levels of SOD, CAT, GSH, and GPx in LYP-treated rats. On the other hand, evident oxidative damage was observed in the kidneys of IFO-treated rats as evidenced by decreased kidney SOD, CAT, GSH, and GPx levels. This is consistent with earlier observations. However, pretreatment with LYP increased kidney levels of SOD, CAT, GSH, and GPx in a dose-dependent fashion.
LPO is the breakdown of polyunsaturated fatty acid by oxidative radicals, thereby impairing the functional integrity of cellular structures which can lead to cell death in severe cases. MDA is one of the byproducts of LPO that is primarily used to evaluate the extent of LPO. In this study, kidney MDA levels were normal in LYP-treated rats, but were increased in the kidneys of IFO-treated rats. The observation in IFO-treated rats agrees with earlier findings. The observed LPO in the kidneys of IFO-treated rats was abrogated in a dose-dependent fashion in LYP-pretreated rats marked by decreased MDA levels. Kidney histological alteration is a common feature of IFO-induced Fanconi syndrome; therefore, this study investigated histological alterations in the kidneys of rats in the experimental and control groups. The kidneys of LYP-treated rats showed normal histology. Histological changes characterized by glomerulus with sclerosis, lipid accumulation, and tubular necrosis occurred in the kidneys of IFO-treated rats. These observations support earlier findings. However, the aforementioned morphologic changes were abrogated in LYP pretreated rats. In this study, the observed biochemical changes correlate with structural changes in the kidneys of IFO-treated rats. IFO is a pro-drug that is oxidized intracellularly by the liver and kidney to two primary toxic metabolites: acrolein and chloroacetaldehyde (CAA) which have been associated with its nephrotoxicity. Studies have shown that CAA may be responsible for IFO-induced Fanconi syndrome. CAA produced by the side-chain oxidation of IFO in renal tubular cells causes ROS production leading to OS in the kidney. It can cause impairment of several transport mechanisms in renal proximal tubules and cellular necrosis in a concentration-dependent fashion. It can cause dysfunction of mitochondrial oxidative phosphorylation in renal proximal tubules which impairs energy production, thereby resulting in multiple metabolic abnormalities and cellular damage. Acrolein is a highly reactive metabolite that triggers the production of ROS, which causes LPO, protein carbonylation, and oxidative DNA damage. ROS can also activates multiple signaling molecules, including nuclear factor-kappa B, eventually resulting in cell death. In this study, LYP protected against IFO-induced Fanconi syndrome, probably by inhibiting the nephrotoxic activity of CAA. This could be due to its inhibitory effect on CAA-induced OS in the kidney. Studies have shown that LYP can scavenge oxidative radicals such as hydroxyl radical, hydrogen peroxide radical, and singlet oxygen, thereby preventing OS., It can stabilize antioxidants and prevent their depletion, thereby facilitating their activities. LYP has been shown to protect against oxidation of lipids, proteins, and DNA. Furthermore, inflammatory mediators which include tumor necrosis factor α, interleukin-1 beta (IL-1 β), and IL-6 have been associated with IFO-induced Fanconi syndrome. LYP might have abrogated IFO-induced Fanconi syndrome by downregulating the activities of the aforementioned inflammatory mediators.
| Conclusions|| |
LYP may be clinically use as prevention or treatment for Fanconi syndrome caused by IFO.
The authors kindly acknowledge the technical assistance offered by Dr. Ebinyo Clemente Nelson and Mr. Harold Agbadabina of the Faculty of Pharmacy, Niger Delta University, Nigeria.
Financial support and sponsorship
Conflicts of interest
The authors declare no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]