|Year : 2019 | Volume
| Issue : 4 | Page : 65-71
Coenzyme Q10 and resveratrol abrogate paclitaxel-induced hepatotoxicity in rats
Elias Adikwu, Nelson Clemente Ebinyo, Loritta Wasini Harris
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria
|Date of Submission||26-Oct-2019|
|Date of Acceptance||21-Nov-2019|
|Date of Web Publication||26-Dec-2019|
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: Hepatotoxicity is one of the adverse effects that may characterize the clinical use of paclitaxel (PCL). This study examined the protective effects of coenzyme Q10 (CoQ10) and resveratrol (RSV) on PCL-induced hepatotoxicity in albino rats.
Methods: Forty-five adult male albino rats randomized into nine groups of n = 5 were used. Group 1 (placebo control) and Group 2 (solvent control) received 0.2 mL of normal saline and corn oil intraperitoneally (ip) daily for 5 days, respectively. Groups 3–5 received CoQ10 (20 mg/kg), RSV (20 mg/kg), and CoQ10 + RSV ip daily for 5 days, respectively. Group 6 received a dose of 20 mg/kg of PCL ip on the 5th day. Groups 7–9 were pretreated daily with CoQ10 (20 mg/kg), RSV (20 mg/kg), and CoQ10 + RSV ip for 5 days and treated with a dose of PCL on the 5th day, respectively. Rats were sacrificed after treatment; liver samples were estimated for histology and biochemical markers. Serum samples were estimated for liver function markers.
Results: The liver of PCL-treated rats showed necrosis which correlates with significant (P < 0.001) increases in serum and liver biochemical indexes; gamma glutamyl transferase, lactate dehydrogenase, bilirubin, aminotransferases, alkaline phosphatase, and malondialdehyde levels when compared to control. Liver superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels were significantly (P < 0.001) decreased in PCL-treated rats when compared to control. Importantly, PCL-induced hepatotoxicity was significantly mitigated in CoQ10 (P < 0.05), RSV (P < 0.01), and CoQ10 + RSV (P < 0.001) pretreated rats when compared to PCL.
Conclusion: CoQ10 and RSV were effective against PCL-induced hepatotoxicity in albino rats.
Keywords: Antioxidants, liver, protection, rats, taxol, toxicity
|How to cite this article:|
Adikwu E, Ebinyo NC, Harris LW. Coenzyme Q10 and resveratrol abrogate paclitaxel-induced hepatotoxicity in rats. Cancer Transl Med 2019;5:65-71
|How to cite this URL:|
Adikwu E, Ebinyo NC, Harris LW. Coenzyme Q10 and resveratrol abrogate paclitaxel-induced hepatotoxicity in rats. Cancer Transl Med [serial online] 2019 [cited 2020 Feb 26];5:65-71. Available from: http://www.cancertm.com/text.asp?2019/5/4/65/274030
| Introduction|| |
Hepatotoxicity caused by chemotherapy occurs frequently from an unpredictable or idiosyncratic reaction and is a significant cause of mortality. Studies have shown that up to 85% of cancer patients on chemotherapy are most likely to develop hepatotoxicity. The major mechanisms underlying chemotherapy-related hepatotoxicity are based on the production of reactive metabolites, immunological injury, and mitochondrial dysfunction. Furthermore, chemotherapy-induced hepatotoxicity is thought to be secondary to the production of reactive oxygen species (ROS) intended to induce tumor cell apoptosis.
Paclitaxel (PCL) is used for the treatment of a broad range of human cancers, which include ovarian, breast, lung, cervical, pancreatic, cancers and Kaposi sarcoma. In cancer cells, PCL causes the formation of parallel microtubule bundles at interphase and abnormal spindle asters at mitosis inducing cell cycle blockage in phase M or G2 causing cell death. The clinical use of PCL has been promising, but may be associated with hepatotoxicity. Hepatic necrosis and hepatic encephalopathy leading to death have been reported. In addition, elevations in serum aminotransferases in 7%–26% have occurred in cancer patients treated with PCL.
Coenzyme Q10 (CoQ10) is present in biological membranes of cellular organelles, such as peroxisomes and lysosomes, and is principally located in the inner mitochondrial membrane as part of the electron transport chain, which is responsible for adenosine triphosphate synthesis. CoQ10 has drawn lots of research attentions due to its different pharmacological activities, which include immunomodulatory, anti-inflammatory, antiaging, and antioxidant effects. Its antioxidant effect is primarily pivoted on the scavenging of free radicals, especially ROS, thereby inhibiting oxidative stress (OS) and lipid peroxidation (LPO). It also prevents nitrosative stress in tissues by inhibiting the production of excess reactive nitrogen species. Due to its antioxidant property, it can effectively prevent the oxidation of proteins, lipids and DNA and can suppress the activity of enzymes involved in the production of ROS. Furthermore, CoQ10 exhibits anti-inflammatory activity by reducing the release of proinflammatory cytokines during inflammatory injury, probably by inhibiting the expression of nuclear factor-kappa B (NF-kB) gene. The therapeutic potential of CoQ10 has been shown in mitochondrial dysfunction and OS-related disorders, such as cancer, diabetes, cardiovascular and neurodegenerative disorders. In addition, CoQ10 has shown potential hepatoprotective effect by reducing liver fibrosis and improving liver function through significant reductions in OS markers and preservation of antioxidant factors. Also, it has reduced hepatic inflammation by inhibiting the production of pro-inflammatory cytokines, which include interleukin-6 and tumor necrosis factor alpha (TNF-α) in rat with hepatic fibrosis.
Resveratrol (RSV) is a phytoalexin found in over 300 edible plants, including peanuts, berries, and grapes. It is produced by plants as a defense mechanism against pathogen attack or environmental stress. It has been shown to have antioxidant, anti-inflammatory, vasorelaxant, anticarcinogenic, phytoestrogenic, cardioprotective, and neuroprotective effects. As an antioxidant, it has the capacity to scavenge ROS, inhibit OS and LPO in cell membrane, and protect against biomolecular damage. Its anti-inflammatory effect includes the inhibition of NF-kB, a transcription factor that stimulates inflammatory reactions, and it also reduces the expression of several proinflammatory cytokines. In addition, it can increase the expression of antioxidant genes, thereby facilitating antioxidant activities., RSV can prevent or slow down the progression of a wide variety of ailments, such as malignancies, neurodegenerative diseases, cardiovascular diseases, ischemic injury, and viral infections. Moreover, it has shown potential protection against liver damage caused by hepatotoxins. It has prevented hepatic lipids, proteins and DNA damage and has upregulated hepatic antioxidant activities.
| Methods|| |
Drugs chemicals and animals
CoQ10 capsules used were manufactured by Bactolac Pharmaceuticals Inc., 7 Oser Avenue, Hauppauge, NY 11788, USA. PCL injection was manufactured by Getwell Pharmaceuticals Gurgaon, Haryana, India. All other chemicals used which are of analytical grade were stored following storage instructions recommended by the manufacturers. Adult male albino rats weighing 200–250 g were used for the experiment. The rats were sourced from the Animal Breeding Facility of the Department of Pharmacology and Toxicology, Faculty of Pharmacy, Niger Delta University, Bayelsa State, Nigeria. The rats were housed under natural conditions and allowed to revert to environmental conditions for 7 days with unhindered access to rat chow and water ad libitum. The rats were handled according to the standard ethical principles based on the university's regulations for the handling of experimental animals.
Drug administration, animal sacrifice, and sample collection
Forty-five adult male albino rats used were divided into 9 groups of 5 rats per group. Group 1 (placebo control) and group 2 (solvent control) received 0.2 mL of normal saline and corn oil intraperitoneally (ip) daily for 5 days, respectively. Groups 3–5 received CoQ10(20 mg/kg), RSV (20 mg/kg), and CoQ10+ RSV ip daily for 5 days, respectively. Group 6 received a dose of 20 mg/kg of PCL ip on the 5th day. Groups 7–9 were pretreated daily with CoQ10(20 mg/kg), RSV (20 mg/kg), and CoQ10+ RSV ip for 5 days and treated with a dose of PCL on the 5th day, respectively. At the end of treatment, rats in all groups were sacrificed under anesthesia (diethyl ether), blood samples were collected, and liver tissues were harvested. Liver tissues were fixed in 10% neutral-buffered formalin for 24 h for histological analysis. Blood samples were centrifuged (1500 g for 15 min) and sera were extracted for liver function assessment. Liver tissues were rinsed in ice-cold saline and homogenized in 0.1 M Tris-HCl buffer, pH 7.4. The homogenates were centrifuged at 1200 g for 15 min and the supernatants were collected for the assessment of biochemical parameters.
Measurement of biochemical parameters
Liver function markers
Serum and liver alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), conjugated bilirubin (CB), total bilirubin (TB), gamma glutamyl transferase (GGT), and lactate dehydrogenase (LDH) were evaluated using commercial test kits (Randox Laboratories Ltd., Crumlin, UK).
Oxidative stress markers
Liver total protein was assayed using the principle of Gonall et al. 1949. Reduced glutathione (GSH) was assayed as reported by Sedlak and Lindsay, 1968. Malondialdehyde (MDA) was measured as described by Buege and Aust, 1978. Superoxide dismutase (SOD) was assessed using the method of Sun and Zigman, 1978. The method of Aebi, 1984 was used to determine catalase (CAT). Glutathione peroxidase (GPX) was assayed using the method of Rotruck et al. 1973.
Histological examination of the liver
Liver tissues were collected from euthanized rats and fixed in 10% neutral-buffered formalin for 24 h. The liver tissues were removed and dehydrated in ascending concentrations of ethanol. The liver tissues were processed and embedded in parafix, and 5-μm sections were obtained with the aid of a microtome. The sections were stained with hematoxylin and eosin and examined for histological changes using a light microscope (Olympus C-2100).
The values are expressed as mean ± standard error of mean (SEM). One-way analysis of variance was used for statistical analysis followed by Tukey's multiple comparison test using GraphPad Prism 5.0 software (GraphPad Software Inc., La Jolla, CA, USA). Significance was set at P < 0.05, <0.01, and < 0.001.
| Results|| |
Effect on serum and liver tissue biochemical parameters
Treatment with CoQ10 and RSV did not produce significant (P > 0.05) effects on the serum and liver AST, ALT, ALP, GGT, TB, CB, and LDH levels when compared to control. However, the aforementioned parameters were significantly (P < 0.001) increased in rats treated with PCL when compared to control [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] and [Table 1]. PCL-induced elevations in serum AST, ALT, ALP, GGT, TB, CB, and LDH were significantly reduced in rats pretreated with CoQ10 (P < 0.05) and RSV (P < 0.001) when compared to PCL [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] and [Table 1]. Serum and liver AST, ALT, ALP, GGT, TB, CB, and LDH levels were further reduced in rats pretreated with CoQ10 + RSV with significance observed at P < 0.001 when compared to PCL [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7] and [Table 1].
|Figure 1: Effects of CoQ10 and RSV on serum AST of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; AST: Aspartate aminotransferase; SEM: Standard error of mean|
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|Figure 2: Effects of CoQ10 and RSV on serum ALT of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; ALT: Alanine aminotransferase; SEM: Standard error of mean|
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|Figure 3: Effects of CoQ10 and RSV on serum ALP of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; ALT: Alkaline phosphatase; SEM: Standard error of mean|
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|Figure 4: Effects of CoQ10 and RSV on serum GGT of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; GGT: Gamma glutamyl transferase; SEM: Standard error of mean|
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|Figure 5: Effects of CoQ10 and RSV on serum TB of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; TB: Total bilirubin; SEM: Standard error of mean|
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|Figure 6: Effects of CoQ10 and RSV on serum CB of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; CB: Conjugated bilirubin; SEM: Standard error of mean|
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|Figure 7: Effects of CoQ10 and RSV on serum LDH of rats treated with paclitaxel. Data are expressed as mean ± SEM, n = 5. #Significant at P < 0.001 when compared to control; *Significant at P < 0.05 when compared to PCL; **Significant at P < 0.01 when compared to PCL; ***Significant at P < 0.001 when compared to PCL. CoQ10: Coenzyme Q10; RSV: Resveratrol; PCL: Paclitaxel; LDH: Lactate dehydrogenase; SEM: Standard error of mean|
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|Table 1: Effects of coenzyme Q10 and resveratrol on liver tissue biochemical parameters of paclitaxel-treated rats|
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Effects on liver oxidative stress indexes
Liver SOD, CAT, GSH, GPX, and MDA levels were normal (P > 0.05) in rats treated with CoQ10 and RSV when compared to control. On the other hand, when rats were treated with PCL, liver SOD, CAT, GSH, and GPX levels were significantly (P < 0.001) decreased whereas MDA levels were significantly (P < 0.001) increased in comparison to control [Table 2]. However, pretreatment with CoQ10 and RSV significantly increased liver SOD, CAT, GSH, and GPX levels whereas MDA levels were significantly decreased at P < 0.05 and P < 0.01, respectively, when compared to PCL. Further increases in liver SOD, CAT, GSH, and GPX levels with decreases in MDA levels were obtained in rats pretreated with CoQ10 + RSV at P < 0.001 when compared to PCL [Table 2].
|Table 2: Effects of coenzyme Q10 and resveratrol on liver oxidative stress markers of paclitaxel-treated rats|
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Effects on histology of the liver
The liver of rats in the control group showed normal histology [Figure 8]a whereas the liver of rats in the group treated with PCL showed hepatocyte necrosis [Figure 8]b. Furthermore, the liver of rats in the group treated with 20 mg/kg of CoQ10 and 20 mg/kg of PCL showed mild hepatocyte necrosis [Figure 8]c whereas the liver of rats in the group treated with 20 mg/kg of RSV and 20 mg/kg of PCL showed congestion of the central vein [Figure 8]d. However, the liver of rats in the group treated with CoQ10 and 20 mg/kg of RSV and 20 mg/kg of PCL showed normal hepatocytes [Figure 8]e.
|Figure 8: The liver of control rat (a) showing normal hepatocytes (H) , whereas the liver of rat treated with PCL (b) showing hepatocyte necrosis (HN). The liver of rat treated with 20 mg/kg of CoQ10 and 20 mg/kg of PCL (c) showing hepatocyte necrosis (HN). The liver of rat treated with 20 mg/kg of RSV and 20 mg/kg of PCL (d) showing central vein congestion (CV). The liver of rat treated with CoQ10 and 20 mg/kg of RSV and 20 mg/kg of PCL (e) showing normal hepatocytes (H) (H and E, ×400)|
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| Discussion|| |
ROS play crucial roles in the pathogenesis of different human diseases, including liver disorders. Liver disorders caused by ROS are characterized by progression from steatosis to chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The abilities of antioxidants to neutralized ROS have instigated studies on the use of antioxidants to minimize or prevent OS-related liver injuries. This study demonstrated the abilities of CoQ10 and RSV to prevent hepatic alterations induced by PCL in albino rats. The hepatotoxic impact of PCL was assessed by measuring ALT, ALP, AST, LDH, GGT, TB, and CB levels, which are relevant clinical hepatic biomarkers. In the current study, the aforementioned hepatic biomarkers were elevated in PCL-treated rats which confirmed its hepatotoxic effect. This observation is consistent with earlier reports. This could be attributed to hepatic damage, resulting in the release and leakage of these hepatic markers from the liver cytosol into the blood. However, pretreatment with individual doses of CoQ10 and RSV reduced AST, ALT, ALP, LDH, TB, and CB activities with most reductions observed in rats pretreated with CoQ10+ RSV. These antioxidants might have restored the levels of the aforementioned hepatic markers by facilitating the regenerative ability of the hepatocytes.
GSH is a nonenzymatic antioxidant that plays a crucial role in the protection of cells from oxidative injury by reducing the activities of hydroperoxides (ROOH). SOD, CAT, and GPX are enzymatic antioxidants that constitute an essential first-line barricade against ROS. Studies have correlated depletions in the levels of hepatic enzymatic and nonenzymatic antioxidants with OS. Antioxidant levels were decreased in the liver of rats treated with PCL. This may be due to increase antioxidant utilization as a result of the scavenging of free radicals generated by PCL. Also, it may be due to the direct binding of PCL to the active sites of the antioxidants thereby inactivating them. Furthermore, PCL impacted the structure of the liver by causing hepatocyte necrosis which is consistent with reports in some studies. However, CoQ10 and RVS showed apparent hepatoprotective potential by increasing hepatic antioxidants and reducing the amount of structural damage inflicted on the liver by PCL. It is of interest to know that structural damage was completely abrogated in rats pretreated with CoQ10 + RSV showing possible complementary actions of these antioxidants.
LPO is a common event in many toxic processes. It is curtailed under normal physiological conditions, but external factors can augment or facilitate LPO process so that it escapes the regulatory effect of cells. This can lead to damage to biomolecules such as proteins, DNA, and lipids in cells causing cell death. In this study, the extent of hepatic LPO caused by PCL was assessed by estimating the concentration of MDA, which is one of the primary by-products of LPO. MDA level was high in the liver of PCL-treated rats showing the vulnerability of hepatic lipids to oxidation by PCL probably through the generation of lipid radicals. Furthermore, PCL might have reacted with polyunsaturated fatty acids and form covalent adducts with lipids and proteins. These events can trigger a chain reaction of LPO and the destruction of cell membranes with consequent hepatic damage., However, CoQ10 and RSV pretreatment arrested the hepatic perioxidative activity caused by PCL marked by low levels of MDA, probably by scavenging or inhibiting the ability of PCL to generate lipid radicals in the liver.
The hepatotoxic effect of PCL may not be far from the induction of OS and LPO as correlated with increased MDA and decreased antioxidants observed in the current study. This can also be correlated with reported increases in the production and activities of hydroperoxides and other ROS known for LPO and OS by PCL. CoQ10 and RSV might have protected against PCL-induced hepatotoxicity by inhibiting OS and LPO. CoQ10 is a component of the electron transport chain that has antioxidant, anti-inflammatory, and antiapoptotic properties. Its antioxidant activity includes scavenging of ROS, thereby inhibiting biomolecular damage that can arise as a consequence of ROS activities. Moreover, it can facilitate the expression of genes essential for the production of antioxidants, which will upregulate antioxidant activities and downregulate OS activities, thereby safeguarding biomolecules. RSV is an antioxidant and anti-inflammatory agent. Its antioxidant effect includes the capacity to scavenge ROS, inhibit OS and LPO, and protect biomolecules such as DNA, lipids, and proteins from damage. In addition, it can upregulate antioxidant synthesis, thereby enhancing more antioxidant activities.
| Conclusion|| |
Findings in this study suggest that CoQ10 and RSV have potential as treatment for hepatotoxicity caused by PCL.
| Acknowledgments|| |
We appreciate the effort of Dr. Yibala Obuma of the Department of Medical Laboratory Sciences, Faculty of Basic Medical Sciences, Niger Delta University, Nigeria, for histological analysis.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
[Table 1], [Table 2]