|Year : 2017 | Volume
| Issue : 2 | Page : 92-98
Hepatoprotective activity of quercetin against paracetamol-induced liver toxicity in rats
Afaf A El Faras, Amel L Elsawaf PhD
Department of Physiology, Medical Research Institute, Alexandria University, Alexandria, Egypt
|Date of Submission||24-Dec-2016|
|Date of Acceptance||18-Mar-2017|
|Date of Web Publication||13-Oct-2017|
Amel L Elsawaf
Department of Physiology, Medical Research Institute, Alexandria Univeristy, Alexandria, 21561
Paracetamol (PCM) overdose induces hepatotoxicity in both humans and experimental animals. The pathogenesis and progression of PCM hepatic toxicity are associated with free radical injury and oxidative stress, which could be partially attenuated by antioxidants and free radical scavengers.
The present study was undertaken to examine the effects of quercetin on PCM-induced hepatic toxicity in rats.
Material and methods
In this experimental study, forty adult male rats were divided into four groups: control, quercetin, PCM groups, and the protective group that was pretreated with quercetin orally [50 mg/kg body weight (b.w.)] daily for 16 days and thereafter received both quercetin (same dose) and PCM (500 mg/kg b.w.) for another 5 days. Twenty-four hours after the administration of PCM, the rats were killed to measure serum hepatotoxic markers, levels of tumor necrosis factor-α, and oxidative stress biomarkers.
Oral administration of PCM (500 mg/kg b.w.) for 5 days resulted in a significant elevation of liver enzymes in serum such as aspartate transaminase, alanine transaminase, alkaline phosphatase, and total bilirubin, and in levels of tumor necrosis factor-α as well as reducing hepatic total protein and albumin concentrations when compared with the results in the control group. As regards oxidative stress biomarkers, there were increased tissue levels of malondialdehyde and decreases in the activity of liver enzymes [superoxide dismutase, catalase, glutathione, glutathione peroxidase, and glutathione-s-transferase] in the group treated with PCM. All of these results were ameliorated by coadministration of quercetin.
These results suggest that the protective role of quercetin in the prevention of PCM-induced hepatic toxicity in rats was associated with a decrease of oxidative stress in hepatic tissues. However, clinical studies are warranted to investigate such an effect in humans.
Keywords: hepatic toxicity, oxidative stress biomarkers, paracetamol, quercetin, tumor necrosis factor-α
|How to cite this article:|
El Faras AA, Elsawaf AL. Hepatoprotective activity of quercetin against paracetamol-induced liver toxicity in rats. Tanta Med J 2017;45:92-8
|How to cite this URL:|
El Faras AA, Elsawaf AL. Hepatoprotective activity of quercetin against paracetamol-induced liver toxicity in rats. Tanta Med J [serial online] 2017 [cited 2017 Dec 14];45:92-8. Available from: http://www.tdj.eg.net/text.asp?2017/45/2/92/216690
| Introduction|| |
Paracetamol (PCM) is a drug of the para-aminophenol group, which is generally considered quite safe at therapeutic doses, and is effective as an analgesic to relieve mild to moderate pain, as well as an antipyretic to reduce fever. However, overdosing or chronic use may lead to severe damage to some tissues, especially in the liver . Liver toxicity impairs various normal physiological functions like metabolism; susceptibility of the liver to injury is much higher than any other organ because of its central role in metabolism as well as its ability to concentrate and biotransform xenobiotics ,.
Chemical toxins include PCM, which is often used as the model substance causing experimental hepatocyte injury in both in-vivo and in-vitro conditions . PCM is considered as the most frequent cause of acute liver failure in many countries. Cytochrome P450 enzymes convert a relatively minor portion of PCM to the highly reactive intermediate metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is thought to be responsible for PCM-induced hepatic toxicity. Under normal physiological conditions, NAPQI conjugates with glutathione (GSH) and is detoxified. In PCM overdose, NAPQI is produced in excess of GSH detoxification capacity, and only part of it can be detoxified by conjugation with GSH. The remaining part of NAPQI subsequently binds to liver proteins and induces oxidative stress, mitochondrial dysfunction, and necrotic cell death . Oxidative stress is recently reported to play a major role in acetaminophen (APAP)-induced hepatotoxicity .
PCM overdose is also known to be associated with inflammation, marked by an increase in the inflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin, as well as the upregulation of nitrogen oxide from serum, macrophages, and hepatocytes .
There are numerous reports indicating that PCM-mediated oxidative stress or hepatotoxicity is attenuated by the use of naturally occurring antioxidants and/or free radical scavengers such as vitamins, medicinal plants, and flavonoids ,,. Recently, flavonoids have been found to play important roles in the nonenzymatic protection against oxidative stress . The antioxidant capacity of these molecules seems to be responsible for many of their beneficial effects and confers a therapeutic potential in diseases such as cardiovascular diseases, gastric or duodenal ulcers, and cancer and hepatic pathologies ,. Quercetin (3, 5, 7, 3′,4′-pentahydroxyflavone) is a polyphenolic flavonol molecule that occurs in many fruits and vegetables such as onions, apples, peanuts, potatoes, broccoli, grapes, and citrus fruits. Quercetin has been reported to have biological, pharmacological, and medicinal activities that are believed to arise from its antioxidant potentials, and can alleviate ethanol-elicited mitochondrial damage ,.
The present study was undertaken with quercetin, a very common dietary component, to examine its effects on PCM-induced hepatic toxicity in rats.
| Materials and methods|| |
Chemicals and kits
Quercetin was purchased from Sigma Chemical Co. (St. Louis, Missouri, USA) and was freshly dissolved in distilled water during treatment.
PCM was supplied by EIPICO (Ramadan City, Egypt), and was suspended in pathogen-free normal distilled water before use.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphate (ALP), serum albumin (Alb), and total bilirubin kits were purchased from Spectrum Diagnostics Co. (Cairo, Egypt). Total protein (TP), glutathione peroxidase (GPx), glutathione-s-transferase (GST), GSH, superoxide dismutase (SOD), lipid peroxidation (MDA), and catalase kits were purchased from Biodiagnostic Co. (Giza, Egypt). All other chemicals used throughout the experiments were of the highest analytical grade available.
Forty adult male albino rats weighing 180–200 g were obtained from the animal house in the Medical Research Institute, Alexandria University, Alexandria, Egypt. Rats were kept in plastic cages throughout the experimental period while maintaining a 12 h light-dark cycle at room temperature. The animals were provided with a standard laboratory diet and water. All protocols used in this study were approved by the Committee of Alexandria University.
The experimental animals were divided into four groups with 10 animals in each and were orally administered treatment as mentioned below:
Group I consisted of normal controls that received water and standard feed for 21 days
Group II consisted of rats that received quercetin orally at a dose of 50 mg/kg body weight (b.w.) daily through gavage for 21 days .
Group III consisted of rats that received PCM (500 mg/kg b.w.) daily for the last 5 days of the experimental period .
Group IV consisted of rats that were pretreated with the same dose of quercetin (50 mg/kg b.w.) alone for 16 days and thereafter received both quercetin (50 mg/kg b.w.) and PCM (500 mg/kg b.w.) for another 5 days.
Twenty-four hours after the end of the treatment period (i.e. day 21), blood samples were collected by cardiac puncture into sterile plastic tubes under ether anesthesia. Sera were separated using cooling centrifugation and stored at −20°C until analysis. The sera were used for the determination of ALT , AST , ALP , TP , Alb , and bilirubin .
The levels of serum tumor necrosis factor alpha (TNF-α) were measured using commercially available enzyme-linked immunosorbent assay kits .
Immediately after blood collection, the animals were killed by cervical dislocation, and thereafter the livers were rapidly removed. A part of each liver was weighed and homogenized using glass homogenizer with ice-cooled saline to prepare 25% W/V homogenate. This homogenate was centrifuged at 1700 rpm and at 40°C for 10 min; the supernatant was stored at −70°C until analysis. This supernatant was used for the colorimetrical determination of hepatic MDA  and the activities of SOD , CAT , GPx , GST , and GSH .
Statistical analysis of the data
Data were fed to the computer and analyzed using IBM SPSS software package version 20.0. (Armonk, NY: IBM Corp). F-test (ANOVA) was used for normally distributed quantitative variables to compare between more than two groups, and Post Hoc test (Tukey) for pairwise comparisons. Significance of the obtained results was judged at the 5% level.
| Results|| |
The means±SD values of biochemical parameters for all groups are presented in [Table 1] and [Figure 1],[Figure 2],[Figure 3].
|Table 1 Effect of quercetin on serum liver enzymes (aspartate transaminase, alanine transaminase, and alkaline phosphatase), bilirubin, total protein, albumin, and tumor necrosis factor-α in rats treated with paracetamol (n=10)|
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|Figure 1 Effect of quercetin on serum AST, ALT, and ALP (U/l) of paracetamol-induced hepatotoxicity in rats. ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; PCM, paracetamol; Q, quercetinb.|
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|Figure 2 Effect of quercetin on serum bilirubin (mg/dl) of paracetamol-induced hepatotoxicity in rats. PCM, paracetamol; Q, quercetin.|
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|Figure 3 Effect of quercetin on serum total protein and albumin (g/dl) of paracetamol-induced hepatotoxicity in rats. PCM, paracetamol; Q, quercetin.|
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The administration of PCM to rats resulted in a significant increased serum AST, ALT, and ALP levels (P≤0.001) when compared with the normal values ([Figure 1]). Levels of bilirubin were also significantly elevated in these rats when compared with that in controls ([Figure 2]). However, intoxication with PCM resulted in a significant (P≤0.001) decrease in serum TP and Alb levels ([Figure 3]). Prophylactic treatment with quercetin ameliorated these altered biochemical parameters toward normal values in comparison with the PCM group ([Figure 1],[Figure 2],[Figure 3]).
PCM, orally administered to rats, markedly increased serum TNF-α, whereas rats treated with quercetin before PCM (group IV) restored the altered values to near normality ([Figure 4]).
|Figure 4 Effect of quercetin on serum TNF-α (ng/ml) of paracetamol-induced hepatotoxicity in rats. PCM, paracetamol; Q, quercetin; TNF-α, tumor necrosis factor-α.|
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The means±SD values of the markers of oxidative stress for all groups are presented in [Table 2] and [Figure 5],[Figure 6],[Figure 7].
|Table 2 Effect of quercetin administration on hepatic malondialdehyde and antioxidant enzymes in rats treated with paracetamol (n=10)|
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|Figure 5 Effect of quercetin on liver MDA and GSH (μmol/mg) of paracetamol-induced hepatotoxicity in rats. GSH, glutathione; MDA, malondialdehyde; PCM, paracetamol; Q, quercetin.|
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|Figure 6 Effect of quercetin on liver SOD and CAT (μmol/mg) of paracetamol-induced hepatotoxicity in rats. CAT, catalase; PCM, paracetamol; Q, quercetin; SOD, superoxide dismutase.|
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|Figure 7 Effect of quercetin on liver GPX and GST (μmol/mg) of paracetamol-induced hepatotoxicity in rats. GPX, glutathione peroxidase; GST, glutathione-s-transferase; PCM, paracetamol; Q, quercetin.|
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Data in [Figure 5] showed a significant elevation in liver MDA content after PCM administration, whereas it caused marked depletion of hepatic GSH stores. Pretreatment with quercetin ameliorated MDA elevation and protected against GSH depletion, compared with the group treated with PCM.
The activities of antioxidant enzymes GPx, GST, SOD, and CAT were also found to be significantly lower in PCM-intoxicated rats when compared with the normal controls (P≤0.001). This effect was prevented by pretreatment with quercetin ([Figure 6] and [Figure 7]).
| Discussion|| |
The liver is highly affected primarily by toxic agents, and hence the liver marker enzymes are very sensitive markers of toxicity and have been found to be of great importance in the assessment of hepatic damage. Activities of ALT, AST, ALP, and the level of serum bilirubin are largely used as the most common biochemical markers to evaluate liver injury.
PCM-induced hepatic injury is considered as one of the most commonly used models and reliable method for screening of hepatoprotective agents . In the current study, the significant elevation of the enzyme levels, particularly AST, ALT, ALP and bilirubin level in rats treated with PCM, are indicative of cellular leakage and loss of functional integrity of the liver cell membrane . This is in agreement with previous studies, which reported that overdose of APAP could be toxic to the hepatocytes ,.
Coadministration of quercetin in this study suppresses the increased serum marker enzymes AST, ALT, and ALP, and the bilirubin level. Recovery toward normalization of the enzymes following quercetin treatment suggested that quercetin exhibits excellent hepatoprotective properties and has some role in preserving structural integrity of the hepatocellular membrane, thus preventing enzyme leakage into the blood circulation, as well as repairing of hepatic tissue damage caused by PCM. This effect is in agreement with the commonly accepted view that serum levels of transaminases return to normal with the healing of hepatic parenchyma and the regeneration of hepatocytes. ,.
In the present study, PCM intoxication also decreased serum TP and Alb, whereas it increased serum bilirubin. The liver is the major source of most of the serum proteins, in which the parenchymal cells are responsible for synthesis of Alb, fibrinogen, and other coagulation factors and most of the αglobulins and β-globulins .
TP reflects the functional status of the liver, because the liver is furnished with machineries for synthesizing serum proteins excluding γ-globulins. Thus, liver damage is characterized by hypoproteinemia and decreased Alb, which can affect the whole physiological status of animals ,.
Alb, being the most abundant plasma protein, accounts for 60% of the total serum protein and is incorporated in many physiological processes.
Qualitative and quantitative disturbance of protein synthesis is a consequence of impaired hepatic function. The observed decrease in Alb by PCM administration in the current study could be a result of a decline in the number of cells responsible for Alb synthesis in the liver through necrosis. The direct interference with the Alb −synthesizing mechanism in the liver as a result of inflammation may also be implicated for decrease in Alb .
The present work showed that the total bilirubin level was elevated by PCM administration, which is in accordance with Perlstein et al. , Replace:=wdReplaceAll, Format:=True, Forward:=True, MatchWildcards:=False, Wrap:=wdFindStop, who found that a high serum total bilirubin level may protect neurologic damage due to stroke. Others reported that serum bilirubin significantly contributes to total antioxidant capacity. It was discovered that bilirubin had anti-inflammatory effects as well as acting as a scavenger of reactive oxygen species .
In the present study, a significant increase (P<0.05) in serum TP and Alb, and decreased serum bilirubin in the quercetin pretreated group suggests increased protein synthesis. The reports of Malami et al.  are in accordance with our findings, showing increased content of TP and Alb levels in CCl4-induced hepatotoxicity when treated with aqueous extract of Mangifera indica stem bark.
Inflammation has been considered as a protective reaction against invading pathogens or chemicals in order to maintain body health . During inflammation, many cytokines are upregulated and accumulated in the liver; among them, TNF-α has been implicated as a critical mediator of APAP −induced hepatotoxicity . Serum TNF-α content was markedly increased after PCM administration, as shown in the current investigation, suggesting that a severe inflammatory reaction had taken place. These results are in harmony with those of Farghaly and Hussein ,which showed that hepatocytes treated with PCM release factors that activate proinflammatory cytokines such as TNF-α and interleukins. In addition, the involvement of Kupffer cells, TNF-α, and interleukin 1-α in APAP hepatotoxicity have been reported .
In the current study, oral administration of quercetin at a concentration of 50 mg/kg b.w. daily before PCM administration produced a significant decrease in serum TNF-α level and exhibits anti-inflammatory properties by inhibiting the activities of TNF-α in the serum.
Mechanisms of hepatoprotection that could take place include prevention of the process of MDA. The elevated levels of MDA demonstrated in the present study are in accordance with those of other investigators who reported the association between PCM toxicity and MDA. However, the levels of MDA were significantly decreased in quercetin pretreated rats compared with the PCM-treated group, indicating that quercetin may exert antioxidant activities and protect the tissues from lipid peroxidation. This result was supported by previous studies showing that quercetin induced reduction of the increased level of MDA ,.
In the present study, PCM treatment caused significant reduction in GSH levels with simultaneous inhibition in the activities of antioxidant enzymes GPx, GST, SOD, and CAT in rats. This agrees with the report of Sabiu et al. , where APAP −mediated hepatic oxidative insults in rats had induced significant decrease in the activities of antioxidant enzymes.
In quercetin-treated animals, SOD activity is increased, which could be due to the increase in GPx activity that lowered the levels of H2O2, thereby preventing the retroinhibition on SOD. This is in accordance with earlier reports .
Furthermore, quercetin restored the reduced activities of GSH-related enzymatic antioxidants. Quercetin is recognized to have a strong scavenging activity of oxygen radicals and protection against lipid and protein oxidation, which have been primarily attributed to its flavonoid fraction ,,,,,.
Quercetin supplementation attenuated all alterations in antioxidant enzymes SOD, CAT, and reduced GSH in PCM-treated animals. Quercetin showed beneficial effects on liver damage by enhancing antioxidant enzyme activity and decreasing pro-oxidant effect . This is due to the ability of quercetin to interact with hydroxyl, superoxide, alkoxyl, and peroxyl radicals thereby subsequently scavenging them. This agrees with recent reports by Eldin and colleagues ,,,.
| Conclusion|| |
The results of the present study suggest that quercetin may exert antioxidant and anti-inflammatory activities. These findings led us to postulate that quercetin may offer a new strategy for prophylactically treating PCM-induced hepatic damage.
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]
[Table 1], [Table 2]