Basic Study
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World J Hepatol. Nov 27, 2020; 12(11): 949-964
Published online Nov 27, 2020. doi: 10.4254/wjh.v12.i11.949
Aceclofenac-induced hepatotoxicity: An ameliorative effect of Terminalia bellirica fruit and ellagic acid
Ashutosh Gupta, Abhay K Pandey
Ashutosh Gupta, Abhay K Pandey, Department of Biochemistry, University of Allahabad, Prayagraj 211002, Uttar Pradesh, India
Author contributions: Pandey AK conceptualized and designed the study; Gupta A performed the experiments, collected the data, and wrote the manuscript; Gupta A and Pandey AK analyzed and interpreted the data; Pandey AK critically reviewed and finalized the manuscript. All authors have read and approved the final manuscript.
Institutional animal care and use committee statement: The study was reviewed and approved by the Institutional Animal Ethics Committee, University of Allahabad, Prayagraj, India (IAEC/AU/2019(1)/16).
Conflict-of-interest statement: The authors declare that there are no conflicts of interest.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Abhay K Pandey, PhD, Professor, Department of Biochemistry, University of Allahabad, Prayagraj - 211002, Uttar Pradesh, India. akpandey23@rediffmail.com
Received: June 16, 2020
Peer-review started: June 16, 2020
First decision: August 22, 2020
Revised: September 5, 2020
Accepted: September 22, 2020
Article in press: September 22, 2020
Published online: November 27, 2020
Processing time: 160 Days and 19.7 Hours
Abstract
BACKGROUND

Aceclofenac (ACF), a widely used nonsteroidal anti-inflammatory drug, has been associated with a number of severe cases of clinical hepatotoxicity. Terminalia bellirica, an evergreen tree, is known to have several ethnomedicinal uses including antioxidant and hepatoprotective effects. Hence T. bellirica fruit extracts and its phytoconstituent ellagic acid (EA) are expected to provide protection against oxidative stress and liver damage produced by long-term use of ACF.

AIM

To evaluate the antioxidant and hepatoprotective activities of T. bellirica fruit extracts and EA against ACF-induced toxicity in albino Wistar rats.

METHODS

The in vitro antioxidant activities of T. bellirica fruit ethyl acetate and aqueous extracts were measured by metal ion chelation and nitric oxide radical scavenging assays. The in vivo antioxidant and hepatoprotective effects of T. bellirica extracts (200 mg/kg) and EA (40 mg/kg) in ACF-induced hepatotoxic rats were assessed in serum and liver tissue after oral administration for 21 d. Silymarin (40 mg/kg) was used as a standard control. Oxidative stress markers in the blood (ferric reducing ability of plasma and lipid peroxidation inhibition) and liver tissues (superoxide dismutase, catalase and malondialdehyde) were analyzed using standard protocols. Liver function markers such as alkaline phosphatase, glutamic pyruvic transaminase, glutamic oxaloacetic transaminase, lactate dehydrogenase, γ-glutamyl transferase, creatinine, total protein, and uric acid were evaluated in rat serum.

RESULTS

The T. bellirica fruit ethyl acetate extract exhibited superior metal ion chelating and nitric oxide radical scavenging abilities during in vitro antioxidant assays as compared to aqueous extracts. Oral administration of ACF in rats (15 mg/kg) for 21 d produced oxidative stress and adversely affected liver function suggesting liver injury. Treatment with extracts (ethyl acetate and aqueous), EA and silymarin accounted for a significant reduction in the adverse effects of ACF on oxidative stress and liver function markers in serum and hepatic tissue in rats. Histopathological evaluation of the liver indicated that the extracts and EA significantly decreased the degree of liver damage. The in vivo efficacy of EA was higher than T. bellirica fruit extracts. Of these extracts, ethyl acetate extract revealed comparatively better antioxidant and hepatoprotective activity.

CONCLUSION

Ellagic acid and T. bellirica fruit extracts exhibited considerable hepatoprotective and antioxidant activities in long-term ACF-treated rats.

Keywords: Terminalia bellirica; Ellagic acid; Aceclofenac; Hepatotoxicity; Antioxidant; Histopathology

Core Tip: Hepatotoxicity is the most serious adverse effects of aceclofenac (ACF). In this study, ACF-induced hepatic damage in rats was investigated. ACF administration (15 mg/kg/d) for 21 d produced severe hepatotoxicity and oxidative stress as demonstrated by abnormal elevations in serum and tissue markers. Co-administration of Terminalia bellirica fruit extracts (200 mg/kg) and ellagic acid (40 mg/kg) significantly attenuated ACF-induced hepatotoxicity. These results showed that supplementation with the test compounds led to restoration of serum liver function markers (SGOT, GPT, GGT, LDH, ALP, total protein, urea, uric acid, creatinine) and hepatic antioxidant status (superoxide dismutase, catalase, TBARS). Hence T. bellirica fruit extracts and ellagic acid have the potential to act as a hepatoprotectant and antioxidant in the treatment of drug-induced hepatotoxicity and oxidative stress. To the best of our knowledge, this is the first study to evaluate the therapeutic efficacy of T. bellirica fruit extracts and ellagic acid as hepatoprotective agents against ACF-induced hepatotoxicity.