HEPATOPROTECTIVE EFFECT OF MELATONIN ON PARACETAMOL INDUCED HEPATOTOXICITY IN ALBINO RATS

DEEPAK SHANKARAPPA; LOURDU JAFRIN A; JAYAPRIYA B; MAHARANI B

doi:10.22159/ajpcr.2021.v14i9.42539

Authors

DEEPAK SHANKARAPPA Department of Pharmacology, Madurai medical college (previously), General Practitioner, Bengaluru, Karnataka, India.
LOURDU JAFRIN A Department of Pharmacology, Indira Gandhi Medical College and Research Institute, Pondicherry, India.
JAYAPRIYA B Department of Pharmacology, Govt. Medical College, Virudhunagar, Tamil Nadu, India.
MAHARANI B Department of Pharmacology, Indira Gandhi Medical College and Research Institute, Pondicherry, India.

DOI:

https://doi.org/10.22159/ajpcr.2021.v14i9.42539

Keywords:

Drug-induced liver injury, hepatotoxicity, paracetamol, N-acetyl cysteine, melatonin

Abstract

Objective: Liver is the most important organ involved in the biotransformation of drugs and hence also a prime site for drug-induced liver injury (DILI). Among the hepatotoxic drugs, paracetamol which is commonly used is a major offender, leading to about 40% of DILI. N-acetyl cysteine is commonly used to manage paracetamol poisoning. However, it has its own disadvantages. This study has been designed to probe into the possibility of an alternative drug for paracetamol-induced hepatotoxicity. The objective is to study the hepatoprotective effect of melatonin on paracetamol-induced hepatotoxicity in albino rats.

Materials and Methods: After prior approval from the IAEC, 36 albino rats were divided into six groups of six each. Each group received distilled water, paracetamol, paracetamol+N-acetyl cysteine, paracetamol+melatonin, and paracetamol+melatonin+N-acetyl cysteine, respectively. The liver function tests and histopathology of the liver of all the groups were compared. One-way ANOVA and post hoc Dunnett’s test were used.

Results: Melatonin alone and in combination with N-acetyl cysteine is found to have significant hepatoprotective effect in paracetamol-induced acute liver injury.

Conclusion: The main reason for hepatotoxicity is depletion of glutathione which is essential for conjugating the toxic metabolite N acetyl-p- benzoquinonimine (NAPQI) and CYP2E1 is playing the vital role of being the rate limiting enzyme initiating the cascade of events leading to acetaminophen hepatotoxicity. This is postulated to be reversed by melatonin.

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References

Shapiro MA, Lewis JH. Causality assessment of drug-induced hepatotoxicity: Promises and pitfalls. Clin Liver Dis 2007;11:477-505.

Shen T, Liu Y, Shang J, Xie Q, Li J, Yan M, et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology 2019;156:2230-41.e11.

Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullak-Ublick GA, Watkins PB, et al. Drug-induced liver injury. Nat Rev Dis Primers 2019;5:58.

Lee WM. Drug-induced hepatotoxicity.N Engl J Med 2003;349:474-85.

Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: Results of a United States multicenter, prospective study. Hepatology 2005;42:1364-72.

Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc 2014;89:95-106.

Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135:1924-34, 1934.e1-4.

Ribeiro AJ, Yang X, Patel V, Madabushi R, Strauss DG. Liver microphysiological systems for predicting and evaluating drug effects. Clin Pharmacol Ther 2019;106:139-47.

Grant DM. Detoxification pathways in the liver.J Inherit Metab Dis 1991;14:421-30.

García-Suástegui WA, Ramos-Chávez LA, Rubio-Osornio M, Calvillo- Velasco M, Atzin-Méndez JA, Guevara J, et al. The role of CYP2E1 in the drug metabolism or bioactivation in the brain. Oxid Med Cell Longev 2017;2017:4680732.

Ahmed OM, Fahim HI, Ahmed HY, Al-Muzafar HM, Ahmed RR, Amin KA, et al. The preventive effects and the mechanisms of action of navel orange peel hydroethanolic extract, Naringin, and Naringenin in N-acetyl-p-aminophenol-induced liver injury in Wistar rats. Oxid Med Cell Longev 2019;2019:2745352.

Brune K, Renner B, Tiegs G. Acetaminophen/paracetamol:A history of errors, failures and false decisions. Eur J Pain 2015;19:953-65.

Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, et al. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology 1998;27:748-54.

Walker RM, Racz WJ, McElligott TF. Acetaminophen-induced hepatotoxic congestion in mice. Hepatology 1985;5:233-40.

Laskin DL, Pilaro AM, Ji S. Potential role of activated macrophages in acetaminophen hepatotoxicity. II. Mechanism of macrophage accumulation and activation. Toxicol Appl Pharmacol 1986;86:216-26.

Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine-a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007;7:355-9.

Hu J, Zhang Q, Ren X, Sun Z, Quan Q. Efficacy and safety of acetylcysteine in “non-acetaminophen” acute liver failure:A meta-analysis of prospective clinical trials. Clin Res Hepatol Gastroenterol 2015;39:594-9.

Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther 2014;141:150-9.

Liang YL, Zhang ZH, Liu XJ, Liu XQ, Tao L, Zhang YF, et al. Melatonin protects against apoptosis-inducing factor (AIF)-dependent cell death during acetaminophen-induced acute liver failure. PLoS One 2012;7:e51911.