Effects of treatment with sitagliptin on hepatotoxicity induced by acetaminophen in mice

Wafaa Ahmed Hewedy

doi:10.1590/s2175-97902019000418482

Wafaa Ahmed Hewedy

Open Access

https://doi.org/10.1590/s2175-97902019000418482

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Abstract

Up to date, the management of hepatotoxicity induced by a suicidal or unintentional overdose of acetaminophen (APAP) remains a therapeutic challenge. The present study aimed to elucidate the potential effect of sitagliptin, a DPP-4 inhibitor, to ameliorate the acute injurious effects of acetaminophen on the liver. APAP toxicity was induced in mice by an intraperitoneal injection of APAP (400 mg/kg). The effect of treatment with sitagliptin, initiated 5 days prior to APAP injection, was evaluated. Serum indices of hepatotoxicity, oxidative stress markers in liver tissues, serum IL-1β, and TNF-α in addition to hepatic- NF-E2-related factor-2 (Nrf2) were determined. Our results showed that APAP induced marked hepatic injury as evidenced by an increase in serum levels of ALT and AST, in addition to the deterioration of histological grading. Oxidative stress markers, serum TNF-α, and IL-1β were also elevated. Sitagliptin successfully ameliorated the histological changes induced by APAP, improving liver function tests and liver oxidant status accompanied with a marked increase in Nrf2 level in hepatic tissues. Thus, the hepatoprotective effects of sitagliptin in this animal model seem to involve Nrf2 modulation, coincidental with its anti-inflammatory and antioxidant effects.

Highlights

Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is considered as a serious and silent killer
The increases in serum ALT and AST levels were successively attenuated by sitagliptin administration (10 mg/kg/day) for 5 days prior to APAP injection
We evaluated hepatic oxidative status in the liver tissues by measuring malondialdehyde (MDA) content, as an end-product of lipid peroxidation, reduced glutathione, and glutathione peroxidase activity

Summary

Introduction

Acetaminophen (N-acetyl-p-aminophenol; APAP) overdose is considered as a serious and silent killer. It may initially present with few, if any, symptoms that may progress into acute liver failure and death if not treated promptly (Lancaster, Hiatt, Zarrinpar, 2015). Chronic liver injury is recognized in some patients on long-term APAP treatment (Watelet et al, 2007). Malnutrition, chronic alcohol misuse, and nonalcoholic fatty liver disease (NAFLD) are recognized as risk factors for APAP-induced hepatotoxicity (Michaut et al, 2014). N-Acetylcysteine remains the gold standard for acute APAP-hepatotoxicity (Lancaster, Hiatt, Zarrinpar, 2015). Once acute liver failure is developed, the role of NAC is questionable. Efforts in developing novel treatments for APAP-induced hepatotoxicity, with more potency than N-acetyl cysteine, are warranted

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