The Ameliorative Effects of L-2-Oxothiazolidine-4-Carboxylate on Acetaminophen-Induced Hepatotoxicity in Mice

Jiwon Choi,Kwang-Hyun Park,Jun Shin,Seon-Il Jang,Sung Kim

doi:10.3390/molecules18033467

Abstract

The aim of the study was to investigate the ameliorative effects and the mechanism of action of l-2-oxothiazolidine-4-carboxylate (OTC) on acetaminophen (APAP)-induced hepatotoxicity in mice. Mice were randomly divided into six groups: normal control group, APAP only treated group, APAP + 25 mg/kg OTC, APAP + 50 mg/kg OTC, APAP + 100 mg/kg OTC, and APAP + 100 mg/kg N-acetylcysteine (NAC) as a reference control group. OTC treatment significantly reduced serum alanine aminotransferase and aspartate aminotransferase levels in a dose dependent manner. OTC treatment was markedly increased glutathione (GSH) production and glutathione peroxidase (GSH-px) activity in a dose dependent manner. The contents of malondialdehyde and 4-hydroxynonenal in liver tissues were significantly decreased by administration of OTC and the inhibitory effect of OTC was similar to that of NAC. Moreover, OTC treatment on APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner. Furthermore, the activity of caspase-3 in liver tissues was reduced by administration of OTC in a dose dependent manner. The ameliorative effects of OTC on APAP-induced liver damage in mice was similar to that of NAC. These results suggest that OTC has ameliorative effects on APAP-induced hepatotoxicity in mice through anti-oxidative stress and anti-apoptotic processes.

Highlights

Acetaminophen (APAP) is one of the most common analgesic and antipyretic drug and it has been used as a powerful tool to study mechanisms of hepatotoxicity
APAP-induced hepatotoxicity significantly reduced the formation of nitrotyrosin and terminal deoxynucleotidyl transferase dUTP nick end labeling positive areas of liver tissues in a dose dependent manner
OTC Treatment was Effective in Preventing APAP-induced Liver Damage

Summary

Introduction

Acetaminophen (APAP) is one of the most common analgesic and antipyretic drug and it has been used as a powerful tool to study mechanisms of hepatotoxicity It is safe at therapeutic doses, overdoses of APAP can cause severe liver injury or acute liver failure and during the last decade, APAP became the most frequent cause of acute liver failure in many countries [1]. APAP-induced reactive metabolites deplete glutathione (GSH) and subsequently cause protein binding, as a critical event in the toxicity [2,3,4]. Based on this mechanism, N-acetylcysteine (NAC) has been used to treat patients with APAP-induced toxicity [5], and NAC is the most popular therapeutic agent for this application [6]. Patients presenting later may benefit from increased metabolic flux, but the likelihood of a positive outcome is notably decreased [7,8]

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