Quercitrin from Toona sinensis (Juss.) M.Roem. Attenuates Acetaminophen-Induced Acute Liver Toxicity in HepG2 Cells and Mice through Induction of Antioxidant Machinery and Inhibition of Inflammation.

Van-Long Truong,Se-Yeon Ko,Woo-Sik Jeong,Mira Jun

doi:10.3390/nu8070431

Abstract

Quercitrin is found in many kinds of vegetables and fruits, and possesses various bioactive properties. The aim of the present study was to elucidate hepatoprotective mechanisms of quercitrin isolated from Toona sinensis (Juss.) M.Roem. (syn. Cedrela sinensis Juss.), using acetaminophen (APAP)-treated HepG2 cell and animal models. In an in vitro study, quercitrin suppressed the production of reactive oxygen species and enhanced expression of nuclear factor E2-related factor 2 (Nrf2), activity of antioxidant response element (ARE)-reporter gene, and protein levels of NADPH: quinone oxidoreductase 1 (NQO1), catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase 2 (SOD-2) in APAP-treated HepG2 cells. In an in vivo study, Balb/c mice were orally administered with 10 or 50 mg/kg of quercitrin for 7 days and followed by the injection with single dose of 300 mg/kg APAP. Quercitrin decreased APAP-caused elevation of alanine aminotransferase and aspartate aminotransferase levels, liver necrosis, the expression of pro-inflammatory factors including inducible nitric oxide synthase, cyclooxygenase 2 and inerleukin-1β, and phosphorylation of kinases including c-Jun N-terminal kinase and p38. Quercitrin restored protein levels of Nrf2, NQO1 and activities and expressions of CAT, GPx, SOD-2. The results suggested that quercitrin attenuates APAP-induced liver damage by the activation of defensive genes and the inhibition of pro-inflammatory genes via the suppressions of JNK and p38 signaling.

Highlights

Acetaminophen (APAP, marketed as Paracetamol® or Tylenol® ), a widely used over-the-counter analgesic and antipyretic drug, is safe and effective at therapeutic dose
Pretreatment with quercitrin for 1 h blocked the effect of APAP on the decreased expression of antioxidant enzymes. These results obviously suggested that quercitrin prevents APAP‐induced reactive oxygen species (ROS) formation and cell death through the induction of antioxidant enzymes in HepG2 cells
The results showed that treatment of 300 mg/kg APAP caused slightly reduced protein expressions of these antioxidant enzymes

Summary

Introduction

Acetaminophen (APAP, marketed as Paracetamol® or Tylenol® ), a widely used over-the-counter analgesic and antipyretic drug, is safe and effective at therapeutic dose. It can cause acute liver failures such as serve hepatic necrosis, hepatic lesions and cirrhosis, and even death when taken in high doses. APAP-induced hepatotoxicity is initiated by formation of excess reactive intermediate. NAPQI depletes cellular glutathione (GSH) and adenosine triphosphate (ATP), causes mitochrondrial dysfunction and damage, and causes DNA fragmentation and apoptosis. Acetaminophen contributes to overproduction of reactive oxygen species (ROS) [2]. Lipid peroxidation resulting from oxidative stress has been demonstrated to contribute to the initiation and progression of APAP-induced liver damage [3]. Accumulating evidence indicates that acetaminophen overdose triggers the transcriptional activation

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