Tempol Protects Against Acetaminophen Induced Acute Hepatotoxicity by Inhibiting Oxidative Stress and Apoptosis.

Zheng Ge,Junjie Zhang,Chenyu Wang,Junhong Hu,Xiwang Li

doi:10.3389/fphys.2019.00660

Zheng Ge, Junjie Zhang + Show 3 more

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https://doi.org/10.3389/fphys.2019.00660

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Abstract

Acetaminophen (APAP)-induced acute hepatotoxicity is the leading cause of drug-induced acute liver failure. The aim of this study was to evaluate the effects of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (tempol) on the protection of APAP-induced hepatotoxicity in mice. Mice were pretreated with a single dose of tempol (20 mg/kg per day) orally for 7 days. On the seventh day, mice were injected with a single dose of APAP (300 mg/kg) to induce acute hepatotoxicity. Our results showed that tempol treatment markedly improved liver functions with alleviations of histopathological damage induced by APAP. Tempol treatment upregulated levels of antioxidant proteins, including superoxide dismutase, catalase, and glutathione. Also, phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt) and protein expression of nuclear factor erythroid 2-related factor (Nrf 2) and heme oxygense-1 (HO-1) were all increased by tempol, which indicated tempol protected against APAP-induced hepatotoxicity via the PI3K/Akt/Nrf2 pathway. Moreover, tempol treatment decreased pro-apoptotic protein expressions (cleaved caspase-3 and Bax) and increased anti-apoptotic Bcl-2 in liver, as well as reducing apoptotic cells of TUNEL staining, which suggested apoptotic effects of tempol treatment. Overall, we found that tempol normalizes liver function in APAP-induced acute hepatotoxicity mice via activating PI3K/Akt/Nrf2 pathway, thus enhancing antioxidant response and inhibiting hepatic apoptosis.

Highlights

Acetaminophen (APAP) is a widely used drug for its antipyretic and analgesic properties
We found that tempol treatment significantly improved pathological changes in hepatic function parameters and liver histological changes induced by APAP
There changes in APAP group were all reduced by tempol treatment, which may due to the protective effects of tempol on the hepatic cellular structures and membranes

Summary

Introduction

Acetaminophen (APAP) is a widely used drug for its antipyretic and analgesic properties. It was reported that APAP-induced acute hepatotoxicity is the most common cause of druginduced acute liver injury and liver failure in many countries (Canbay et al, 2009; Blieden et al, 2014). Previous studies used 300 mg/kg APAP to induce acute liver injury in mice to explore the underlying pathogenesis (Huang et al, 2017; Liao et al, 2017; Cai et al, 2018). The detailed mechanisms of APAP-induced acute liver injury are still not fully clear. Great efforts should be made to further understand the exact mechanism of APAP-induced liver toxic effects

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