3,4-Dihydroxyphenylacetic acid, a microbiota-derived metabolite of quercetin, attenuates acetaminophen (APAP)-induced liver injury through activation of Nrf-2

Abstract

1. Acetaminophen (APAP) overdose leads to severe hepatotoxicity. 3,4-dihydroxyphenylacetic acid (DOPAC) is a scarcely studied microbiota-derived metabolite of quercetin. The aim of this study was to determine the protective effect of DOPAC against APAP-induced liver injury.

2. Mice were treated intragastrically with DOPAC (10, 20 or 50 mg/kg) for 3 days before APAP (300 mg/kg) injection. APAP alone caused increase in serum aminotransferase levels and changes in hepatic histopathology. APAP also promoted oxidative stress by increasing lipid peroxidation and decreasing anti-oxidant enzyme activities. These events led to hepatocellular necrosis and reduced liver function. DOPAC increased nuclear factor erythroid 2-related factor 2 (Nrf-2) translocation to the nucleus and enhanced the expression of phase II enzymes and anti-oxidant enzymes, and thereby reduced APAP hepatotoxicity and enhanced anti-oxidant ability.

3. Our data provide evidence that DOPAC protected the liver against APAP-induced injury, which is involved in Nrf-2 activation, implying that DOPAC can be considered as a potential natural hepatoprotective agent.

• 3,4-Dihydroxyphenylacetic acid
• acetaminophen
• hepatic detoxification
• Nrf-2
• quercetin

Acknowledgments

We thank Prof. Dr. Gordon M. Kirby, from University of Guelph, Canada, for proofreading the manuscript.

Declaration of interest

The authors declare that there are no conflicts of interest. This work was financially supported by the high-end foreign experts recruitment program of State Administration of Foreign Experts Affairs (GDW20146100228); the Ministry of Education and State Administration of Foreign Experts Affairs “overseas teacher” project (MS2011XBNL057); the Key International Cooperation Base of Shaanxi Province, China (2015SD0018).