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Am J Chin Med. 2019;47(8):1833-1851. doi: 10.1142/S0192415X19500939. Epub 2019 Dec 3.

Aged Citrus Peel (Chenpi) Prevents Acetaminophen-Induced Hepatotoxicity by Epigenetically Regulating Nrf2 Pathway.

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Department of Bioscience Technology, Chung Yuan Christian University, Taoyuan City, Taiwan.
Institute of Food Science and Technology, National Taiwan University, Taipei, Taiwan.
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan.
Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan.


Excessive consumption of analgesic drug acetaminophen (APAP) can cause severe oxidative stress-mediated liver injury. Here, we investigated the protective effect and mechanism of aged citrus peel (Chenpi, CP), a Chinese herb usually used in foods in Asia, against APAP-induced hepatotoxicity. CP water (CP-WE), ethanolic (CP-EE), and water extraction residue ethanolic (CP-WREE) extracts were prepared. We found that CP-WREE contained higher content of bioactive flavonoids, including narirutin, nobiletin, and tangeretin, and more effectively enhanced the Nrf2 pathway in ARE-luciferase reporter gene transfected human HepG2-C8 cells. In mouse AML-12 hepatocytes, CP-WREE minimized APAP-induced damage and lipid peroxidation and increased mRNA and protein expressions of Nrf2 and its downstream defense enzymes (HO-1, NQO1, and UGT1A). CP-WREE also downregulated HDACs and DNMTs, upregulated KDMs, and increased the unmethylated Nrf2 promoter level. Additionally, CP-WREE blocked in vitro DNA methyltransferase activity. Taken together, CP-WREE might attenuate oxidative stress-induced hepatotoxicity through epigenetically regulating Nrf2-mediated cellular defense system.


Acetaminophen; Aged Citrus Peel; Epigenetics; Hepatotoxicity; Liver; Nrf2


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