Tangeretin and 4′-demethyltangeretin prevent damage to mouse hepatocytes from oxidative stress by activating the Nrf2-related antioxidant pathway via an epigenetic mechanism

Zheng Yuan Su*, Jen Chun Chien, Yen Chen Tung, Tien Yuan Wu, Jie An Liao, Guor Jien Wei*

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review

Abstract

Polymethoxyflavones (PMFs) in citrus fruits have a variety of biological activities, including antioxidant, anti-inflammatory, anticancer, and anti-atherosclerotic effects. The liver is the major detoxifying organ of the human body; however, factors such as acetaminophen (APAP) overdose may increase oxidative stress in liver cells and lead to severe liver failure. In this study we examined the effects of tangeretin (TAN), a common citrus PMF, and its metabolite 4′-demethyltangeretin (4′-OH-TAN) on activation of the Nrf2 antioxidant system in mouse AML-12 hepatocytes through regulation by epigenetic mechanisms. The ability of TAN and 4′-OH-TAN to inhibit APAP-induced hepatotoxicity was also evaluated. The results showed that TAN and 4′-OH-TAN significantly increased the mRNA and protein levels of Nrf2 and Nrf2-mediated antioxidant and detoxifying enzymes (UGT1A, HO-1, and NQO1) in AML-12 cells. TAN and 4′-OH-TAN also suppressed protein expression of histone deacetylases (HDACs) and DNA methyltransferases (DMNTs) and reduced DNA methylation of the nrf2 promoter. Furthermore, TAN and 4′-OH-TAN prevented APAP-induced injury and inhibited APAP-induced ROS generation in AML-12 cells. Based on these results, we conclude that TAN and 4′-OH-TAN may increase the antioxidant capacity of liver cells by regulating epigenetic alteration to activate the Nrf2-related antioxidant system, thereby preventing liver cells from being damaged by APAP-induced oxidative stress.

Original languageEnglish
Article number110650
JournalChemico-Biological Interactions
Volume382
DOIs
StatePublished - 1 Sep 2023

Keywords

  • 4′-demethyltangeretin
  • Acetaminophen
  • Epigenetics
  • Liver
  • Nrf2
  • Oxidative stress
  • Tangeretin

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