Hesperetin attenuated acetaminophen-induced hepatotoxicity by inhibiting hepatocyte necrosis and apoptosis, oxidative stress and inflammatory response via upregulation of heme oxygenase-1 expression

Int Immunopharmacol. 2020 Jun:83:106435. doi: 10.1016/j.intimp.2020.106435. Epub 2020 Mar 26.

Abstract

Acetaminophen (APAP) is a common antipyretic and analgesic drug, but its overdose can induce acute liver failure with lack of effective therapies. Hesperetin, a dihydrogen flavonoid compound, has been revealed to exert multiple pharmacological activities. Here, we explored the protective effects and mechanism of hesperetin on APAP-induced hepatotoxicity. The results showed that pretreatment with hesperetin dose-dependently attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities, hepatic pathological damage and apoptosis. Moreover, hesperetin mitigated APAP-induced oxidative stress and inflammatory response in mice by inhibiting oxidative molecules but increasing antioxidative molecules production, reducing inflammatory cells infiltration and proinflammatory cytokines production, blocking Toll-like receptor (TLR)-4 signal activation. In vitro experiment indicated that hesperetin dose-dependently inhibited APAP-primed cytotoxicity, apoptosis, and reactive oxygen species (ROS) in murine AML12 hepatocytes. Notably, hesperetin up-regulated expression of heme oxygenase-1 (HO-1) mRNA and protein in the liver of mice and AML12 cells exposed to APAP. Furthermore, knockdown of HO-1 by adenovirus-mediated HO-1 siRNA reverted these beneficial effects of hesperetin on APAP-induced hepatocytotoxicity as well as ROS and inflammatory response in vivo and in vitro. These findings demonstrated that hesperetin exerted a protective prophylaxis on APAP-induced acute liver injury by inhibiting hepatocyte necrosis and apoptosis, oxidative stress and inflammatory response via up-regulating HO-1 expression.

Keywords: Acetaminophen (APAP); Heme oxygenase (HO)-1; Hepatotoxicity; Hesperetin; Inflammatory response; Oxidative stress.

MeSH terms

  • Acetaminophen / toxicity*
  • Animals
  • Apoptosis / drug effects
  • Cell Death / drug effects
  • Cell Line
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Dose-Response Relationship, Drug
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Hepatocytes / cytology
  • Hepatocytes / drug effects*
  • Hesperidin / pharmacology*
  • Hesperidin / therapeutic use*
  • Inflammation / drug therapy
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Necrosis / prevention & control
  • Oxidative Stress / drug effects
  • Transaminases / blood
  • Up-Regulation

Substances

  • Acetaminophen
  • Hesperidin
  • Heme Oxygenase-1
  • Transaminases
  • hesperetin