2. Academic Validation
  3. Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice

Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice

  • Toxicol Lett. 2018 Jun 15:290:97-109. doi: 10.1016/j.toxlet.2018.03.024.
Ming-Shiun Tsai 1,  Ying-Han Wang 2,  Yan-Yun Lai 2,  Hsi-Kai Tsou 3,  Gan-Guang Liou 4,  Jiunn-Liang Ko 5,  Sue-Hong Wang 6
Affiliations

Affiliations

  • 1 Department of BioIndustry Technology, Da-Yeh University, Taiwan, ROC.
  • 2 Department of Biomedical Sciences, Chung Shan Medical University, Taiwan, ROC.
  • 3 Functional Neurosurgery Division, Neurological Institute, Taichung Veterans General Hospital, Taiwan, ROC.
  • 4 Institute of Molecular Biology, Academia Sinica, Taiwan, ROC.
  • 5 Institute of Medicine, Chung Shan Medical University, Taiwan, ROC.
  • 6 Department of Biomedical Sciences, Chung Shan Medical University, Taiwan, ROC; Department of Medical Research, Chung Shan Medical University Hospital, Taiwan, ROC. Electronic address: wangsh@csmu.edu.tw.
PMID: 29574133 DOI: 10.1016/j.toxlet.2018.03.024
Abstract

Acetaminophen (APAP) overdose can induce acute liver injury (ALI) with significant morbidity and mortality. Propacetamol is an APAP prodrug, which is clinically bioequivalent to APAP. Kaempferol, a dietary flavonoid, has antioxidant, anti-inflammatory, and anti-apoptotic effects. In this study, we investigated the protective effect of kaempferol on propacetamol-induced ALI and its underlying mechanism in mice. Kaempferol pretreatment (125 mg/kg) before propacetamol injection significantly decreased propacetamol-induced serum ALT and AST activities, and DNA fragmentation. Kaempferol administration also reduced propacetamol-induced oxidative stress by inhibiting thiobarbituric acid reactive substances (TBARS) and 3-nitrotyrosine (3-NT) formation partly through downregulation of Cytochrome P450 2E1 (CYP2E1) expression, upregulation of UDP glucuronosyltransferase family 1 member A1 (UGT1A1) expression, restoration of the activities of antioxidant Enzymes including SOD, GPx and catalase toward normal, recovery of propacetamol-suppressed Nrf2 and GCLC expressions, and maintenance of normal glutathione level. Furthermore, kaempferol markedly attenuated APAP-induced serum TNF-α and IL-6 productions, downregulated APAP-induced phosphorylations of JNK and ERK, and decreased early hepatic Apoptosis via decreasing Bax/Bcl-2 ratio and Caspase 3 activation. Furthermore, administration of N-acetylcysteine (NAC) and kaempferol significantly rescued more mice than a low dose of NAC only did when a lethal dose of propacetamol injected and therapized at a delayed time point. These data suggested that kaempferol protects the liver against propacetamol-induced injury through anti-oxidative, anti-inflammatory and anti-apoptotic activities.

Keywords

Acetaminophen-induced acute liver injury; Anti-apoptosis; Anti-inflammation; Anti-oxidation; Kaempferol; Liver protection.

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