Kaempferol protects against propacetamol-induced acute liver injury through CYP2E1 inactivation, UGT1A1 activation, and attenuation of oxidative stress, inflammation and apoptosis in mice. |
| Authors: |
Tsai, Ming-Shiun Wang, Ying-Han Lai, Yan-Yun Tsou, Hsi-Kai Liou, Gan-Guang Ko, Jiunn-Liang Wang, Sue-Hong
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| Citation: |
Tsai MS, etal., Toxicol Lett. 2018 Jun 15;290:97-109. doi: 10.1016/j.toxlet.2018.03.024. Epub 2018 Mar 21. |
| RGD ID: |
14402051 |
| Pubmed: |
PMID:29574133 (View Abstract at PubMed) |
| DOI: |
DOI:10.1016/j.toxlet.2018.03.024 (Journal Full-text) |
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.
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| Genes (Rattus norvegicus) |
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| Ugt1a1 (UDP glucuronosyltransferase family 1 member A1) |
| Genes (Mus musculus) |
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| Ugt1a1 (UDP glucuronosyltransferase 1 family, polypeptide A1) |
| Genes (Homo sapiens) |
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| UGT1A1 (UDP glucuronosyltransferase family 1 member A1) |
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