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Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2.
- Source :
-
Toxicology Letters . Jan2015, Vol. 232 Issue 1, p326-332. 7p. - Publication Year :
- 2015
-
Abstract
- This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5 mg/kg, sc for 4 days) and the genetic alteration of Nrf2 (Nrf2-null, wild-type, and Keap1-HKO mice) to examine the role of Nrf2 in protection against phalloidin hepatotoxicity. Mice were given phalloidin (1.5 mg/kg, ip for 8 h) to examine liver injury and the expression of toxicity-related genes. Phalloidin increased serum enzyme activities and caused extensive hepatic hemorrhage and necrosis in Nrf2-null and wild-type mice, but less injury was seen in Keap1-HKO mice and OA-pretreated mice. Phalloidin increased the expression of neutrophil-specific chemokine mKC and MIP-2 in Nrf2-null and WT mice, but such increases were attenuated in Keap1-HKO and OA-pretreated mice. Phalloidin increased, while Nrf2 activation attenuated, the expression of genes involved in acute-phase response (Ho-1) and DNA-damage response genes (Gadd45 and Chop10). Phalloidin is taken up by hepatocytes through Oatp1b2, but there was no difference in basal and phalloidin-induced Oatp1b2 expression among Nrf2-null, wild-type, and Keap1-HKO mice. In contrast, OA decreased phalloidin-induced Oatp1b2. Phalloidin activated MAPK signaling (p-JNK), which was attenuated by activation of Nrf2. In conclusion, this study demonstrates that protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03784274
- Volume :
- 232
- Issue :
- 1
- Database :
- Academic Search Index
- Journal :
- Toxicology Letters
- Publication Type :
- Academic Journal
- Accession number :
- 100023239
- Full Text :
- https://doi.org/10.1016/j.toxlet.2014.09.027