title: Protection against phalloidin-induced liver injury by oleanolic acid involves Nrf2 activation and suppression of Oatp1b2.
abstract: This study utilized pharmacological activation of Nrf2 with oleanolic acid (OA, 22.5mg/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 (1.5mg/kg, ip for 8h) 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.
authors.affiliation: University of Kansas Medical Center, Kansas City, KS, USA; Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical College, Zunyi, China.
authors.forename: Yuan-Fu
authors.initials: YF
authors.lastname: Lu
authors.affiliation: University of Kansas Medical Center, Kansas City, KS, USA; Key Lab for Basic Pharmacology of Ministry of Education, Zunyi Medical College, Zunyi, China. Electronic address: Jie@Liuonline.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Kai Connie
authors.initials: KC
authors.lastname: Wu
authors.affiliation: University of Kansas Medical Center, Kansas City, KS, USA. Electronic address: curtisklaassenphd@gmail.com.
authors.forename: Curtis D
authors.initials: CD
authors.lastname: Klaassen
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019610:Cytoprotection; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D018836:Inflammation Mediators / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009828:Oleanolic Acid / Q000494:pharmacology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D010590:Phalloidine; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3
chemical_list: D018836:Inflammation Mediators; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C421207:Slco1b2 protein, rat; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D010590:Phalloidine; D009828:Oleanolic Acid
keywords: Inflammation; Keap1-HKO mice; Nrf2-null mice; Oatp1b2; Oleanolic acid; Phalloidin hepatotoxicity