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, 22.5 mg/kg, sc for 4d) and the genetic Nrf2 activation (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.

Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high doses

“…Phalloidin is taken up by hepatocytes through the Oatp1b2 transporter, which was also suppressed by OA. Thus, protection against phalloidin hepatotoxicity by OA involves activation of Nrf2 and suppression of Oatp1b2, with Oatp1b2 mediating the uptake of phalloidin into the liver to produce toxicity …”

“…Induction of Nrf2 (1) promotes GSH biosynthesis and GSH conjugation; (2) increases in Nqo1 and HO ‐1 detoxify electrophiles; (3) increases in Phase‐2 detoxification conjugation; and (4) increases in the Mrp efflux pumps to eliminate toxic bile acids out of hepatocytes . In addition, OA decreases CYP 2E1 to reduce bioactivation of CC l 4 and acetaminophen and decreases Oatp1b2 to reduce hepatic uptake of phalloidin . OA is a TGR 5 activator to produce proinflammatory cytokines in the biliary tree implicating in cholestasis…”

“…OA activation of Nrf2 also offers the protection in other organs and diseases. 75 In addition to Nrf2 activation, other mechanisms also offer OAinduced hepatoprotection, such as a decrease in CYP2E1 (eg CCl 4 , 27 acetaminophen 23 ), decrease in Oatp1b2 (eg phalloidin 34 ), modulation of the immune response and inflammation (eg d-Gal/LPS 28 ). These mechanisms play an integrated role in programming the liver against toxic stimuli.…”

Hepatoprotective effect of ganoderma triterpenoids against oxidative damage induced bytert-butyl hydroperoxide in human hepatic HepG2 cells

“…Many effects have recently been made to develop the complementary and alternative medicines for reducing oxidative stress and improving liver functions. Therapeutically effective agents from natural sources, exemplified by quercetin (Mariee et al 2012), silymarin (Ahmad et al 2013) and oleanolic acid (Lu et al 2014), are particularly attractive for treatments as they have the potential to reduce the risk of drug toxicity (Shivananjappa et al 2013). Ganoderma, a traditional Chinese medicinal mushroom, has been widely used for treating and preventing chronic hepatopathy of various etiologies (Peng et al 2013).…”

Preparation and evaluation of molecularly imprinted composite membranes for inducing crystallization of oleanolic acid in supercritical CO2

“…1 Recently, more and more attentions are paid to OA, due to its pharmacological activities, such as anti-inflammation, [2][3][4] antivirus, 5 antitumor, [6][7][8][9] hepatoprotective, [9][10][11] hypolipidemic and hypoglycemic effects. 1 Recently, more and more attentions are paid to OA, due to its pharmacological activities, such as anti-inflammation, [2][3][4] antivirus, 5 antitumor, [6][7][8][9] hepatoprotective, [9][10][11] hypolipidemic and hypoglycemic effects.…”