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

Abstract

Oleanolic acid (OA) is a triterpenoid that exists widely in fruits, vegetables and medicinal herbs. OA is included in some dietary supplements and is used as a complementary and alternative medicine (CAM) in China, India, Asia, the USA and European countries. OA is effective in protecting against various hepatotoxicants, and one of the protective mechanisms is reprogramming the liver to activate the nuclear factor erythroid 2-related factor 2 (Nrf2). OA derivatives, such as CDDO-Im and CDDO-Me, are even more potent Nrf2 activators. OA has recently been shown to also activate the Takeda G-protein-coupled receptor (TGR5). However, whereas a low dose of OA is hepatoprotective, higher doses and long-term use of OA can produce liver injury, characterized by cholestasis. This paradoxical hepatotoxic effect occurs not only for OA, but also for other OA-type triterpenoids. Dose and length of time of OA exposure differentiate the ability of OA to produce hepatoprotection vs hepatotoxicity. Hepatotoxicity produced by herbs is increasingly recognized and is of global concern. Given the appealing nature of OA in dietary supplements and its use as an alternative medicine around the world, as well as the development of OA derivatives (CDDO-Im and CDDO-Me) as therapeutics, it is important to understand not only that they program the liver to protect against hepatotoxic chemicals, but also how they produce hepatotoxicity.

CCl4-Induced Liver Injury Was Ameliorated by Qi-Ge Decoction through the Antioxidant Pathway

“…When excessive xenobiotics, such as toxic drugs, chemicals, and viruses, cannot be eliminated in a timely manner, they can damage the liver (often by ROS), leading to acute or chronic liver injury [15][16][17]. CCl 4 is a toxic xenobiotic that causes hepatocyte necrosis and liver damage and is often used as a model toxin for the induction of liver injury and evaluating the protective effect of drugs [18,19].…”

Oleanolic Acid Induces Apoptosis and Necrosis in Lo2 Cells

“…Though the hepatoprotective effect of OA has been well established, a recent study showed that repeated oral administration of OA induced cholestatic liver injury in mice [17] and OA altered bile acid homeostasis and produced cholestatic liver injury in C57 mice [18] . Thus, OA is effective in protecting against various hepatotoxicants at low dosages while higher dosages and long-term application could produce liver injury [19] . These observation provided evidence that OA could also be toxic to liver.…”

“…However, it was recently observed that high dosage and long duration of OA treatment could induce liver injury in experimental mice [17,18] . Furthermore, this paradoxical hepatotoxic effect occurs not only for OA, but also for other OA-type triterpenoids [19] . Thus, in the present study, the cytotoxic effect of OA on LO2 hepatocytes were determined.…”

Transcriptome Analyses Revealed Adaptive-Responses in Livers of Mice Treated With Hua-Feng-Dan and Its “Guide Drug” Yaomu

“…The use of traditional medicines to modulate innate and adaptive immune functions has been reviewed [17]. Oleanolic acid, a triterpenoid from many herbs/fruits, could reprogram the liver to protect against a variety of hepatotoxicants at the low doses, but is hepatotoxic at higher doses [18]. Thus, learn to program the liver would help us to understand the bene cial or harmful effects of traditional medicines such as Hua-Feng-Dan.…”