Licorice Compounds Glycyrrhizin and 18β-Glycyrrhetinic Acid Are Potent Modulators of Bile Acid-induced Cytotoxicity in Rat Hepatocytes

Abstract

The accumulation of hydrophobic bile acids results in cholestatic liver injury by increasing oxidative stress, mitochondrial dysfunction, and activation of cell signaling pathways. Licorice root and its constituents have been utilized as antihepatotoxic agents. The purpose of this study was to evaluate the potential modulation by a primary component of licorice root, glycyrrhizin (GL), and its metabolite, 18␤-glycyrrhetinic acid (GA), in a hepatocyte model of cholestatic liver injury. Preincubation of fresh rat hepatocyte suspensions with GL or GA reduced glycochenodeoxycholic acid (GCDC)-dependent reactive oxygen species generation, with GA more potent than GL. Interestingly, GL and GA had opposing effects toward GCDC-induced cytotoxicity; GA prevented both necrosis and apoptosis, whereas GL enhanced apoptosis. GCDC promoted activation of caspase 10, caspase 3, and PARP; all were inhibited by GA but not GL. Induction of apoptosis by GCDC was also associated with activation of JNK, which was prevented by GA. Activation of caspase 9 and dissipation of mitochondrial membrane potential were prevented by GA but not GL. In liver mitochondrial studies, GL and GA were both potent inhibitors of the mitochondrial permeability transition, reactive oxygen species generation, and cytochrome c release at submicromolar concentrations. Results from this study suggest that GL exhibits proapoptotic properties, whereas GA is a potent inhibitor of bile acid-induced apoptosis and necrosis in a manner consistent with its antioxidative effect.

Cryptotanshinone Ameliorates Hepatic Normothermic Ischemia and Reperfusion Injury in Rats by Anti-mitochondrial Apoptosis

“…37) Taken together, these results suggested an important role of MAPKs in the regulation of apoptosis during liver I/R. Previous study has shown that CT protected primary cultured rat hepatocytes from bile acid-induced apoptosis by inhibiting JNK phosphorylation.…”

Chemopreventive Effects of Licorice and Its Components

“…Gc has been used against chronic viral hepatitis [21] and is reportedly active against a number of other viruses, including latent Kaposi sarcoma-associated herpes virus [22], severe acute respiratory distress syndrome (SARS) [23,24], and EpsteinBarr Virus (EBV) (Lin, 2008 #307). It was reported to exert protection against carbon tetrachloride-induced liver injury in mice [25], liver damage associated with aflatoxin-induced oxidative stress [26] and other types of liver damage induced by oxidative stress [27]. These licorice compounds also can induce interferon production [26,28] and protect against neurotoxicity by modulating the binding of nuclear factorkappaB to its molecular targets [29].…”

A Novel Approach towards Green Extraction for Glycyrrhitinic Acid by Ionic Liquid Based Microwave Assisted Extraction and Optimization through Response Surface Methodology

“…Additionally, GA and GL had antagonistic effects toward GCDC-induced cytotoxicity; GL enhanced apoptosis whereas GA prevented both necrosis and apoptosis. 9 GA effect on the subcutaneous fat thickness was performed through topically applied cream containing GA, results in reduction of unwanted local fat accumulation. It was found to be due to the blockage of 11β-hydroxysteroid dehydrogenase type 1 at the level of fat cells.…”