Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice.

Abstract

Diammonium glycyrrhizinate (DG), an active compound extracted and purified from liquorices root, has been reported to exhibit antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect and underlying mechanisms of DG on the hepatotoxicity induced by valproic acid (VPA). DG at the dose of 60mg/kg was orally administered with VPA (100mg/kg) to mice once daily for 14 consecutive days. DG treatment attenuated VPA-induced liver dysfunction, structural damage, glutathione depletion and decrease in antioxidant enzymes in BALB/C mice. DG prevented VPA-induced depletion of cytosolic nuclear factor E2-related factor 2 (Nrf2) and suppression of nuclear translocation of Nrf2, which, in turn, up-regulated phase II/antioxidant enzyme activities. The effects of VPA and DG on Nrf2 expression in HepG2 cells were in consistent with that of mice. Furthermore, an increase in the nuclear levels of nuclear factor-kappaB (NF-κB) was observed in the livers of VPA-treated mice that coincided with induction of inflammatory cytokines. In contrast, DG inhibited NF-κB translocation and that subsequently decreased inflammatory cytokines. Taken together, these results demonstrate that DG attenuates VPA-induced liver injury through increasing the expression of Nrf2 mediated phase II/antioxidant enzymes and simultaneously decreasing the expression of inflammatory mediators.

• Authors: Jing Jin, Tianqin Xiong, Xiangyu Hou, Xiaozhe Sun, Jiayi Liao, Zhiying Huang, Min Huang, Zhongxiang Zhao
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 73 Pg. 95-104 (Nov 2014) ISSN: 1873-6351 [Electronic] England
• PMID: 25152329 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Anticonvulsants
• Cytokines
• DNA Primers
• Inflammation Mediators
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, mouse
• Valproic Acid
• Glycyrrhizic Acid

Topics

• Animals
• Anticonvulsants (toxicity)
• Base Sequence
• Cytokines (metabolism)
• DNA Primers
• Gene Expression Regulation (drug effects)
• Glycyrrhizic Acid (pharmacology)
• Hep G2 Cells
• Humans
• Inflammation Mediators (metabolism)
• Liver (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• NF-E2-Related Factor 2 (metabolism, physiology)
• NF-kappa B (antagonists & inhibitors)
• Real-Time Polymerase Chain Reaction
• Valproic Acid (toxicity)