Carnosic acid protects against acetaminophen-induced hepatotoxicity by potentiating Nrf2-mediated antioxidant capacity in mice.
10.4196/kjpp.2016.20.1.15
- Author:
Qi GUO
1
;
Zhiyang SHEN
;
Hongxia YU
;
Gaofeng LU
;
Yong YU
;
Xia LIU
;
Pengyuan ZHENG
Author Information
1. Department of Ultrasound, The Second Hospital Affiliated of Zhengzhou University, Zhengzhou, Henan 450014, P. R. China.
- Publication Type:Original Article
- Keywords:
Acetaminophen;
Anti-oxidation;
Carnosic acid;
Hepatotoxicity;
Nuclear factor erythroid 2-related factor 2
- MeSH:
Acetaminophen;
Alanine Transaminase;
Animals;
Aspartate Aminotransferases;
Blotting, Western;
Caspase 3;
Cytokines;
Glutathione;
Hepatocytes;
Injections, Intraperitoneal;
Interleukin-6;
L-Lactate Dehydrogenase;
Liver;
Liver Failure, Acute;
Malondialdehyde;
Mice*;
Necrosis;
Reactive Oxygen Species;
RNA, Messenger;
Tumor Necrosis Factor-alpha
- From:The Korean Journal of Physiology and Pharmacology
2016;20(1):15-23
- CountryRepublic of Korea
- Language:English
-
Abstract:
Acetaminophen (APAP) overdose is one of the most common causes of acute liver failure. The study aimed to investigate the protective effect of carnosic acid (CA) on APAP-induced acute hepatotoxicity and its underlying mechanism in mice. To induce hepatotoxicity, APAP solution (400 mg/kg) was administered into mice by intraperitoneal injection. Histological analysis revealed that CA treatment significantly ameliorated APAP-induced hepatic necrosis. The levels of both alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum were reduced by CA treatment. Moreover, CA treatment significantly inhibited APAP-induced hepatocytes necrosis and lactate dehydrogenase (LDH) releasing. Western blot analysis showed that CA abrogated APAP-induced cleaved caspase-3, Bax and phosphorylated JNK protein expression. Further results showed that CA treatment markedly inhibited APAP-induced pro-inflammatory cytokines TNF-alpha, IL-1beta, IL-6 and MCP-1 mRNA expression and the levels of phosphorylated IkappaBalpha and p65 protein in the liver. In addition, CA treatment reduced APAP- induced hepatic malondialdehyde (MDA) contents and reactive oxygen species (ROS) accumulation. Conversely, hepatic glutathione (GSH) level was increased by administration of CA in APAP-treated mice. Mechanistically, CA facilitated Nrf2 translocation into nuclear through blocking the interaction between Nrf2 and Keap1, which, in turn, upregulated anti-oxidant genes mRNA expression. Taken together, our results indicate that CA facilitates Nrf2 nuclear translocation, causing induction of Nrf2-dependent genes, which contributes to protection from acetaminophen hepatotoxicity.
