Carnosic acid protects against acetaminophen-induced hepatotoxicity by potentiating Nrf2-mediated antioxidant capacity in mice

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-α, IL-1β, IL-6 and MCP-1 mRNA expression and the levels of phosphorylated IκBα 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.

Protective effect of carnosic acid on acrylamide‐induced liver toxicity in rats: Mechanistic approach over Nrf2‐Keap1 pathway

“…It is conceivable in our study that carnosic acid rescued the liver against acrylamide in a way that the body did not need to activate Nrf2 activation, which is related to bodily antioxidant‐oxidant balance. In contrast to our study, Guo et al [ 35 ] reported that carnosic acid facilitated Nrf2 translocation and stimulated genes associated with Nrf2 in a study in which the protective role of carnosic acid in acetaminophen‐induced hepatotoxicity in mice was demonstrated. This discrepancy might stem from different experimental duration and substance dose regimen as well as the interplay between the toxic and the protective substances.…”

Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice

“…The levels of serum AST, ALT and LDH are the most sensitive biomarkers that can directly indicate the extent of hepatic damage. (29) APAP caused a significant increase in the levels of AST, ALT and LDH (Fig. 2).…”

Protective Effects of Tormentic Acid, a Major Component of Suspension Cultures of Eriobotrya japonica Cells, on Acetaminophen-Induced Hepatotoxicity in Mice

“…NF-κB also modulates the expression of a variety of genes, including the genes encoding iNOS and COX-2, resulting in an increased production of TNF-α and NO in tissues [ 49 ]. APAP was shown to activate the NF-κB pathway by promoting NF-κB translocation [ 49 ] and IκBα degradation [ 50 ]. In this study, APAP-induced NF-κB translocation was blocked by either TA or NAC ( Figure 7 ).…”