Korean red ginseng extract prevents APAP‐induced hepatotoxicity through metabolic enzyme regulation: The role of ginsenoside Rg3, a protopanaxadiol

Abstract

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. We evaluated the beneficial effect and molecular mechanism of Korean red ginseng (KRG) on the APAP-mediated hepatotoxicity and identified a major component of KRG for hepatoprotection. Survival test, liver function test, histopathological study, APAP-metabolic profiling and gene expression were examined in mice. We determined the enzyme expression and upstream signalling in H4IIE cells analysed by RT-PCR, immunoblotting, siRNA gene knockdown and promoter-luciferase assay. High doses of KRG reduced mortality at the LD50 of APAP. APAP increased AST and ALT activities, which were abrogated by low doses of KRG. These protective effects were consistent with the results from histopathological examinations. KRG altered APAP metabolic profiles through inhibition of cytochrome P450 2E1 and induction of glutathione S-transferase A2 (GSTA2). Knockdown of GSTA2 catalyses the conjugation of glutathione reversed KRG-mediated protection against N-acetyl-p-benzoquinone imine in H4IIE cells. The nuclear Nrf2 and C/EBPβ, which are essential transcriptional factors for GSTA2 were increased by KRG. These effects were downstream of multiple signalling, including PI3K, JNK or PKA. Ginsenoside Rg3 but not Rb1, Rc and Rg1 significantly increased GSTA2 protein expression. Rg3 resulted in the transcriptional activation of GSTA2 downstream of the multiple cellular signalling. These results demonstrate that KRG is efficacious in protection against APAP-induced hepatotoxicity and mortality through metabolic regulation and that Rg3 is a major component of KRG for the GST induction, implying that Rg3 should be considered to be a potential hepatoprotective agent.