Reversing effects of ginsenosides on LPS-induced hepatic CYP3A11/3A4 dysfunction through the pregnane X receptor

Abstract

Ethnopharmacological relevanceGinseng (Panax ginseng C. A. Meyer), a traditional Chinese medicine, is widely used in the adjunctive therapy of the liver diseases. Aim of the studyGinsenosides are one kind of the main active ingredients in ginseng. Although hepatoprotective mechanisms of ginsenosides, such as anti-oxidation, anti-inflammation and anti-apoptosis, have been well studies, little is known about the effect of ginsenosides on drug metabolism in liver. Since CYP3A11/3A4 is a major enzyme catalyzing the drug metabolism in liver, an investigation of the enzyme's expression during the progression of a liver disease will gain valuable information about the hepatic drug metabolism. The purpose of this study was to determine the effect of ginsenosides on the expression of hepatic CYP3A11/3A4 in the lipopolysaccharides (LPS) injured human HepG2 cells and mice. We hypothesize that ginsenosides are important to stabilize CYP3A11/3A4 expression in an injured liver. Materials and methodsIn this study, LPS was intraperitoneally intermittently injected to induce the liver injury in mice. Ginsenosides were intragastrically administered to mice for 7 days to treat the liver injury. Serum biochemical analysis and histopathological study were taken to evaluate the hepatoprotective effect of ginsenosides. The effect of ginsenosides was also evaluated in human HepG2 cells in the presence and absence of LPS. Real-time PCR and western blotting method were used to detect the mRNA and protein levels of CYP3A11/3A4 in mouse liver tissue and human HepG2 cells. The reporter gene-transfected cells were used to identify upstream targets in HepG2 cells. ResultsLPS injection in mice resulted in the up-regulation of pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α in liver, up-regulation of hepatic enzymes such as Tbil, ALT, AST and ALP in serum, and down-regulation of CYP3A11/3A4 expression in liver. Ginsenosides treatment reversed the up-regulation of pro-inflammatory cytokines and serum hepatic enzymes elicited by LPS. Pathological results suggest that ginsenosides reduced liver damage. Moreover, ginsenosides reversed the decrease of CYP3A11/3A4 expression in the liver of LPS-injured mouse and in LPS-treated HepG2 cells. To further investigate the regulatory mechanisms, we found that ginsenosides enhanced the rifampicin-induced pregnane X receptor (PXR) transactivation of the CYP3A4 promoter. Treatment of hPXR–over-expressed cells with ginsenosides increased the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. ConclusionGinsenosides reverse the effects of LPS-induced hepatic CYP3A11/3A4 dysfunction, suggesting that the stabilization of the CYP3A11/3A4 expression in an injured liver appears a novel hepatoprotective mechanism of ginsenosides.