2,3,4′,5-tetrahydroxystilbene-2-O-β-D-glucoside exacerbates acetaminophen-induced hepatotoxicity by inducing hepatic expression of CYP2E1, CYP3A4 and CYP1A2

Hepatotoxicity induced by medicinal herb Polygonum multiflorum Thunb. attracts wide attention in the world recently. 2,3,4',5-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG) is a main active compound in Polygonum multiflorum Thunb. This study aims to observe TSG-provided the aggravation on acetaminophen (APAP)-induced hepatotoxicity in mice by inducing hepatic expression of cytochrome P450 (CYP450) enzymes. Serum alanine/aspartate aminotransferase (ALT/AST) analysis and liver histological evaluation showed that TSG (200, 400, 800 mg/kg) exacerbated the hepatotoxicity induced by sub-toxic dose of APAP (200 mg/kg) in mice, but TSG alone had no hepatotoxicity. TSG aggravated hepatic reduced glutathione (GSH) depletion and APAP-cysteine adducts (APAP-CYS) formation induced by APAP in mice. TSG increased the expression of CYP2E1, CYP3A4 and CYP1A2 both in mice and in human normal liver L-02 hepatocytes. TSG also enhanced liver catalytic activity of CYP2E1, CYP3A4 and CYP1A2 in mice. TSG induced the nuclear translocation of aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR), and TSG-provided the aggravation on APAP-induced hepatotoxicity in mice was reversed by PXR or AHR inhibitors. In summary, our results demonstrate that TSG enhances hepatic expression of CYP3A4, CYP2E1 and CYP1A2, and thus exacerbates the hepatotoxicity induced by APAP in mice. PXR and AHR both play some important roles in this process.