Paradoxical Effects of Emodin on ANIT-Induced Intrahepatic Cholestasis and Herb-Induced Hepatotoxicity in Mice

Abstract

Emodin is an active ingredient in many herbal medicines and has a broad spectrum of pharmacological activities. The current data indicate that emodin exerts its beneficial effect on alpha-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis through its anti-oxidant and anti-inflammatory activities. Emodin has little effect on the concentrations of bile acids (BAs) in livers of ANIT-treated mice. Instead, emodin shows a potential pro-cholestatic effect by interfering with the crosstalk between AMP-activated protein kinase (AMPK) and farnesoid X receptor (Fxr) in the liver, which leads to a suppression of bile salt export pump (Bsep). Two emodin-containing herbs, namely Polygonum multiflorum (PM) and Semen cassiae (SC), markedly aggravate the intrahepatic cholestasis in ANIT-treated mice. SC interferes with the AMPK-Fxr crosstalk and suppresses Bsep in livers of mice. ANIT markedly increases the hepatic retention of emodin in SC-treated mice. The major SC constituents, in particular three anthraquinones, are able to activate AMPK in HepG2 cells and inhibit Bsep in primary mouse hepatocytes, with emodin showing the strongest activities. Together, the present study identifies a potential pro-cholestatic role of emodin in the hepatotoxicity of herbs.

Keywords: AMPK; ANIT-induced cholestasis; emodin.