Protective effects of hepatocyte-specific glycyrrhetic derivatives against carbon tetrachloride-induced liver damage in mice

Glycyrrhetic acid (GA), the main hydrolysate of glycyrrhizic acid extracted from the roots of the Chinese herb Glycyrrhiza glabra, was reported to be accumulated in hepatocytes due to the extensive distribution of GA receptors in liver. A series of hepatocyte-specific derivatives on the basis of anetholtrithione and glycyrrhizic were designed and synthesized. The potential beneficial effect was evaluated in carbon tetrachloride (CCl₄)-induced liver injury model. In addition, the hepatoprotective activity of these derivatives was assessed by measuring levels of serum marker enzymes, including serum glutamate oxaloacetate transaminase (GOT), serum glutamate pyruvate transaminase (GPT), alkaline phosphatase (AKP), lactate dehydrogenase (LDH) and the ratio of GSH to GSSG. Gratifyingly, compounds 5a–c (100 mg/kg, p.o.) markedly prevented CCl₄-induced elevation of levels of serum GPT, GOT. A comparative histopathological study of liver exhibited almost a normal liver lobular architecture and cell structure of the livers, as compared to CCl₄-treated group. These findings were confirmed with the histopathological observations, where hepatocyte-specific glycyrrhetic acid derivatives 5a–c were capable of reversing the toxic effects of CCl₄ on hepatocytes.