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

Yifei Yang; Lingyun Yang; Yaodan Han; Zhenwei Wu; Pan Chen; Huibin Zhang; Jinpei Zhou

doi:10.1016/j.bioorg.2017.03.009

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

Bioorg Chem. 2017 Jun:72:42-50. doi: 10.1016/j.bioorg.2017.03.009. Epub 2017 Mar 20.

Authors

Yifei Yang¹, Lingyun Yang², Yaodan Han², Zhenwei Wu², Pan Chen¹, Huibin Zhang³, Jinpei Zhou⁴

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: zhanghb80@163.com.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: jpzhou668@163.com.

PMID: 28346874
DOI: 10.1016/j.bioorg.2017.03.009

Abstract

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 (100mg/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.

Keywords: Anethol trithione; Glycyrrhetic acid; Hepatic injury; Hepatoprotective.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Carbon Tetrachloride
Chemical and Drug Induced Liver Injury / drug therapy*
Chemical and Drug Induced Liver Injury / metabolism
Chemical and Drug Induced Liver Injury / pathology
Disease Models, Animal
Dose-Response Relationship, Drug
Glycyrrhetinic Acid / chemical synthesis
Glycyrrhetinic Acid / chemistry
Glycyrrhetinic Acid / pharmacology*
Hepatocytes / drug effects*
Liver / drug effects*
Liver / pathology
Mice
Molecular Structure
Structure-Activity Relationship

Substances

Carbon Tetrachloride
Glycyrrhetinic Acid