Target profiling analyses of bile acids in the evaluation of hepatoprotective effect of gentiopicroside on ANIT-induced cholestatic liver injury in mice

Xiaowen Tang; Qiaoling Yang; Fan Yang; Junting Gong; Han Han; Li Yang; Zhengtao Wang

doi:10.1016/j.jep.2016.08.049

Target profiling analyses of bile acids in the evaluation of hepatoprotective effect of gentiopicroside on ANIT-induced cholestatic liver injury in mice

J Ethnopharmacol. 2016 Dec 24:194:63-71. doi: 10.1016/j.jep.2016.08.049. Epub 2016 Aug 28.

Authors

Xiaowen Tang¹, Qiaoling Yang², Fan Yang³, Junting Gong⁴, Han Han⁵, Li Yang⁶, Zhengtao Wang⁷

Affiliations

¹ The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: shs912vv@126.com.
² The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: cherish0814@126.com.
³ The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: sailseem1111@hotmail.com.
⁴ The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: 576621831@qq.com.
⁵ The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: 837270636@qq.com.
⁶ The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: yangli7951@hotmail.com.
⁷ The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.

PMID: 27582267
DOI: 10.1016/j.jep.2016.08.049

Abstract

Ethnopharmacological relevance: Gentiopicroside (GPS), one of iridoid glucoside representatives, is the most potential active component in Gentiana rigescens Franch. ex Hemsl and Gentiana macrophylla Pall. These two herbs have been used to treat jaundice and other hepatic and billiary diseases in traditional Chinese medicine for thousands of years.

Aim of the study: This study aimed to investigate the protective effects and mechanisms of GPS on α-naphthylisothiocyanate (ANIT) induced cholestatic liver injury in mice.

Materials and methods: Mice were treated with GPS (130mg/kg, ig) for 5 consecutive days. On the third day, mice were given a single dose of Alpha-naphthylisothiocyanate (75mg/kg, ig). Serum biochemical markers and individual bile acids in serum, liver, urine and feces were measured at different time points after ANIT administration. The expression of hepatic bile acid synthesis, uptake and transporter genes as well as ileum bile acid transporter genes were assayed.

Results: In this study, ANIT exposure resulted in serious cholestasis with liver injury, which was demonstrated by dramatically increased serum levels of ALT, ALP, TBA and TBIL along with TCA CA, MCAs and TMCAs accumulation in both liver and serum. Furthermore, ANIT significantly decreased bile acid synthesis related gene expressions, and increased expression of bile acid transporters in liver. Continuous treatment with GPS attenuated ANIT-induced acute cholestasis as well as liver injury and correct the dyshomeostasis of bile acids induced by ANIT. Our data showed that GPS significantly upregulated the hepatic mRNA levels of synthesis enzymes (Cyp8b1 and Cyp27a1) and transporters (Mrp4 Mdr1 and Ost-β) as well as ileal bile acid circulation mediators (Asbt and Fgf15), accompanied by serum and hepatic bile acid levels decrease and further urinary and fecal bile acid levels increase.

Conclusion: GPS can change bile acids metabolism which highlights its importance in mitigating cholestasis, resulting in the marked decrease of intracellular bile acid pool back toward basal levels. And the protective mechanism was associated with regulation of bile acids-related transporters, but the potential mechanism warrants further investigation.

Keywords: Alpha-naphthylisothiocyanate (ANIT); Bile acids (BAs); Cholestasis; Gentiopicroside (GPS); Traditional Chinese Medicine.

MeSH terms

1-Naphthylisothiocyanate / toxicity*
Animals
Bile Acids and Salts / antagonists & inhibitors*
Bile Acids and Salts / metabolism
Chemical and Drug Induced Liver Injury / etiology
Chemical and Drug Induced Liver Injury / prevention & control*
Cholestasis / chemically induced*
Homeostasis
Iridoid Glucosides / pharmacology*
Liver / drug effects*
Mice
Mice, Inbred C57BL

Substances

Bile Acids and Salts
Iridoid Glucosides
gentiopicroside
1-Naphthylisothiocyanate