Dose-related liver injury of Geniposide associated with the alteration in bile acid synthesis and transportation

Sci Rep. 2017 Aug 21;7(1):8938. doi: 10.1038/s41598-017-09131-2.

Abstract

Fructus Gardenia (FG), containing the major active constituent Geniposide, is widely used in China for medicinal purposes. Currently, clinical reports of FG toxicity have not been published, however, animal studies have shown FG or Geniposide can cause hepatotoxicity in rats. We investigated Geniposide-induced hepatic injury in male Sprague-Dawley rats after 3-day intragastric administration of 100 mg/kg or 300 mg/kg Geniposide. Changes in hepatic histomorphology, serum liver enzyme, serum and hepatic bile acid profiles, and hepatic bile acid synthesis and transportation gene expression were measured. The 300 mg/kg Geniposide caused liver injury evidenced by pathological changes and increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and γ-glutamytransferase (γ-GT). While liver, but not sera, total bile acids (TBAs) were increased 75% by this dose, dominated by increases in taurine-conjugated bile acids (t-CBAs). The 300 mg/kg Geniposide also down-regulated expression of Farnesoid X receptor (FXR), small heterodimer partner (SHP) and bile salt export pump (BSEP). In conclusion, 300 mg/kg Geniposide can induce liver injury with associated changes in bile acid regulating genes, leading to an accumulation of taurine conjugates in the rat liver. Taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA) as well as tauro-α-muricholic acid (T-α-MCA) are potential markers for Geniposide-induced hepatic damage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11 / metabolism
  • Alanine Transaminase / blood
  • Alkaline Phosphatase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Bile Acids and Salts / analysis
  • Bile Acids and Salts / metabolism*
  • Biomarkers / metabolism*
  • Chemical and Drug Induced Liver Injury / diagnosis
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Disease Models, Animal
  • Early Diagnosis
  • Gene Expression Regulation / drug effects
  • Iridoids / adverse effects*
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • gamma-Glutamyltransferase / blood

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • Abcb11 protein, mouse
  • Bile Acids and Salts
  • Biomarkers
  • Iridoids
  • Receptors, Cytoplasmic and Nuclear
  • nuclear receptor subfamily 0, group B, member 2
  • farnesoid X-activated receptor
  • geniposide
  • gamma-Glutamyltransferase
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Alkaline Phosphatase