Covalent binding of Geniposide metabolites to hepatic proteins: A potential mechanism for its hepatotoxicity

Abstract

Gardeniae fructus (GF) is a widely used traditional Chinese medicine; however, its application is limited due to the hepatotoxicity of its main active component, Geniposide (GE). To investigate the material basis and mechanisms of GE-induced hepatotoxicity. We utilized an in vitro gastrointestinal model to examine metabolic processes, conducted in vivo experiments to study GE's hepatotoxic effects and performed cellular experiments to verify toxic effects. Results indicated that GE-induced hepatotoxicity is associated with its metabolite Genipin (GP), with GP's hemiacetal structure being a key factor. Upon exposure of the C-1 hydroxyl group of GP, a covalent binding reaction occurs with amino acids. This reaction readily proceeds as a phase II conjugation with the amino group of lysine (LYS), resulting in the formation of genipin-lysine (GP-LYS) adducts. These adducts affect cellular oxidative stress and trigger cascading reactions leading to hepatotoxicity. Our findings not only highlight chemical structure as a crucial factor influencing toxicity but also advance the understanding of GE's toxic action mechanism. This study provides a foundation for guiding rational clinical use of GE and offers valuable insights for the development of novel GE-based pharmaceuticals.