Role of intestinal microbiota-mediated genipin dialdehyde intermediate formation in geniposide-induced hepatotoxicity in rats

• Published in: Toxicology and applied pharmacology 2019-08, Vol.377, p.114624, Article 114624
• Main Authors: Li, Yi, Pan, Hong, Li, Xiaobing, Jiang, Neng, Huang, Linyan, Lu, Yuanfu, Shi, Fuguo
• Format: Article
• Language: English
• Subjects: Aldehydes; Amino Acids - metabolism; Animals; Anti-Bacterial Agents - pharmacology; beta-Glucosidase - pharmacology; Bile - metabolism; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - microbiology; Covalent Binding; Dialdehyde Intermediate; Gastrointestinal Microbiome - drug effects; Gastrointestinal Microbiome - physiology; Genipin; Geniposide; Glutathione - metabolism; Glycoside Hydrolases - metabolism; Hepatotoxicity; Iridoids - metabolism; Iridoids - toxicity; Liver - drug effects; Liver - metabolism; Lysine - metabolism; Male; Protein Adducts; Rats; Rats, Sprague-Dawley
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.114624

Geniposide is a natural hepatotoxic iridoid glycoside. Its hydrolysate of intestinal microbiota, genipin, is thought to be responsible for the hepatotoxicity. However, the underlying mechanism that genipin contributes to the hepatotoxicity of geniposide is not well understood. In this study, we found that genipin spontaneously converted into a reactive dialdehyde intermediate and covalently bond to the primary amine group of free amino acids in both of the phosphate buffers and geniposide-treated rats. Furthermore, genipin dialdehyde can form the covalent linkage to the primary amino group (ε) of lysine side chains of the hepatic proteins in geniposide-treated rats. Pretreatment with β-glucosidase or antibiotics significantly modulated the genipin dialdehyde formation and protein modification, revealing the essential role of microbial glycosidases. The levels of protein adduct were that mapped onto the hepatotoxicity of geniposide. In summary, this study demonstrates that the intestinal microbiota mediated covalent modification of the hepatic protein by genipin dialdehyde may play a crucial role in the liver injury of geniposide. The study is also helpful for understanding the contribution of intestinal microbiota to the metabolic activation of xenobiotics. [Display omitted] •Genipin spontaneously converts into a reactive dialdehyde intermediate.•Genipin dialdehyde can covalently bind to the primary amine of amino acids.•Genipin dialdehyde can covalently modify lysine residue of hepatic proteins.•Intestinal microbiota play a key role in Genipin dialdehyde formation in rat.•Genipin dialdehyde may be responsible for Geniposide-induced hepatotoxicity in rat.