期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 377, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2019.114624
关键词
Geniposide; Genipin; Hepatotoxicity; Covalent Binding; Protein Adducts; Dialdehyde Intermediate
资金
- National Natural Science Foundation of China [81603077]
- First-Class Disciplines Fund of Education Department of Guizhou Province [GNYL [2017]006 YLXKJS-YS-05]
- Science and Technology Fund of Science and Technology Department of Guizhou Province [QKH-JC-[2017]1221, [2018]1186]
- Joint Fund of the Department of Science and Technology of Zunyi City [[2017]13]
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 (epsilon) of lysine side chains of the hepatic proteins in geniposide-treated rats. Pretreatment with beta-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.
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