Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism.

Yulin Zhao, Haoyan Huang, Ning Lv, Chunyan Huang, Huili Chen, Han Xing, Chaorui Guo, Ning Li, Di Zhao, Xijing Chen, Yongjie Zhang

Journal of agricultural and food chemistry 2023 Feb 08

filter terms:

Genipin (GP), the reactive metabolite of geniposide (GE), is responsible for GE-induced hepatotoxicity. As a potential detoxification pathway, the inactivation of GP by glutathione S-transferases (GSTs) has not yet been characterized. In this study, the thiol-GSH conjugates of GP, M532-1 and M532-2 were first identified and the catalytic activities of GSTs were investigated both in vitro and in vivo. GSTA1-1 and GSTA4-4 showed high activity in the formation of both thiol-GSH conjugates, whereas GSTA4-4 specifically catalyzed M532-2 formation in vitro. The active GST isoforms protect against alkylation of N-acetylcysteine (NAC), a classic model nucleophile. GST inhibition attenuated M532-1 formation in rat bile, confirming the in vivo catalytic role of GSTs. In conclusion, this study demonstrated the inactivation of GP by GSTs and implied that interindividual variability of GSTs may be a risk factor for susceptibility to GE-induced hepatotoxicity.

Citation

Yulin Zhao, Haoyan Huang, Ning Lv, Chunyan Huang, Huili Chen, Han Xing, Chaorui Guo, Ning Li, Di Zhao, Xijing Chen, Yongjie Zhang. Glutathione S-Transferases Mediate In Vitro and In Vivo Inactivation of Genipin: Implications for an Underlying Detoxification Mechanism. Journal of agricultural and food chemistry. 2023 Feb 08;71(5):2399-2410