The protein adduction derived from reactive metabolites of multiple furanoids in cortex Dictamni-treated mice

The association of herb medicine Cortex Dictamni (CD) with severe even fatal hepatotoxicity has been widely reported. Recently, we demonstrated that the metabolic activation of at least ten furanoids in CD was responsible for the liver injury caused by the ethanol extract of CD (ECD) in mice. Protein adduction by reactive metabolites is considered to initiate the process of liver injury. Unlike single chemicals, the mode of and the details of protein modification by multiple components in an herb is unclear. This study aimed to characterize protein adductions derived from the reactive metabolite of furanoids in ECDtreated mice and define the association of protein adduction with liver injury. The hepatic cysteine-and lysine-based protein adducts derived from epoxide or cis-enedione of at least six furanoids were identified in mice. The furanoids with an earlier serum content T-max were mainly to bind with hepatic glutathione and no protein adducts were formed except for dictamnine. The hepatic proteins were modified by the later absorbed furanoids. The levels of hepatic protein adduct were correlated with the degree of liver injury. In addition, the reactive metabolites of different furanoids can simultaneously bind to the model peptide by the identical reactive moiety, indicating the additive effects of the individual furanoids in the modification of hepatic proteins. In conclusion, hepatic protein adduction by multiple furanoids may play a role in ECD-induced liver injury. The earlier absorbed furanoids were mainly to bind with glutathione whereas the hepatic proteins were modified by the later furanoids.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

This study demonstrates that the metabolic activation of furanoids in Cortex Dictamni (CD) is responsible for liver injury in mice. Multiple furanoids can modify hepatic proteins through reactive metabolites, and the levels of protein adducts are correlated with the severity of liver injury. Early absorbed furanoids mainly bind with glutathione, while later absorbed furanoids modify hepatic proteins.