Anastrozole and related glucuronic acid conjugate are electrophilic species

Anastrozole (ANA), is an inhibitor of non-steroidal aromatase, widely employed for the treatment of breast cancer. However, ANA-associated liver injury cases have been documented in the application of the drug.The major purposes of the present study were to identify the structure of reactive metabolites derived from ANA and to study related metabolic pathways of ANA.We found ANA itself is an electrophilic species reactive to GSH. ANA can be metabolised to ANA-N+-glucuronide (1) catalysed by UGT1A4. An ANA GSH conjugate (2) was detected in bile and livers of rats treated with ANA. UGT1A4 participated in the phase II metabolic pathway.This work allowed us to better understand the mechanisms of the hepatotoxicity of ANA and provided new avenue to define the possible role of metabolic activation in hepatotoxicity.