Evidence for endogenous amine conjugation and cytotoxicity arising from metabolic activation of trazodone
Abstract:
Trazodone (TRZ), a tetracyclic antidepressant, is commonly utilized either independently or in combination with other antidepressants to treat depression. It has also been reported to be associated with multiple cases of acute liver injury, cholestasis, and jaundice, possibly due to its extensive metabolism in the liver by cytochrome P450 enzymes. Triazolopropionic aldehyde (M1) has been identified as a metabolite of TRZ. In this study, we investigated the interaction of M1 with endogenous amines and successfully detected the corresponding conjugates in rat microsomal incubation supplemented with TRZ and individual endogenous amines, including lysine, arginine, spermidine, and spermine. The corresponding conjugates were detected in cultured rat primary hepatocytes and bile samples of rats treated with TRZ. Exposure to TRZ or M1 resulted in concentration-dependent cytotoxicity in hepatocytes. Pretreatment with ketoconazole or lysine in the culture medium reduced the susceptibility of hepatocytes to the cytotoxicity of TRZ. SIGNIFICANCE STATEMENT: This study identified that triazolopropionic aldehyde, a metabolite of trazodone, can covalently bind to endogenous amines and interfere with the biosynthesis and availability of cellular glutathione. The aldehyde group is the key structural determinant of triazolopropionic aldehyde-induced cytotoxicity and plays an important role in trazodone-induced hepatocellular injury.
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