Metabolic Activation of Aegeline Mediated by CYP2C19.

1. Aegeline (AGL) is a natural alkaloidal amide mainly isolated from the leaves and fruits of tropical plant Aegle marmelos, with multiple pharmacological activities.2. As one component of several dietary supplements, AGL caused a series of acute and chronic liver injuries. Nevertheless, the mechanisms of AGL-induced hepatotoxicity remain unclear. This study was conducted to identify reactive metabolite(s), to determine related metabolic pathways, and define the possible association of the bioactivation with AGL cytotoxicity.3. A demethylation metabolite (M1) and a GSH conjugate (M2) were detected in rat liver microsomal incubations containing AGL and GSH. The two metabolites were both found in bile of rats and rat primary hepatocytes after AGL administration.4. Recombinant P450 enzyme incubations showed that CYP2C19 was the principal enzyme catalyzing this metabolic activation.5. Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to the cytotoxicity of AGL. The results suggest that AGL was metabolized to a p-quinone methide intermediate which could in part participate in AGL-induced cytotoxicity.