In vitro and in vivo metabolic activation of berbamine to quinone methide intermediate.

Berbamine (BBM) is a bisbenzylisoquinoline alkaloid isolated from herbal medicine Berberis amurensis. BBM has been widely used for the treatment of leukemia. Recent studies demonstrated that exposure to BBM can give rise to cytotoxicity. The major objective of this study was to explore the metabolic activation of BBM in vitro and in vivo. Two oxidative metabolites (M1 and M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in human liver microsomal incubations of BBM supplemented with NAC, and the formation of all metabolites was NADPH dependent. Microsomal inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the major enzyme responsible for the metabolic activation of BBM. In addition, a BBM-cysteine conjugate (M4) was detected in the urine of rats given BBM. The metabolism study will facilitate the understanding of the biochemical mechanisms of BBM-induced cytotoxicity.