title: In vitro and in vivo metabolic activation of berbamine to quinone methide intermediate.
abstract: 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.
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.
authors.forename: Tong
authors.initials: T
authors.lastname: Yao
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, People's Republic of China.|Key Laboratory of Pharmaceutics of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, 550004, People's Republic of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zheng
mesh_terms: D065767:Activation, Metabolic; D000818:Animals; D044182:Benzylisoquinolines / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D045563:Indolequinones / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats
chemical_list: D044182:Benzylisoquinolines; D045563:Indolequinones; C068040:quinone methide; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C027870:berbamine
keywords: berbamine; metabolic activation; quinone methide