title: Interspecies variation in phase I metabolism of bufalin in hepatic microsomes from mouse, rat, dog, minipig, monkey, and human.
abstract: 1. Bufalin (BF), one of the major bioactive compounds in traditional Chinese medicine (TCM) Chansu, has been found with various pharmacological and toxicological effects. This study aims to investigate the species differences in phase I metabolism of BF in hepatic microsomes from human and five common experimental animals. 2. Metabolite profiling demonstrated that two major metabolites were formed in liver microsomes from human and animal species in NADPH-generating system. Two major metabolites were identified as 5β-hydroxyl-bufalin and 3-keto-bufalin, with the help of authentic standards. CYP3A was assigned as the main isoform involved in both 5β-hydroxylation and 3-oxidation in all studied liver microsomes. The apparent kinetic parameters including substrate affinity and catalytic efficiency for 5β-hydroxylation and 3-oxidation of BF were also determined. 3. In summary, CYP3A mediated 5β-hydroxylation and 3-oxidation were two major metabolic pathways of BF in hepatic microsomes from human and five studied animals, but kinetic analysis demonstrated that the intrinsic clearances of these two metabolic pathways were much different among various species. The qualitative and quantitative interspecies study indicated that minipig exhibited the similar metabolic profile, kinetic behaviors and intrinsic metabolic clearances of BF phase I biotransformation in comparison with that of human.
authors.affiliation: a Dalian Medical University , Dalian , China .|b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Jing
authors.initials: J
authors.lastname: Ning
authors.affiliation: c Department of Biochemistry and Molecular Biology , Dalian Medical University , Dalian , China .
authors.forename: Jie
authors.initials: J
authors.lastname: Hou
authors.affiliation: b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Zi-Ru
authors.initials: ZR
authors.lastname: Dai
authors.affiliation: b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Zou
authors.affiliation: d College of Medicine, Yangzhou University , Yangzhou , China , and.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: e Research Institute of Integrated Traditional and Western Medicine, Dalian Medical University , Dalian , China.
authors.forename: Xiao-Chi
authors.initials: XC
authors.lastname: Ma
authors.affiliation: b Laboratory of Pharmaceutical Resource Discovery , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian , China .
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D000818:Animals; D002018:Bufanolides / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013552:Swine; D013556:Swine, Miniature
chemical_list: D002018:Bufanolides; C022777:bufalin
keywords: 3-Oxidation; 5β-hydroxylation; bufalin; cytochrome P450 3A; species differences