Metabolism of diosbulbin B in vitro and in vivo in rats: formation of reactive metabolites and human enzymes involved

doi:10.1124/dmd.114.058222

	Metabolism of diosbulbin B in vitro and in vivo in rats: formation of reactive metabolites and human enzymes involved
	Yang, Baohua 2,3; Liu, Wei 2,3; Chen, Kaixian2,3 ; Wang, Zhengtao 1,2; Wang, Changhong 1,2
刊名	Drug metabolism and disposition: the biological fate of chemicals
	2014-10
卷号	42 期号:10 页码:1737-50
ISSN号	1521-009X
DOI	10.1124/dmd.114.058222
文献子类	Article
英文摘要	Diosbulbin B (DB), a major constituent of the furano-norditerpenes in Dioscorea bulbifera Linn, exhibits potential antineoplasmic activity and hepatotoxicity. The metabolism and reactive metabolites of DB in vitro (with human and animal liver microsomes) and in vivo in rats were investigated. The human enzymes involved in DB metabolism were identified. DB was first catalyzed into reactive metabolites of 2-butene-1,4-dial derivatives dependent on NADPH and then trapped by Tris base or oxidized to hemiacetal lactones (M12 and M13) in microsomal incubations. Tris base was used as buffer constituent and as a trapping agent for aldehyde. Methoxylamine and glutathione (GSH) were also used as trapping agents. DB metabolism in vivo in rats after oral administration was consistent with that in vitro. The structures of M12 and M13, as well as mono-GSH conjugates of DB (M31), were confirmed by nuclear magnetic resonance spectroscopy of the chemically synthesized products. The bioactivation enzymes of DB were identified as CYP3A4/5, 2C9, and 2C19. CYP3A4 was found to be the primary enzyme using human recombinant cytochrome P450 enzymes, specific inhibitory studies, and a relative activity factor approach for pooled human liver microsomes. Michaelis-Menten constants K(m) and V(max) were determined by the formation of M31. The reactive metabolites may be related to the hepatotoxicity of DB. The gender difference in CYP3A expression in mice and rats contributed to the gender-related liver injury and pharmacokinetics in mice and rats, respectively.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266549]
专题	中国科学院上海药物研究所
通讯作者	Wang, Zhengtao; Wang, Changhong
作者单位	1.and Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China (K.C., Z.W., C.W.) 2.Ministry of Education Key Laboratory for Standardization of Chinese Medicines, State Administration of Traditional Chinese Medicine Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China (B.Y., W.L., K.C., Z.W., C.W.); 3.and Shanghai R&D Centre for Standardization of Chinese Medicines, Shanghai, China (K.C., Z.W., C.W.);
推荐引用方式 GB/T 7714	Yang, Baohua,Liu, Wei,Chen, Kaixian,et al. Metabolism of diosbulbin B in vitro and in vivo in rats: formation of reactive metabolites and human enzymes involved[J]. Drug metabolism and disposition: the biological fate of chemicals,2014,42(10):1737-50.
APA	Yang, Baohua,Liu, Wei,Chen, Kaixian,Wang, Zhengtao,&Wang, Changhong.(2014).Metabolism of diosbulbin B in vitro and in vivo in rats: formation of reactive metabolites and human enzymes involved.Drug metabolism and disposition: the biological fate of chemicals,42(10),1737-50.
MLA	Yang, Baohua,et al."Metabolism of diosbulbin B in vitro and in vivo in rats: formation of reactive metabolites and human enzymes involved".Drug metabolism and disposition: the biological fate of chemicals 42.10(2014):1737-50.