Subject Area物理化学
Metabolic Activation of Strychnine to Reactive Intermediates by Human Liver Microsomes and CYP3A4
Mao YX(毛玉玺); Fang ZZ(房中则); Ge GB(葛广波); Yang L(杨凌); Ling Yang
Conference Name9th International Meeting of the International Society for the Study of Xenobiotics in Istanbul
Conference Date2010-9-4
Conference Place土耳其
Alternative Title士的宁在人肝微粒体和CYP3A4中生物激活产生活性中间体
Funding Organization国际药物代谢学会
AbstractStrychnine is one of the main active components of Semen Strychni which has been used as a traditional Chinese medicine for the treatment of nervous diseases, vomiting and arthritic and traumatic pains. It is highly toxic to humans and most domestic animals and acts as the poison curare originating from South America. Chemically reactive metabolites may induce toxicities and adverse side reactions, which might lead to withdrawing of the drug from market. There is exiting metabolic pathways in which Strychnine is oxidized to hydroxyl metabolites which might undergo a two-electron oxidation leading to formation of an electrophilic quinine imine intermediate. It is of significant interest to detect and characterization of reactive intermediates generated in the disposition of strychnine. Bioactivation potential of strychnine in human liver microsomes and recombinant CYP isoforms were performed. LC-MS/MS analysis of extracts of human liver microsomal incubations containing strychnine (200 μM), NADPH and GSH revealed a GSH adduct of the metabolite of strychnine was detected. Among tested recombinant CYP isoforms, CYP3A4 had the highest activity to catalyze the bioactivation of strychnine. Selective chemical inhibition investigation demostrated that ketoconazole dramatically inhibited the formation of GSH adduct. In the further stage of this investigation, GSH adduct is to be chemically synthesized to examine whether strychnine or GSH adduct plays a role in the toxicity of strychnine.
WOS IDWOS:000281147700405
Citation statistics
Document Type会议论文
Corresponding AuthorLing Yang
Recommended Citation
GB/T 7714
Mao YX,Fang ZZ,Ge GB,et al. Metabolic Activation of Strychnine to Reactive Intermediates by Human Liver Microsomes and CYP3A4[C],2010:229/2.
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