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学科主题: 物理化学
题名: Deoxyschizandrin Could Attenuate Cytochrome P450 3A4-Mediated Bioactivation of Gomisin A in Human Liver Microsomes
作者: Zhang YY(张延延) ;  Yang L(杨凌)
会议名称: 9th International Meeting of the International Society for the Study of Xenobiotics
会议日期: 2010-9-4
出版日期: 2010-09-04
会议地点: 土耳其
其他题名: 五味子甲素能够降低戈米辛A在人肝微粒体中的经细胞色素P450 3A4代谢生物激活的程度
通讯作者: 杨凌
ISSN: 0360-2532
部门归属: 十八室
主办者: ISSX学会
摘要: Deoxyschizandrin Could Attenuate Cytochrome P450 3A4-Mediated Bioactivation of Gomisin A in Human Liver Microsomes Yan-Yan Zhang, Ling Yang Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023 China Dibenzocyclooctadiene lignans are discussed as the major absorbed effective ingredients of Schisandra fruit, which is widely used as an antitussive, sedative, tonic agent, and a component of dietary supplement products. Our previous investigations have revealed that biotransformation of the methylenedioxy lignans (e.g. gomisin A) by cytochrome P450 (CYP) 3A can lead to mechanism-based inactivation and reactive ortho-quinone metabolites. In the present study, to gain insight into the clinical value of this herb medicine, a detailed study on the metabolic and inhibitory properties of deoxyschizandrin, another schisandra lignan without methylenedioxy functionality, was conducted. Its influence on the bioactivation of gomisin A was also evaluated. In human liver microsomes (HLMs), deoxyschizandrin underwent C-7 monohydroxylation. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs and enzyme kinetics (Km, 1.6±0.1 μM; Vmax, 623±9.9 pmol/min/mg protein) indicated that its metabolite was generated predominantly by CYP3A4. However, no GSH adduct was observed, which was quite different from gomisin A under the same incubation conditions. Deoxyschizandrin was also found to potently inhibit CYP3A in a competitive manner (Ki, 2.6 μM). IC50 shift studies demonstrated that deoxyschizandrin was not a time and cofactor-dependent inhibitor of CYP3A. Co incubation of deoxyschizandrin (0~100 μM) with gomisin A (50 μM) in HLMs resulted in great reduction of time-dependent inhibitory potential of gomisin A against CYP3A (% activity remaining, 20~80). Moreover, the production of GSH adduct demethylenated gomisin A could be strongly impaired by deoxyschizandrin in vitro. These results collectively demonstrated that deoxyschizandrin might exhibit significant modulatory effects on CYP3A4 activity, thus reducing the bioactivation potential of gomisin A. The presence of deoxyschizandrin in Schisandra fruit could increase the clinical safety of this herb medicine.
语种: 中文
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内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/114186
Appears in Collections:中国科学院大连化学物理研究所_会议论文

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Recommended Citation:
Zhang YY,Yang L. Deoxyschizandrin Could Attenuate Cytochrome P450 3A4-Mediated Bioactivation of Gomisin A in Human Liver Microsomes[C]. 见:9th International Meeting of the International Society for the Study of Xenobiotics. 土耳其. 2010-9-4.
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