Subject Area物理化学
Deoxyschizandrin Could Attenuate Cytochrome P450 3A4-Mediated Bioactivation of Gomisin A in Human Liver Microsomes
Zhang YY(张延延); Yang L(杨凌)
Conference Name9th International Meeting of the International Society for the Study of Xenobiotics
Conference Date2010-9-4
Conference Place土耳其
Alternative Title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
Funding OrganizationISSX学会
AbstractDeoxyschizandrin 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.
WOS IDWOS:000281147700249
Citation statistics
Cited Times:1[WOS]   [WOS Record]     [Related Records in WOS]
Document Type会议论文
Corresponding AuthorYang L(杨凌)
Recommended Citation
GB/T 7714
Zhang YY,Yang L. Deoxyschizandrin Could Attenuate Cytochrome P450 3A4-Mediated Bioactivation of Gomisin A in Human Liver Microsomes[C],2010:193/2.
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