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学科主题: 物理化学
题名: BIOTRANSFORMATION OF GOMISIN A BY CYTOCHROME P450 3A4 LEADS TO METABOLITE–P450 COMPLEX FORMATION AND IRREVERSIBLE INHIBITION
作者: Zhang YY(张延延) ;  Yang L(杨凌)
会议名称: International Society for the Study of Xenobiotics
会议日期: 2009-10-18
出版日期: 2009-10-18
会议地点: 美国
其他题名: 戈米辛A经CYP3A4代谢之后产生代谢产物中间体-P450复合物
通讯作者: Ling Yang
部门归属: 十八室
主办者: AllChemie Inc.
摘要: Gomisin A is one of the major dibenzocyclooctadiene lignans isolated from the traditional Chinese medicine Fructus Schisandrae. Pharmacological studies have revealed that gomisin A shows protective effects on chemicals-induced hepatotoxicity and glutamate induced oxidative neuronal damage. In the present study, to gain insight into the potential of schisandra-prescription drug interactions, a detailed study on the metabolic pathway of gomisin A was conducted. The influence of gomisin A as a CYP3A4 reversible inhibitor or irreversible inactivator was also evaluated. In human liver microsomes, gomisin A was oxidized to demethylenation gomisin A and one monohydroxylated metabolites. A combination of correlation analysis, chemical inhibition studies, assays with recombinant CYPs and enzyme kinetics indicated that both metabolites were generated predominantly by CYP3A4. IC50 shift studies demonstrated that gomisin A was a time dependent inhibitor of CYP3A4. An apparent Ki value of 1.9 μM without preincubation and an NADPHdependent inhibition with a Kinact of 0.032±0.001 min-1 and a KI of 0.65±0.06 μM were determined. Spectral scanning of recombinant CYP3A4 with gomisin A suggested that the formation of a metabolite intermediate complex was responsible for CYP3A4 inactivation. These results collectively demonstrated that gomisin A might exhibit significant modulatory effects on CYP3A4 activities. The presence of these methylenedioxyphenyl lignans in Fructus Schisandrae may substantially undermine the clinical value of this herb medicine.
语种: 中文
内容类型: 会议论文
URI标识: http://cas-ir.dicp.ac.cn/handle/321008/113668
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. BIOTRANSFORMATION OF GOMISIN A BY CYTOCHROME P450 3A4 LEADS TO METABOLITE–P450 COMPLEX FORMATION AND IRREVERSIBLE INHIBITION[C]. 见:International Society for the Study of Xenobiotics. 美国. 2009-10-18.
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