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	BIOTRANSFORMATION OF GOMISIN A BY CYTOCHROME P450 3A4 LEADS TO METABOLITE–P450 COMPLEX FORMATION AND IRREVERSIBLE INHIBITION; 戈米辛A经CYP3A4代谢之后产生代谢产物中间体-P450复合物
	Zhang YY(张延延) ; Yang L(杨凌)
	2009-10-18
会议名称	International Society for the Study of Xenobiotics
会议日期	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
页码	152/1
通讯作者	Ling Yang
中文摘要	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.
会议主办者	AllChemie Inc.
学科主题	物理化学
语种	中文
内容类型	会议论文
源URL	[http://159.226.238.44/handle/321008/113668]
专题	大连化学物理研究所_中国科学院大连化学物理研究所
推荐引用方式 GB/T 7714	Zhang YY,Yang L. BIOTRANSFORMATION OF GOMISIN A BY CYTOCHROME P450 3A4 LEADS TO METABOLITE–P450 COMPLEX FORMATION AND IRREVERSIBLE INHIBITION, 戈米辛A经CYP3A4代谢之后产生代谢产物中间体-P450复合物[C]. 见:International Society for the Study of Xenobiotics. 美国. 2009-10-18.

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