Subject Area物理化学
Dibenzocyclooctadiene Lignans from Schisandra chinensis Behave as Dual Inhibitors of Human Cytochrome P450 2C8 and 3A
Zhang YY(张延延); Yang L(杨凌)
Conference Name18th International Symposium on Microsomes and Drug Oxidations
Conference Date2010-5-16
Conference Place中国
Alternative Title五味子中的联苯环辛二烯木脂素作为人体细胞色素P4502C8和3A双重抑制剂
Funding OrganizationISSX学会
AbstractDibenzocyclooctadiene Lignans from Schisandra chinensis Behave as Dual Inhibitors of Human Cytochrome P450 2C8 and 3A 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 Background: Dibenzocyclooctadiene lignans are recognized as the principle absorbed effective ingredients of Fructus Schisandrae, which is extensively used as an antitussive, sedative and tonic agent in China, Korea, Japan, and Russia. Previous investigations have revealed that gomisin group of schisandra lignans exhibited potent inhibitory effects against CYP3A4 (Iwata et al., 2004). Since there appeared to be a degree of overlapping inhibitor specificity between CYP2C8 and CYP3A4 (Ong et al., 2000), structure-metabolism relationships study was performed on a series of 7 major lignans in order to define structural requirements for dual inhibition of both CYPs. Results: Deoxyschizandrin and schizandrin were considered less likely to cause drug-drug interactions via inhibition of either CYP2C8 or CYP3A activity (IC50>10 µM). However, the presence of one methylenedioxy ring in γ-schizandrin, gomisin A, gomisin C, and gomisin G, could enhanced both CYP2C8 and 3A inhibitory activity. The introduction of another methylenedioxy ring markedly abolished inhibitory effect of schizandrin C on CYP2C8, although little impact on CYP3A4 inhibition activity was observed. In addition, IC50 shift studies demonstrated that gomisin A, containing one methylenedioxy ring in molecular framework, was a time-dependent inhibitor of CYP3A4. An apparent Ki value of 1.9 µM without preincubation and an NADPH-dependent inhibition with a Kinact of 0.032±0.001 min-1 and a KI of 0.65±0.06 µM were also determined. Biotransformation of gomisin A by CYP3A4 generated a reactive catechol intermediate, which could be further oxidized to an ortho-quinone. This might be responsible for consumption of GSH in human liver. Conclusions: The presence of these methylenedioxyphenyl lignans in Fructus Schisandrae may lead to schisandra-prescription drug interactions via inhibition of both CYP2C8 and CYP3A. Metabolic activation of gomisin A by CYP3A4 may substantially undermine the clinical value of this herb medicine. References: Iwata H, Tezuka Y, Kadota S, Hiratsuka A, Watabe T. Identification and characterization of potent CYP3A4 inhibitors in Schisandra fruit extract. Drug Metab Dispos 2004; 32(12):1351-1358. Ong CE, Coulter S, Birkett DJ, Bhasker CR, Miners JO. The xenobiotic inhibitor profile of cytochrome P4502C8. Br J Clin Pharmacol 2000; 50(6):573-580.
Document Type会议论文
Corresponding AuthorYang L(杨凌)
Recommended Citation
GB/T 7714
Zhang YY,Yang L. Dibenzocyclooctadiene Lignans from Schisandra chinensis Behave as Dual Inhibitors of Human Cytochrome P450 2C8 and 3A[C],2010:194/2.
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