News DetailsCurrent Position: Home > News List > News Details

Dibenzocyclooctadiene Lignans from Schisandra chinensis extract Behave as Dual Inhibitors of Human Cytochrome P450 2C8 and 3A.

Date:2016/10/8 16:06:12

Dibenzocyclooctadiene Lignans from Schisandra chinensis extract Behave as Dual Inhibitors of Human Cytochrome P450 2C8 and 3A.Dibenzocyclooctadiene Lignans from Schisandra chinensis extract Behave as Dual Inhibitors of Human Cytochrome P450 2C8 and 3AYan-Yan Zhang, Ling YangLaboratory 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 chinensis extract 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>10M). However, the presence of one methylenedioxy ring in 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 1.9M without preincubation and an NADPH-dependent inhibition with a Kinact of 0.0320.001 min-1 and a KI of 0.650.06M 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 chinensis extract 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.