Inhibition of human CYP3A4 and CYP3A5 enzymes by gomisin C and gomisin G, two lignan analogs derived from Schisandra chinensis.
Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1'-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation. Notably, the inhibitory intensity of GC towards CYP3A4 was stronger than CYP3A5 when using midazolam and nifedipine as substrates. While inhibition of GC towards CYP3A5 was weaker than CYP3A4 when using testosterone as substrate. In contrast, GG showed a stronger inhibitory activity on CYP3A5 than CYP3A4 without substrate-dependent behavior. In addition, docking simulations indicated that the π-π interaction between CYP3A4 and GC, and hydrogen-bond interaction between CYP3A5 and GG might result in their different inhibitory actions. Furthermore, the AUC of drugs metabolized by CYP3A was estimated to increase by 8%-321% and 2%-3190% in the presence of GC and GG, respectively. These findings strongly suggested that GC and GG showed high HDI potentials, and the position of methylenedioxy group determined their different inhibitory effect towards CYP3A4 and CYP3A5, which are of significance for the application of Schisandra chinensis-containing herbs.
School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China.
Jin
J
Zhao
Department of Breast Medicine, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
Tao
T
Sun
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.; Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
Jing-Jing
JJ
Wu
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.; Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.; Key Laboratory of Contraceptives and Devices Research (NPFPC), Shanghai Engineer and Technology Research Center of Reproductive Health Drug and Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, China.
Yun-Feng
YF
Cao
Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.; Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Zhong-Ze
ZZ
Fang
Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
Hong-Zhi
HZ
Sun
Key Laboratory of Liaoning Tumor Clinical Metabolomics (KLLTCM), Jinzhou, Liaoning, China.
Zhi-Tu
ZT
Zhu
Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Kun
K
Yang
Department of Toxicology, School of Public Health, Tianjin Medical University, 22 Qixiangtai Road, Heping District, Tianjin 300070, China.
Yong-Zhe
YZ
Liu
Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health, Building 37, Room 3106, Bethesda, MD 20892, USA.
Frank J
FJ
Gonzalez
School of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: yinjun2002@yahoo.com.
Jun
J
Yin
D034242:Cyclooctanes / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D006900:Hydroxylation; D017705:Lignans / Q000494:pharmacology*; D008874:Midazolam / Q000494:pharmacology; D015394:Molecular Structure; D009543:Nifedipine / Q000494:pharmacology; D010084:Oxidation-Reduction; D032141:Schisandra / Q000737:chemistry*; D013739:Testosterone / Q000494:pharmacology
D034242:Cyclooctanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D004149:Dioxoles; D017705:Lignans; D013739:Testosterone; C034557:schizandrer A; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009543:Nifedipine; D008874:Midazolam
CYP3A4; CYP3A5; Gomisin C; Gomisin G; Herb-drug interactions; Inhibition