Inhibitory Effects of Schisandra Lignans on Cytochrome P450s and Uridine 5′-Diphospho-Glucuronosyl Transferases in Human Liver Microsomes
| Autor: | Seung-Bae Ji, Hyung-Ju Seo, Dae Sik Jang, Sin-Eun Kim, Zhexue Wu, Gyung-Min Lee, Kwang-Hyeon Liu, Soyoung Park |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
CYP3A
Schisandra chinensis cytochrome P450 Pharmaceutical Science lcsh:RS1-441 Schisandrin 030226 pharmacology & pharmacy lcsh:Pharmacy and materia medica 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine drug interaction biology CYP1A2 lignans Cytochrome P450 biology.organism_classification uridine 5′-diphosphoglucuronosyl transferase Biochemistry chemistry 030220 oncology & carcinogenesis biology.protein Microsome Gomisin A Schisandra |
| Zdroj: | Pharmaceutics, Vol 13, Iss 371, p 371 (2021) Pharmaceutics Volume 13 Issue 3 |
| ISSN: | 1999-4923 |
| Popis: | Schisandra chinensis has been widely used as a traditional herbal medicine to treat chronic coughs, fatigue, night sweats, and insomnia. Numerous bioactive components including lignans have been identified in this plant. Lignans with a dibenzocyclooctadiene moiety have been known to possess anti-cancer, anti-inflammatory, and hepatoprotective activity. Fragmentary studies have reported the ability of some lignans to modulate some cytochrome P450 (P450) enzymes. Herein, we investigated the drug interaction potential of six dibenzocyclooctadiene lignans (schisandrin, gomisin A, B, C, and N, and wuweizisu C) on nine P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) and six uridine 5′-diphosphoglucuronosyl transferase (UGT) enzymes (UGT1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) using human liver microsomes. We found that lignans with one or two methylenedioxyphenyl groups inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 activities in a time- and concentration-dependent like their CYP3A inhibition. In comparison, these lignans do not induce time-dependent inhibition of CYP1A2, CYP2A6, and CYP2D6. The time-dependent inhibition of gomisin A against CYP2C8, CYP2C19, and CYP3A4 was also elucidated using glutathione as a trapping reagent of reactive carbene metabolites given that gomisin A strongly inhibits these P450 enzymes in a time-dependent manner. A glutathione conjugate of gomisin A was generated in reactions with human recombinant CYP2C8, CYP2C19, and CYP3A4. This suggests that the time-dependent inhibition of gomisin A against CYP2C8, CYP2C9, and CYP3A4 is due to the production of carbene reactive metabolite. Six of the lignans we tested inhibited the activities of six UGT to a limited extent (IC50 > 15 μM). This information may aid the prediction of possible drug interactions between Schisandra lignans and any co-administered drugs which are mainly metabolized by P450s. |
| Databáze: | OpenAIRE |
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