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Open AccessArticle

Strong and Selective Inhibitory Effects of the Biflavonoid Selamariscina A against CYP2C8 and CYP2C9 Enzyme Activities in Human Liver Microsomes

1
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
2
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
3
Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Cau Giay, Hanoi 100000, Vietnam
4
Vietnam Hightech of Medicinal and Pharmaceutical JSC, Group 11 Quang Minh town, Hanoi 100000, Vietnam
*
Author to whom correspondence should be addressed.
Pharmaceutics 2020, 12(4), 343; https://doi.org/10.3390/pharmaceutics12040343
Received: 25 March 2020 / Revised: 7 April 2020 / Accepted: 9 April 2020 / Published: 10 April 2020
(This article belongs to the Special Issue Drug–Drug Interactions)
Like flavonoids, biflavonoids, dimeric flavonoids, and polyphenolic plant secondary metabolites have antioxidant, antibacterial, antiviral, anti-inflammatory, and anti-cancer properties. However, there is limited data on their effects on cytochrome P450 (P450) and uridine 5′-diphosphoglucuronosyl transferase (UGT) enzyme activities. In this study we evaluate the inhibitory potential of five biflavonoids against nine P450 activities (P450s1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) in human liver microsomes (HLMs) using cocktail incubation and liquid chromatography-tandem mass spectrometry (LC–MS/MS). The most strongly inhibited P450 activity was CYP2C8-mediated amodiaquine N-dealkylation with IC50 ranges of 0.019~0.123 μM. In addition, the biflavonoids—selamariscina A, amentoflavone, robustaflavone, cupressuflavone, and taiwaniaflavone—noncompetitively inhibited CYP2C8 activity with respective Ki values of 0.018, 0.083, 0.084, 0.103, and 0.142 μM. As selamariscina A showed the strongest effects, we then evaluated it against six UGT isoforms, where it showed weaker inhibition (UGTs1A1, 1A3, 1A4, 1A6, 1A9, and 2B7, IC50 > 1.7 μM). Returning to the P450 activities, selamariscina A inhibited CYP2C9-mediated diclofenac hydroxylation and tolbutamide hydroxylation with respective Ki values of 0.032 and 0.065 μM in a competitive and noncompetitive manner. However, it only weakly inhibited CYP1A2, CYP2B6, and CYP3A with respective Ki values of 3.1, 7.9, and 4.5 μM. We conclude that selamariscina A has selective and strong inhibitory effects on the CYP2C8 and CYP2C9 isoforms. This information might be useful in predicting herb-drug interaction potential between biflavonoids and co-administered drugs mainly metabolized by CYP2C8 and CYP2C9. In addition, selamariscina A might be used as a strong CYP2C8 and CYP2C9 inhibitor in P450 reaction-phenotyping studies to identify drug-metabolizing enzymes responsible for the metabolism of new chemicals. View Full-Text
Keywords: biflavonoid; cytochrome P450; drug interactions; selamariscina A; uridine 5′-diphosphoglucuronosyl transferase biflavonoid; cytochrome P450; drug interactions; selamariscina A; uridine 5′-diphosphoglucuronosyl transferase
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MDPI and ACS Style

Park, S.-Y.; Nguyen, P.-H.; Kim, G.; Jang, S.-N.; Lee, G.-H.; Phuc, N.M.; Wu, Z.; Liu, K.-H. Strong and Selective Inhibitory Effects of the Biflavonoid Selamariscina A against CYP2C8 and CYP2C9 Enzyme Activities in Human Liver Microsomes. Pharmaceutics 2020, 12, 343.

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