BK21 FOUR Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy, Kyungpook National University, Daegu, Republic of Korea.
School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
Biopharm Drug Dispos. 2023 Oct;44(5):365-371. doi: 10.1002/bdd.2370. Epub 2023 Jul 13.
Suberosin is a natural phytoconstituent isolated from Citropsis articulata, especially employed for its anticoagulant properties. Although metabolic studies assessing suberosin have been conducted, it is possible interactions with drugs and food have not yet been investigated. In the present study, we analyzed the selective inhibitory effects of suberosin on cytochrome P450 (CYP) enzymes using a cocktail probe assay. Various concentrations of suberosin (0-50 μM) were incubated with isoform-specific CYP probes in human liver microsomes (HLMs). We found that suberosin significantly inhibited CYP1A2-catalyzed phenacetin O-deethylation, exhibiting IC values of 9.39 ± 2.05 and 3.07 ± 0.45 μM with and without preincubation in the presence of β-NADPH, respectively. Moreover, suberosin showed concentration-dependent, but not time-dependent, CYP1A2 inhibition in HLMs, indicating that suberosin acts as a substrate and reversible CYP1A2 inhibitor. Using a Lineweaver-Burk plot, we found that suberosin competitively inhibited CYP1A2-catalyzed phenacetin O-deethylation. Furthermore, suberosin showed similar inhibitory effects on recombinant human CYP1A1 and 1A2. In conclusion, suberosin may elicit herb-drug interactions by selectively inhibiting CYP1A2 during the concurrent administration of drugs that act as CYP1A2 substrates.
地檀香醇是从佛手瓜中分离得到的天然植物成分，尤其因其抗凝特性而被应用。虽然已经进行了评估地檀香醇代谢的研究，但它与药物和食物的相互作用尚未被研究。在本研究中，我们使用鸡尾酒探针法分析了地檀香醇对细胞色素 P450（CYP）酶的选择性抑制作用。用不同浓度（0-50 μM）的地檀香醇与人肝微粒体（HLMs）中同工型特异性 CYP 探针孵育。我们发现地檀香醇显著抑制 CYP1A2 催化的非那西汀 O-去乙基化，在有和没有β-NADPH 预孵育的情况下，IC50 值分别为 9.39±2.05 和 3.07±0.45 μM。此外，地檀香醇在 HLMs 中表现出浓度依赖性但非时间依赖性的 CYP1A2 抑制，表明地檀香醇作为底物和可逆 CYP1A2 抑制剂发挥作用。通过 Lineweaver-Burk 作图，我们发现地檀香醇竞争性抑制 CYP1A2 催化的非那西汀 O-去乙基化。此外，地檀香醇对重组人 CYP1A1 和 1A2 也表现出相似的抑制作用。总之，地檀香醇可能通过在同时给予作为 CYP1A2 底物的药物时选择性抑制 CYP1A2 而引起草药-药物相互作用。
