Ryu Ji Hyeon, Yu Jieun, Jeon Jang Su, Jo Seongyea, Lee Soo Min, Kim Hyemin, Park Han-Jin, Oh Soo Jin, Kim Sang Kyum
College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea.
Center for Biomimetic Research, Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea.
Pharmaceutics. 2024 Dec 11;16(12):1581. doi: 10.3390/pharmaceutics16121581.
: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (), is currently in phase I and II clinical trials as a chemotherapeutic agent. In this study, we investigated the effect of POH on cytochrome P450 (CYP) activity for evaluating POH-drug interaction potential. : The investigation was conducted using pooled human liver microsomes (HLMs), recombinant CYP3A4 (rCYP3A4) enzymes, and human pluripotent stem cell-derived hepatic organoids (hHOs) employing liquid chromatography-tandem mass spectrometry. : POH inhibited the activities of CYP2A6 and CYP2B6 with K of 6.35 and 3.78 μM, respectively, whereas it stimulated CYP3A4 activity in pooled HLMs incubated with midazolam (MDZ). In a direct CYP inhibition assay using HLMs, activities of CYP2C9, CYP2C19, and CYP2E1 were also inhibited by POH, with IC values greater than 50 μM, but those of CYP1A2, CYP2C8, CYP2D6, and CYP3A4 (testosterone) were not significantly inhibited. In pooled HLMs, the V/K value of 1'-hydroxy MDZ, but not that of 4-hydroxy MDZ, was increased 2.7-fold by 100 μM POH compared with that in the absence of POH. Moreover, stimulation of MDZ 1'-hydroxylation by CYP3A4 was observed in hHOs and rCYP3A4 with cytochrome but not rCYP3A4 without cytochrome . Furthermore, activation of CYP3A4-mediated metabolism by POH was observed in HLMs incubated with fimasartan but not atorvastatin, buspirone, donepezil, nifedipine, or tadalafil, suggesting a substrate-dependent activation of CYP3A4 by POH. : POH inhibits CYP2A6 and CYP2B6, but it activates CYP3A4. These findings underscore the need for further evaluation of the interactions of clinical drugs with POH.
紫苏醇（POH）是一种从紫苏等植物精油中提取的单萜类天然产物，目前正作为一种化疗药物进行I期和II期临床试验。在本研究中，我们研究了POH对细胞色素P450（CYP）活性的影响，以评估POH与药物相互作用的可能性。：该研究使用混合人肝微粒体（HLM）、重组CYP3A4（rCYP3A4）酶和人多能干细胞衍生的肝类器官（hHO），采用液相色谱-串联质谱法进行。：POH分别以6.35和3.78μM的K值抑制CYP2A6和CYP2B6的活性，而在与咪达唑仑（MDZ）孵育的混合HLM中，它刺激CYP3A4活性。在使用HLM的直接CYP抑制试验中，POH也抑制了CYP2C9、CYP2C19和CYP2E1的活性，IC值大于50μM，但CYP1A2、CYP2C8、CYP2D6和CYP3A4（睾酮）的活性未受到显著抑制。在混合HLM中，与无POH时相比，100μM POH使1'-羟基MDZ的V/K值增加了2.7倍，但4-羟基MDZ的V/K值未增加。此外，在有细胞色素的hHO和rCYP3A4中观察到CYP3A4对MDZ 1'-羟基化的刺激作用，但在无细胞色素的rCYP3A4中未观察到。此外，在与替米沙坦孵育的HLM中观察到POH对CYP3A4介导的代谢有激活作用，但在与阿托伐他汀、丁螺环酮、多奈哌齐、硝苯地平或他达拉非孵育时未观察到，这表明POH对CYP3A4的激活作用具有底物依赖性。：POH抑制CYP2A6和CYP2B6，但激活CYP3A4。这些发现强调了进一步评估临床药物与POH相互作用的必要性。
