Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol
<b>Background/Objectives</b>: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (<i>Perilla frutescens</i>), is currently in phase I and II clinical trials as a chemotherapeutic agent. In this study, we investigate...
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2024-12-01
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| author | Ji Hyeon Ryu Jieun Yu Jang Su Jeon Seongyea Jo Soo Min Lee Hyemin Kim Han-Jin Park Soo Jin Oh Sang Kyum Kim |
| author_facet | Ji Hyeon Ryu Jieun Yu Jang Su Jeon Seongyea Jo Soo Min Lee Hyemin Kim Han-Jin Park Soo Jin Oh Sang Kyum Kim |
| author_sort | Ji Hyeon Ryu |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (<i>Perilla frutescens</i>), 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. <b>Methods</b>: 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. <b>Results</b>: POH inhibited the activities of CYP2A6 and CYP2B6 with K<sub>i</sub> 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<sub>50</sub> values greater than 50 μM, but those of CYP1A2, CYP2C8, CYP2D6, and CYP3A4 (testosterone) were not significantly inhibited. In pooled HLMs, the V<sub>max</sub>/K<sub>m</sub> 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 <i>b</i><sub>5</sub> but not rCYP3A4 without cytochrome <i>b</i><sub>5</sub>. 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. <b>Conclusions</b>: 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. |
| format | Article |
| id | doaj-art-9f32b504b16043ab91781ff71746f745 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-9f32b504b16043ab91781ff71746f7452024-12-27T14:46:35ZengMDPI AGPharmaceutics1999-49232024-12-011612158110.3390/pharmaceutics16121581Heterotropic Activation of Cytochrome P450 3A4 by Perillyl AlcoholJi Hyeon Ryu0Jieun Yu1Jang Su Jeon2Seongyea Jo3Soo Min Lee4Hyemin Kim5Han-Jin Park6Soo Jin Oh7Sang Kyum Kim8College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of KoreaCollege of Pharmacy, Chungnam National University, Daejeon 34134, Republic of KoreaCollege of Pharmacy, Chungnam National University, Daejeon 34134, Republic of KoreaCenter for Biomimetic Research, Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon 34114, Republic of KoreaDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaCenter for Biomimetic Research, Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon 34114, Republic of KoreaCenter for Biomimetic Research, Division of Advanced Predictive Research, Korea Institute of Toxicology, Daejeon 34114, Republic of KoreaDepartment of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of KoreaCollege of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea<b>Background/Objectives</b>: Perillyl alcohol (POH), a monoterpene natural product derived from the essential oils of plants such as perilla (<i>Perilla frutescens</i>), 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. <b>Methods</b>: 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. <b>Results</b>: POH inhibited the activities of CYP2A6 and CYP2B6 with K<sub>i</sub> 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<sub>50</sub> values greater than 50 μM, but those of CYP1A2, CYP2C8, CYP2D6, and CYP3A4 (testosterone) were not significantly inhibited. In pooled HLMs, the V<sub>max</sub>/K<sub>m</sub> 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 <i>b</i><sub>5</sub> but not rCYP3A4 without cytochrome <i>b</i><sub>5</sub>. 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. <b>Conclusions</b>: 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.https://www.mdpi.com/1999-4923/16/12/1581heterotropic activationCYP3A4perillyl alcoholhuman hepatic organoidsdrug interaction |
| spellingShingle | Ji Hyeon Ryu Jieun Yu Jang Su Jeon Seongyea Jo Soo Min Lee Hyemin Kim Han-Jin Park Soo Jin Oh Sang Kyum Kim Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol Pharmaceutics heterotropic activation CYP3A4 perillyl alcohol human hepatic organoids drug interaction |
| title | Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol |
| title_full | Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol |
| title_fullStr | Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol |
| title_full_unstemmed | Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol |
| title_short | Heterotropic Activation of Cytochrome P450 3A4 by Perillyl Alcohol |
| title_sort | heterotropic activation of cytochrome p450 3a4 by perillyl alcohol |
| topic | heterotropic activation CYP3A4 perillyl alcohol human hepatic organoids drug interaction |
| url | https://www.mdpi.com/1999-4923/16/12/1581 |
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