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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Yang, Ai-Hong He, Xin Chen, Jun-Xiu He, Li-Na Jin, Chun-Huan Wang, Li-Li Zhang, Fang-Liang An, Li-Jun |
| Description | Author Affiliation: Yang AH ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.); He X ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China. Electronic address: hexintn@163.com.); Chen JX ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.); He LN ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.); Jin CH ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.); Wang LL ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.); Zhang FL ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.); An LJ ( School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.) |
| Abstract | Myristicin belongs to the methylenedioxyphenyl or allyl-benzene family of compounds, which are found widely in plants of the Umbelliferae family, such as parsley and carrot. Myristicin is also the major active component in the essential oils of mace and nutmeg. However, this compound can cause adverse reactions, particularly when taken inappropriately or in overdoses. One important source of toxicity of natural products arises from their metabolic biotransformations into reactive metabolites. Myristicin contains a methylenedioxyphenyl substructure, and this specific structural feature may allow compounds to cause a mechanism-based inhibition of cytochrome P450 enzymes and produce reactive metabolites. Therefore, the aim of this work was to identify whether the role of myristicin in CYP enzyme inhibition is mechanism-based inhibition and to gain further information regarding the structure of the resulting reactive metabolites. CYP cocktail assays showed that myristicin most significantly inhibits CYP1A2 among five CYP enzymes (CYP1A2, CYP2D6, CYP2E1, CYP3A4 and CYP2C19) from human liver microsomes. The 3.21-fold IC50 shift value of CYP1A2 indicates that myristicin may be a mechanism-based inhibitor of CYP1A2. Next, reduced glutathione was shown to block the inhibition of CYP1A2, indicating that myristicin utilized a mechanism-based inhibition. Phase I metabolism assays identified two metabolites, 5-allyl-1-methoxy-2,3-dihydroxybenzene (M1) and 1'-hydroxymyristicin or 2',3'-epoxy-myristicin (M2). Reduced glutathione capturing assays captured the glutathione-M1 adduct, and the reactive metabolites were identified using UPLC-MS(2) as a quinone and its tautomer. Thus, it was concluded that myristicin is a mechanism-based inhibitor of CYP1A2, and the reactive metabolites are quinone tautomers. Additionally, the cleavage process of the glutathione-M1 adduct was analyzed in further detail. This study provides additional information on the metabolic mechanism of myristicin inhibition and improves risk evaluation for this compound. |
| File Format | HTM / HTML |
| ISSN | 00092797 |
| Volume Number | 237 |
| e-ISSN | 18727786 |
| Journal | Chemico-Biological Interactions |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2015-07-25 |
| Publisher Place | Ireland |
| Access Restriction | One Nation One Subscription (ONOS) |
| Subject Keyword | Discipline Biochemistry Discipline Pharmacology Benzyl Compounds Pharmacology Cytochrome P-450 Cyp1a2 Inhibitors Cytochrome P-450 Cyp1a2 Drug Effects Dioxolanes Pyrogallol Analogs & Derivatives Chromatography, High Pressure Liquid Metabolism Glutathione Humans Inhibitory Concentration 50 Mass Spectrometry Journal Article Research Support, Non-u.s. Gov't |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Toxicology |
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