Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2

Yang, Ai-Hong; He, Xiaolong; Chen, Junxiu; He, Li-Na; Jin, Chunhuan; Wang, Lili; Zhang, Fangliang; An, Li

doi:10.1016/j.cbi.2015.06.018

Cited by 33 publications

(33 citation statements)

References 41 publications

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“…The discrepancy in this effect could be explained by the relatively long incubation time in the cell migration assay (90 min) compared with the [Ca 2+ ] i flux assay (<5 min). Indeed, myristicin, like other allyl-benzenes, can form covalent conjugates with macromolecules during its enzymatic bioconversion 50 . In addition, the activation of neutrophil migration via FPR1 and CXCR1/2 could be independent of TRPV1 channels.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Human Neutrophil Responses by the Essential Oils from Ferula akitschkensis and Their Constituents

Schepetkin

Кушнаренко

Özek

et al. 2016

J. Agric. Food Chem.

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Essential oils were obtained by hydrodistillation of the umbels+seeds and stems of Ferula akitschkensis (FAEOu/s and FAEOstm, respectively) and analyzed by gas chromatography and gas chromatography–mass spectrometry. Fifty two compounds were identified in FAEOu/s. The primary components were sabinene, α-pinene, β-pinene, terpinen-4-ol, eremophilene, and 2-himachalen-7-ol, while the primary components of FAEOstm were myristicin and geranylacetone. FAEOu/s, β-pinene, sabinene, γ-terpinene, geranylacetone, isobornyl acetate, and (E)-2-nonenal stimulated [Ca2]i mobilization in human neutrophils, with the most potent being geranylacetone (EC50 = 7.6 ± 1.9 µM) and isobornyl acetate 6.4 ± 1.7 (EC50 = 7.6 ± 1.9 µM). In addition, treatment of neutrophils with β-pinene, sabinene, γ-terpinene, geranylacetone, and isobornyl acetate desensitized the cells to N-formyl-Met-Leu-Phe (fMLF)- and interleukin-8 (IL-8)-induced [Ca2]i flux and inhibited fMLF-induced chemotaxis. The effects of β-pinene, sabinene, γ-terpinene, geranylacetone, and isobornyl acetate on neutrophil [Ca2+]i flux were inhibited by transient receptor potential (TRP) channel blockers. Furthermore, the most potent compound, geranylacetone, activated Ca2+ influx in TRPV1-transfected HEK293 cells. In contrast, myristicin inhibited neutrophil [Ca2+]i flux stimulated by fMLF and IL-8 and inhibited capsaicin-induced Ca2+ influx in TRPV1-transfected HEK293 cells. These findings, as well as pharmacophore modeling of TRP agonists, suggest that geranylacetone is a TRPV1 agonist, whereas myristicin is a TRPV1 antagonist. Thus, at least part of the medicinal properties of Ferula essential oils may be due to modulatory effects on TRP channels.

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Section: Discussionmentioning

confidence: 99%

Modulation of Human Neutrophil Responses by the Essential Oils from Ferula akitschkensis and Their Constituents

Schepetkin

Кушнаренко

Özek

et al. 2016

J. Agric. Food Chem.

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“…Similarly, the methyenedioxy group in myristicin is oxidized to an o -quinone leading to mechanism-based inhibition of P4501A2. 103 GSH was shown to block the inhibition which suggests that the o -quinone was the inhibitor and not the carbene formed from the methylenedioxy moiety. 103 The SSRI paroxetine was shown to be an inhibitor of P450 2D6, and the o -quinone metabolite was implicated as the reactive intermediate responsible for the inhibitory effect which ultimately leads to clinical drug–drug interactions with other P450 2D6 substrates.…”

Section: Quinone Targets (Figures 5 and 6)mentioning

confidence: 96%

“…130 Several drugs, environmental chemicals, natural products, and endogenous compounds form quinone GSH conjugates and/or cause GSH depletion. 3,10,70,79,92,103,105,106,109,121,141−149 …”

Section: Quinone Targets (Figures 5 and 6)mentioning

confidence: 99%

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Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

Bolton

Dunlap

2016

Chem. Res. Toxicol.

341

247

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Quinones represent a class of toxicological intermediates, which can create a variety of hazardous effects in vivo including, acute cytotoxicity, immunotoxicity, and carcinogenesis. In contrast, quinones can induce cytoprotection through the induction of detoxification enzymes, anti-inflammatory activities, and modification of redox status. The mechanisms by which quinones cause these effects can be quite complex. The various biological targets of quinones depend on their rate and site of formation and their reactivity. Quinones are formed through a variety of mechanisms from simple oxidation of catechols/hydroquinones catalyzed by a variety of oxidative enzymes and metal ions to more complex mechanisms involving initial P450-catalyzed hydroxylation reactions followed by two-electron oxidation. Quinones are Michael acceptors, and modification of cellular processes could occur through alkylation of crucial cellular proteins and/or DNA. Alternatively, quinones are highly redox active molecules which can redox cycle with their semiquinone radical anions leading to the formation of reactive oxygen species (ROS) including superoxide, hydrogen peroxide, and ultimately the hydroxyl radical. Production of ROS can alter redox balance within cells through the formation of oxidized cellular macromolecules including lipids, proteins, and DNA. This perspective explores the varied biological targets of quinones including GSH, NADPH, protein sulfhydryls [heat shock proteins, P450s, cyclooxygenase-2 (COX-2), glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase 1, (NQO1), kelch-like ECH-associated protein 1 (Keap1), IκB kinase (IKK), and arylhydrocarbon receptor (AhR)], and DNA. The evidence strongly suggests that the numerous mechanisms of quinone modulations (i.e., alkylation versus oxidative stress) can be correlated with the known pathology/cytoprotection of the parent compound(s) that is best described by an inverse U-shaped dose–response curve.

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“…4 We can also find myristicin in fennel, celery, and parsley plants. 5 Myristicin is also potential as an effective chemoprotective agent against cancer and hepatoprotective activity. 6,7 Myristicin is a derivative of phenylpropanoid compounds, in the form of a clear liquid, not soluble in water but soluble in organic solvents.…”

Section: Myristicinmentioning

confidence: 99%

The Isolation of Myristicin from Nutmeg Oil by Sequences Distillation

Sudradjat

Timotius²,

Mun’im³

et al. 2018

JYP

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Background: Nutmeg oil is used in Asia as a traditional medicine for a stomach cramps, diarrhea, and insomnia. It's quality need to be improved by increasing myristicin content. Objectives: This study aimed to increase the myristicin content of nutmeg oil by sequences distillations. Methods: Three different conditions of distillations were applied sequentially. The first, second and third distillation were at 110 0 C (0.2 bars), 105 0 C (1 bar), and 145 0 C (0.2 bars) respectively. Myristicin contents determined by gas chromatography-mass spectrometry (GC-MS). Results: the myristicin content of the original nutmeg oil, the first, the second, and the third distillation were 12.93%, 17.50%, 54.21%, and 83.45% respectively. The total yield of the final product resulted after the third distillation was 5.84% v/v from the original oil. Conclusion: The use of sequences distillation with a different condition can increase the myristicin content from the original nutmeg oil.

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Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2

Cited by 33 publications

References 41 publications

Modulation of Human Neutrophil Responses by the Essential Oils from Ferula akitschkensis and Their Constituents

Modulation of Human Neutrophil Responses by the Essential Oils from Ferula akitschkensis and Their Constituents

Formation and Biological Targets of Quinones: Cytotoxic versus Cytoprotective Effects

The Isolation of Myristicin from Nutmeg Oil by Sequences Distillation

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