Effective Cytochrome P450 (CYP) Inhibitor Isolated from Thyme (<i>Thymus saturoides</i>) Purchased from a Japanese Market

Brahmi, Zeineb; Niwa, Hitomi; Yamasato, M; Shigeto, Sakurako; Kusakari, Yuna; Sugaya, Kimio; Onose, Jun‐ichi; Abe, Naoki

doi:10.1271/bbb.110328

Cited by 9 publications

(8 citation statements)

References 17 publications

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“…[28,29] Chrysin has been shown to inhibit cytochrome P450 3A4 in an enzyme activity assay using 7-benzyloxymethyloxy-3-cyanocoumarin as a the marker substrate, and the obtained IC50 value was 95 ± 31 µM. [24] In contrast, when testosterone was used as the marker substrate, IC50 value was determined to be 0.9 µM, similar to this study (0.6 ± 0.5 µM). [30] Figure 2.…”

Section: Results and Discusionsupporting

confidence: 81%

“…[23] Another group obtained an IC50 value of 31 ± 8 µM for apigenin using 7-benzyloxymethyloxy-3-cyanocoumarin as the marker substrate of cytochrome P450 3A4. [24] Use of different substrates for determining cytochrome P450 3A4 enzyme activity can explain observed differences in IC50 values between studies. As the cytochrome P450 3A4 has a large active site when compared to other human liver cytochromes P450, use of at least two marker substrates is advisable for the assessment of inhibition kinetics.…”

Section: Results and Discusionmentioning

confidence: 99%

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Inhibitory Effect of Acacetin, Apigenin, Chrysin and Pinocembrin on Human Cytochrome P450 3A4

Kondža

Rimac

Maleš

et al. 2020

Croat. chem. acta (Online)

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Cytochrome P450 3A4 is the most significant enzyme in metabolism of medications. Flavonoids are common secondary plant metabolites found in fruits and vegetables. Some flavonoids can interact with other drugs by inhibiting cytochrome P450 enzymes. Thus, the objective of this study was to determine inhibition kinetics of cytochrome P450 3A4 by flavonoids: acacetin, apigenin, chrysin and pinocembrin. For this purpose, testosterone was used as marker substrate, and generation of the 6β-hydroxy metabolite was monitored by high performance liquid chromatography coupled with diode array detector. IC50 values, inhibition constants, and rates of inhibition were determined. IC50 values ranged between 0.6 and 11.4 µM. The strongest inhibitor was chrysin (IC50 0.6 µM, inhibition constant 0.6 µM, inhibition rate constant 0.065 min-1 , inhibition efficacy 0.108 min-1 µM-1). Compared to other flavonoids analyzed, chrysin's inhibitory effect can be attributed to the hydrophobic nonsubstituted B ring, as well as rigidity of the structure. When foods rich in chrysin are consumed, e.g. honey and propolis, chrysin can cause food-drug interactions. Further in vitro studies are needed to determine the reactive intermediate responsible for inactivation of cytochrome P450 3A4 enzyme, as well as in vivo studies to determine possible clinical significance of this inhibition.

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Section: Results and Discusionsupporting

confidence: 81%

Section: Results and Discusionmentioning

confidence: 99%

Inhibitory Effect of Acacetin, Apigenin, Chrysin and Pinocembrin on Human Cytochrome P450 3A4

Kondža

Rimac

Maleš

et al. 2020

Croat. chem. acta (Online)

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“…For Thymus species, multiple studies have been conducted using mostly ethanol, methanol, water, and their mixture as solvents, in which not much variety was observed in the flavones extraction of such species as T. alternans, T. caespititius, T. fragrantissimus, T. mastichina, T. pulegioides, T. serpyllum, and T. vulgaris, among others [68,71,[117][118][119][120][121]. However, using fractionation techniques, it is possible to obtain flavones that have not been identified in crude extracts such as 7-methoxyapigenin (genkwanin) [122] and nobiletin [123,124], while, by using dichloromethane, hydroxyluteolin and hydroxyapigenin derivatives can be extracted from T. mastichina [125]. Furthermore, the water residue from hydrodistillation from T. vulgaris process has shown to be a valuable source of flavones such as luteolin and apigenin glucuronide derivatives [126].…”

Section: Extraction Methods Of Flavones From Lamiaceae Plants 41 Conventional Methodsmentioning

confidence: 99%

Extraction Processes Affect the Composition and Bioavailability of Flavones from Lamiaceae Plants: A Comprehensive Review

et al. 2021

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Lamiaceae plants are a widespread family of herbaceous plants with around 245 plant genera and nearly 22,576 species distributed in the world. Some of the most representative and widely studied Lamiaceae plants belong to the Ocimum, Origanum, Salvia, and Thymus genera. These plants are a rich source of bioactive molecules such as terpenes, flavonoids, and phenolic acids. In this sense, there is a subgroup of flavonoids classified as flavones. Flavones have antioxidant, anti-inflammatory, anti-cancer, and anti-diabetic potential; thus, efficient extraction techniques from their original plant matrixes have been developed. Currently, conventional extraction methods involving organic solvents are no longer recommended due to their environmental consequences, and new environmentally friendly techniques have been developed. Moreover, once extracted, the bioactivity of flavones is highly linked to their bioavailability, which is often neglected. This review aims to comprehensively gather recent information (2011–2021) regarding extraction techniques and their important relationship with the bioavailability of flavones from Lamiaceae plants including Salvia, Ocimum, Thymus, and Origanum.

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“…The mobile phase was a solvent mixture of 50% acetonitrile, 49.9% H 2 O, and 0.1% HCO 2 H. A solution of the flavonoid mixture at a concentration of 30 mg/ml, was separated with a flow of 2.8 ml/min for 11 min and analysed at a wavelength of 360 nm, obtaining 15 mg of sideritoflavone 3 and 10 mg of 8-methoxicirsineleol 1 . The compounds were identified by NMR data which were compared with bibliographic data [ 7 , 16 – 18 ].…”

Section: Methodsmentioning

confidence: 99%

Breast cancer cell line toxicity of a flavonoid isolated from Baccharis densiflora

Sotillo

Tarqui

Huang

et al. 2021

BMC Complement Med Ther

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Background Flavonoids are compounds of interest in the search for new anti-cancer therapies. We have previously isolated the methoxyflavones 5,4′-dihydroxy-6,7,8,3′-tetramethoxyflavone (8-methoxycirsilineol), 5,4′-dihydroxy-6,7,8-trimethoxyflavone (xanthomicrol), and 5,4,'3′-trihydroxy-6,7,8-trimethoxyflavone (sideritoflavone) from Baccharis densiflora. Herein, we investigate the toxicity of these methoxyflavones in human breast-derived cell line. Our main aim was to focus on the cancer stem cell (CSC) sub-population of JIMT-1 breast cancer cells. Methods Initially, dose response experiments yielding inhibitory concentration 50 (IC50) values were performed using MCF-7, HCC1937, and JIMT-1 breast cancer, and the MCF-10A normal-like breast cell lines to get an understanding of toxic ranges. Due to a clear difference in the toxicity of the flavones, only sideritoflavone was selected for further studies using the JIMT-1 cell line. Effects on the CSC sub-population was investigated using flow cytometry-based methods. A wound healing assay and digital holographic microscopy were used to investigate effects on cell movement. A reporter assay was used to study effects on signal transduction pathways and Western blot for protein expression. Results The dose response data showed that 8-methoxycirsilineol was non-toxic at concentrations below 100 μM, that the IC50 of xanthomicrol was between 50 and 100 μM, while sideritoflavone was highly toxic with a single digit μM IC50 in all cell lines. Treatment of the JIMT-1 cells with 2 μM sideritoflavone did not selectively effect the CSC sub-population. Instead, sideritoflavone treatment inhibited the proliferation of both the non-CSC and the CSC sub-populations to the same extent. The inhibition of cell proliferation resulted in an accumulation of cells in the G2 phase of the cell cycle and the treated cells showed an increased level of γ-H2A histone family member X indicating DNA double strand breaks. Analysis of the effect of sideritoflavone treatment on signal transduction pathways showed activation of the Wnt, Myc/Max, and transforming growth factor-β pathways. The level of p65/nuclear factor kappa-light-chain-enhancer of activated Β cells was increased in sideritoflavone-treated cells. Cell movement was decreased by sideritoflavone treatment. Conclusions Altogether our data show that the methoxyflavone sideritoflavone has favourable anti-cancer effects that may be exploited for development to be used in combination with CSC specific compounds.

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Effective Cytochrome P450 (CYP) Inhibitor Isolated from Thyme (Thymus saturoides) Purchased from a Japanese Market

Cited by 9 publications

References 17 publications

Inhibitory Effect of Acacetin, Apigenin, Chrysin and Pinocembrin on Human Cytochrome P450 3A4

Inhibitory Effect of Acacetin, Apigenin, Chrysin and Pinocembrin on Human Cytochrome P450 3A4

Extraction Processes Affect the Composition and Bioavailability of Flavones from Lamiaceae Plants: A Comprehensive Review

Breast cancer cell line toxicity of a flavonoid isolated from Baccharis densiflora

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