Developing a high-throughput system for the screening of cytochrome P450 1A1 – Inhibitory polyphenols

Leung, Hau Yi; Wang, Yun; Chan, Eunice HoYee; Leung, Lai K.

doi:10.1016/j.tiv.2007.04.005

Cited by 11 publications

(10 citation statements)

References 26 publications

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“…37,39,68 However, flavanones, like narigenin, are generally weak P450 1 inhibitors with IC 50 values in the micromolar range, which might indicate the importance of the C-ring 2–3 double bond in P450 1 enzyme inhibition. 37,69 Several hydroxychalcones have been tested for the inhibition of P450 1A1 and 1B1 and showed IC 50 values in the low micromolar range. 70 Our results as well as previous studies from Henderson et al showed that the prenylflavanones from hops are more potent inhibitors compared to the parent flavanone, naringenin.…”

Section: Discussionmentioning

confidence: 99%

Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation

Wang

Dunlap

Howell

et al. 2016

Chem. Res. Toxicol.

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Humulus lupulus L. (hops) is a popular botanical dietary supplement used by women as a sleep aid and for postmenopausal symptom relief. In addition to its efficacy for menopausal symptoms, hops can also modulate the chemical estrogen carcinogenesis pathway and potentially protect women from breast cancer. In the present study, an enriched hop extract and the key bioactive compounds [6-prenylnarigenin (6-PN), 8-prenylnarigenin (8-PN), isoxanthohumol (IX), and xanthohumol (XH)] were tested for their effects on estrogen metabolism in breast cells (MCF-10A and MCF-7). The methoxyestrones (2-/4-MeOE1) were analyzed as biomarkers for the nontoxic P450 1A1 catalyzed 2-hydroxylation and the genotoxic P450 1B1 catalyzed 4-hydroxylation pathways, respectively. The results indicated that the hop extract and 6-PN preferentially induced the 2-hydroxylation pathway in both cell lines. 8-PN only showed slight up-regulation of metabolism in MCF-7 cells, whereas IX and XH did not have significant effects in either cell line. To further explore the influence of hops and its bioactive marker compounds on P450 1A1/1B1, mRNA expression and ethoxyresorufin O-dealkylase (EROD) activity were measured. The results correlated with the metabolism data and showed that hop extract and 6-PN preferentially enhanced P450 1A1 mRNA expression and increased P450 1A1/1B1 activity. The aryl hydrocarbon receptor (AhR) activation by the isolated compounds was tested using xenobiotic response element (XRE) luciferase construct transfected cells. 6-PN was found to be an AhR agonist that significantly induced XRE activation and inhibited 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced XRE activity. 6-PN mediated induction of EROD activity was also inhibited by the AhR antagonist CH223191. These data show that the hop extract and 6-PN preferentially enhance the nontoxic estrogen 2-hydroxylation pathway through AhR mediated up-regulation of P450 1A1, which further emphasizes the importance of standardization of botanical extracts to multiple chemical markers for both safety and desired bioactivity.

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Section: Discussionmentioning

confidence: 99%

Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation

Wang

Dunlap

Howell

et al. 2016

Chem. Res. Toxicol.

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“…Inhibitors of CYP1A1 have received particular interest due to this isoform's role as an activator of carcinogens and, thus, the inhibitors' potential role as chemoprotectors. Several such natural ingredients include quercetin (IC 50 = 1.36 μM) [14], curcumin (IC 50 = 20 μM), demethoxycurcumin (IC 50 = 21 μM), εviniferin (IC 50 = 1 μM), resveratrol (IC 50 = 30 μM), and sanguinarine (K i = 2 μM). Other synthetic compounds such as hydroxystilbene (IC 50 = 61 μM) and pentamethoxystilbene have been reported to be potent inhibitors of CYP1A1 (IC 50 = 0.14 μM).…”

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confidence: 99%

Inhibition of CYP1A1 by Quassinoids Found inPicrasma excelsa

et al. 2008

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Infusions of the plant Picrasma excelsa, known as Jamaican bitterwood tea, are commonly consumed to lower blood sugar levels in diabetics who are already on prescription medicines. We therefore investigated the inhibition properties of this tea against a panel of cytochrome P450 (CYP) enzymes, which are primarily responsible for the metabolism of a majority of drugs on the market. The two major ingredients, quassin and neoquassin, were then isolated and used for further characterization. Inhibition of the activities of heterologously expressed CYP microsomes (CYPs 2D6, 3A4, 1A1, 1A2, 2C9, and 2C19) was monitored, and the most potent inhibition was found to be against CYP1A1, with IC (50) values of 9.2 microM and 11.9 microM for quassin and neoquassin, respectively. The moderate inhibition against the CYP1A1 isoform by quassin and neoquassin displayed partial competitive inhibition kinetics, with inhibition constants ( K(i)) of 10.8 +/- 1.6 microM, for quassin and competitive inhibition kinetics, with a K(i) of 11.3 +/- 0.9 microM, for neoquassin. We then docked these two inhibitors into the active site of a model of CYP1A1, which provided insight at the atomic level into the structure-activity relationship of quassinoids with respect to this important CYP isoform known to be an activator of carcinogens, thus providing a useful basis for the search for more potent inhibitors of CYP1A1 that may have implications in chemoprotection.

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“…Several classes of natural compounds [22], including flavonoids [23,24] and organosulfur compounds [13,25,26], have demonstrated great potential in chemoprevention and thus provide the impetus for the search for others. Both PBQs potently (IC 50 < 1 μM) inhibited the activity of CYP1A1while PBQ2 also displayed potency toward CYP1B1.…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic and potent CYP1 inhibitors from the marine algae Cymopolia barbata

et al. 2012

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BackgroundExtracts from the marine algae Cymopolia barbata have previously shown promising pharmacological activity including antifungal, antitumor, antimicrobial, and antimutagenic properties. Even though extracts have demonstrated such bioactivity, isolated ingredients responsible for such bioactivity remain unspecified. In this study, we describe chemical characterization and evaluations of biological activity of prenylated bromohydroquinones (PBQ) isolated from the marine algae C. barbata for their cytotoxic and chemopreventive potential.MethodsThe impact of PBQs on the viability of cell lines (MCF-7, HT29, HepG, and CCD18 Co) was evaluated using the MTS assay. In addition, their inhibitory impact on the activities of heterologously expressed cytochrome P450 (CYP) enzymes (CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4) was evaluated using a fluorescent assay.Results7-Hydroxycymopochromanone (PBQ1) and 7-hydroxycymopolone (PBQ2) were isolated using liquid and column chromatography, identified using 1 H and 13 C NMR spectra and compared with the spectra of previously isolated PBQs. PBQ2 selectively impacted the viability of HT29, colon cancer cells with similar potency to the known chemotherapeutic drug, fluorouracil (IC50, 19.82 ± 0.46 μM compared to 23.50 ± 1.12 μM, respectively) with impact toward normal colon cells also being comparable (55.65 ± 3.28 compared to 55.51 ± 3.71 μM, respectively), while PBQ1 had no impact on these cells. Both PBQs had potent inhibition against the activities of CYP1A1 and CYP1B1, the latter which is known to be a universal marker for cancer and a target for drug discovery. Inhibitors of CYP1 enzymes by virtue of the prevention of activation of carcinogens such as benzo-a-pyrene have drawn attention as potential chemopreventors. PBQ2 potently inhibited the activity of CYP1B1 (IC50 0.14 ± 0.04 μM), while both PBQ1 and PBQ2 potently inhibited the activity of CYP1A1 (IC50s of 0.39 ± 0.05 μM and 0.93 ± 0.26 μM, respectively). Further characterizations showed partial noncompetitive enzyme kinetics for PBQ2 with CYP1B1 with a Ki of 4.7 × 10–3 ± 5.1 × 10–4 μM and uncompetitive kinetics with CYP1A1 (Ki = 0.84 ± 0.07 μM); while PBQ1 displayed partial non competitive enzyme kinetics with CYP1A1 (Ki of 3.07 ± 0.69 μM), noncompetitive kinetics with CYP1A2 (Ki = 9.16 ± 4.68 μM) and uncompetitive kinetics with CYP1B1 (Ki = 0.26 ± 0.03 μM) .ConclusionsWe report for the first time, two isolated ingredients from C. barbata, PBQ1 and PBQ2, that show potential as valuable chemotherapeutic compounds. A hydroxyl moiety resident in PBQ2 appears to be critical for selectivity and potency against the cancer colon cells, HT29, in comparison to the three other malignant cell lines studied. PBQs also show potency against the activities of CYP1 enzyme which may be a lead in chemoprevention. This study, the first on isolates from these marine algae, exemplifies the value of searching within nature for unique structural motifs that can display multiple biological activities.

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Developing a high-throughput system for the screening of cytochrome P450 1A1 – Inhibitory polyphenols

Cited by 11 publications

References 26 publications

Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation

Hop (Humulus lupulus L.) Extract and 6-Prenylnaringenin Induce P450 1A1 Catalyzed Estrogen 2-Hydroxylation

Inhibition of CYP1A1 by Quassinoids Found inPicrasma excelsa

Cytotoxic and potent CYP1 inhibitors from the marine algae Cymopolia barbata

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