Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells

Surichan, Somchaiya; Androutsopoulos, Vasilis P.; Sifakis, Stavros; Koutala, Eleni; Tsatsakis, Aristidis; Arroo, R. R. J.; Boarder, Michael R.

doi:10.1016/j.fct.2012.06.030

Cited by 57 publications

(57 citation statements)

References 38 publications

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“…This suggested that metabolite 4 was a didemethylated derivative of compound 1 . Recent in vitro studies on nobiletin metabolism have also demonstrated the occurrence of demethylation in the B ring of nibiletin .…”

Section: Resultsmentioning

confidence: 99%

Identification of novel bioactive metabolites of 5-demethylnobiletin in mice

Zheng

Song

Dong

et al. 2013

Mol. Nutr. Food Res.

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Section: Resultsmentioning

confidence: 99%

Identification of novel bioactive metabolites of 5-demethylnobiletin in mice

Zheng

Song

Dong

et al. 2013

Mol. Nutr. Food Res.

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“…As shown in Figure , galangin can be oxidized to kaempferol in TCDD‐pretreated Caco‐2 cells with decreased activity in suppression of CYP1s expression induced by TCDD . As opposed to their parent compounds, in most cases, the metabolic products of flavonoids were demonstrated to have relatively higher cytostatic effects toward cancer cells without clearly affecting the viability of normal cells, with the exception that bio‐deactivation occurred in some cases . Based on this observation, it is reasonable to presume that the elicited tumor‐suppressing effects are strongly associated with their increased levels of metabolites.…”

Section: Interactions Of Flavonoids With Cyp1smentioning

confidence: 92%

“…[57] As opposed to their parentc ompounds, in most cases, the metabolic products of flavonoids were demonstrated to have relativelyh igher cytostatic effects towardc ancerc ells without clearly affecting the viability of normal cells, with the exception that bio-deactivation occurred in some cases. [58,59] Based on this observation, it is reasonable to presumet hat the elicited tumor-suppressing effects are strongly associatedw ith their increased levels of metabolites. As reported previously,f lavonoids containing am ethoxy group are most susceptible to being metabolized by CYP1s, but some hydroxylated flavonoids, such as baicalein, do not act as CYP1 substrates.…”

Section: Flavonoids As Cyp1 Substratesmentioning

confidence: 97%

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

et al. 2016

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The human cytochrome P450 family 1 enzymes consist of three members, CYP1A1, CYP1A2 and CYP1B1, which are predominantly involved in the phase I metabolism of xenobiotics. Because they have been implicated in carcinogenesis, cancer progression, and drug resistance, the inhibition of these enzymes has been widely considered an effective oncological therapeutic strategy. Some natural and synthetic flavonoids and naphthoflavonoids have been extensively documented to exert pronounced influence in the modulation of CYP1s, including functioning as inhibitors, substrates, and aryl hydrocarbon receptor (AhR) ligands. However, the molecular determinants behind these effects are still unknown. This review summarizes the structural features responsible for the CYP1 inhibitory effects of the reported flavonoids and naphthoflavonoids. Additionally, a three-dimensional quantitative structure-activity relationship (3D-QSAR) study was performed to better understand the effect of their structural properties on biological activities. We hope this review provides a useful foundation for the rational design of potent and selective CYP1 isozyme inhibitors, thereby accelerating the drug discovery process.

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“…A similar methodology to that described in previous studies was used [24,25]. A Luna 5µ C 18 4.6 x 150mm column (Phenomenex, Cheshire, United Kingdom) was used, with a mobile phase flow rate of 1 ml/min, at a temperature of 37°C.…”

Section: Methodsmentioning

confidence: 99%

Expression Profile of CYP1A1 and CYP1B1 Enzymes in Colon and Bladder Tumors

et al. 2013

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BackgroundThe cytochrome P450 CYP1A1 and CYP1B1 enzymes are involved in carcinogenesis via activation of pro-carcinogenic compounds to carcinogenic metabolites. CYP1A1 and CYP1B1 have shown elevated levels in human tumors as determined by qRT-PCR and immunohistochemical studies. However studies that have examined CYP1 expression by enzyme activity assays are limited. ResultsIn the current study the expression of CYP1A1 and CYP1B1 was investigated in a panel of human tumors of bladder and colorectal origin by qRT-PCR and enzyme activity assays. The results demonstrated that 35% (7/20) of bladder tumors and 35% (7/20) of colon tumors overexpressed active CYP1 enzymes. CYP1B1 mRNA was overexpressed in 65% and 60% of bladder and colon tumors respectively, whereas CYP1A1 was overexpressed in 65% and 80% of bladder and colon tumors. Mean mRNA levels of CYP1B1 and CYP1A1 along with mean CYP1 activity were higher in bladder and colon tumors compared to normal tissues (p<0.05). Statistical analysis revealed CYP1 expression levels to be independent of TNM status. Moreover, incubation of tumor microsomal protein in 4 bladder and 3 colon samples with a CYP1B1 specific antibody revealed a large reduction (72.5 ± 5.5 % for bladder and 71.8 ± 7.2% for colon) in catalytic activity, indicating that the activity was mainly attributed to CYP1B1 expression. ConclusionsThe study reveals active CYP1 overexpression in human tumors and uncovers the potential use of CYP1 enzymes and mainly CYP1B1 as targets for cancer therapy.

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Bioactivation of the citrus flavonoid nobiletin by CYP1 enzymes in MCF7 breast adenocarcinoma cells

Cited by 57 publications

References 38 publications

Identification of novel bioactive metabolites of 5-demethylnobiletin in mice

Identification of novel bioactive metabolites of 5-demethylnobiletin in mice

Flavonoids and Naphthoflavonoids: Wider Roles in the Modulation of Cytochrome P450 Family 1 Enzymes

Expression Profile of CYP1A1 and CYP1B1 Enzymes in Colon and Bladder Tumors

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