Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein

Shimada, Hideaki; Eto, Masashi; Ohtaguro, Misa; Ohtsubo, Michihiro; Mizukami, Yosuke; Idé, Tsuyoshi; Imamura, Yorishige

doi:10.1002/jbt.20328

Cited by 13 publications

(10 citation statements)

References 20 publications

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“…estimated the daily flavonoid intake of adults in the US of about 189mg, with the major identified flavonoid sources being tea, citrus fruits including juices, and wine 79. Flavonoids have been reported to inhibit CYP1A2 before,36b,80 and the only X‐ray crystal structure of this isoform available so far, was reported in complex with the synthetic flavonoid α‐naphthoflavone (PDB entry 2HI412). Here we report another flavonoid, 7‐hydroxyflavanon ( 9 ), as inhibitor of CYP1A2, and weak inhibitor of CYP2C9 and CAP3A4.…”

Section: Discussionmentioning

confidence: 99%

In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance

Kaserer

Höferl

Müller

et al. 2015

Molecular Informatics

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The cytochrome P450 (CYP) superfamily represents the major enzyme class responsible for the metabolism of exogenous compounds. Investigation of clearance pathways is therefore an integral part in early drug development, as any alteration of metabolic enzymes may markedly influence the toxicological profile and efficacy of novel compounds. In silico methods are widely applied in drug development to complement experimental approaches. Several different tools are available for that purpose, however, for CYP enzymes they have only been applied retrospectively so far. Within this study, pharmacophore- and shape-based models and a docking protocol were generated for the prediction of CYP1A2, 2C9, and 3A4 inhibition. All theoretically validated models, the validated docking workflow, and additional external bioactivity profiling tools were applied independently and in parallel to predict the CYP inhibition of 29 compounds from synthetic and natural origin. After subsequent experimental assessment of the in silico predictions, we analyzed and compared the prospective performance of all methods, thereby defining the suitability of the applied techniques for CYP enzymes. We observed quite substantial differences in the performances of the applied tools, suggesting that the rational selection of that virtual screening method that proved to perform best can largely improve the success rates when it comes to CYP inhibition prediction.

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Section: Discussionmentioning

confidence: 99%

In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance

Kaserer

Höferl

Müller

et al. 2015

Molecular Informatics

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“…The natural flavone apigenin showed a potent inhibitory effect on CYP1A2 with an inhibition mechanism similar to a-naphthoflavone (Shimada et al, 2010;von Moltke et al, 2004). Fluvoxamine at low concentrations selectively inhibited the activity of CYP1A2 (Nakajima et al, 1999;Pastrakuljic et al, 1997).…”

Section: Chemical Inhibition Assaymentioning

confidence: 97%

Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: metabolite elucidation and main contributions from CYP1A2 and UGT1A1

Zhang

et al. 2015

Xenobiotica

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1. Niclosamide is an old anthelmintic drug that shows potential in fighting against cancers. Here, we characterized the metabolism of niclosamide by cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) using human liver microsomes (HLM) and expressed enzymes. 2. NADPH-supplemented HLM (and liver microsomes from various animal species) generated one hydroxylated metabolite (M1) from niclosamide; and UDPGA-supplemented liver microsomes generated one mono-O-glucuronide (M2). The chemical structures of M1 (3-hydroxy niclosamide) and M2 (niclosamide-2-O-glucuronide) were determined through LC-MS/MS and/or NMR analyses. 3. Reaction phenotyping revealed that CYP1A2 was the main enzyme responsible for M1 formation. The important role of CYP1A2 in niclosamide metabolism was further confirmed by activity correlation analyses as well as inhibition experiments using specific inhibitors. 4. Although seven UGT enzymes were able to catalyze glucuronidation of niclosamide, UGT1A1 and 1A3 were the enzymes showed the highest metabolic activities. Activity correlation analyses demonstrated that UGT1A1 played a predominant role in hepatic glucuronidation of niclosamide, whereas the role of UGT1A3 was negligible. 5. In conclusion, niclosamide was subjected to efficient metabolic reactions hydroxylation and glucuronidation, wherein CYP1A2 and UGT1A1 were the main contributing enzymes, respectively.

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“…Chrysin was reported to inhibit CYP1A1 activity in Chinese hamster V79 cells expressing human or rat CYP450 (Lautraite and others 2002). Apigenin may inhibit recombinant human CYP1A2 activity (Shimada and others 2010). Though single compound may inhibit activities of CYP450s, their combined effect was induction.…”

Section: Resultsmentioning

confidence: 99%

Increased Exposure of Vitamin A by Chrysanthemum morifolium Ramat Extract in Rat Was Not via Induction of CYP1A1, CYP1A2, and CYP2B1

Wang

Pan

Chen

et al. 2012

Journal of Food Science

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The aim of this study was to investigate the effect of Chrysanthemum morifolium Ramat (CM) extract on the pharmacokinetics of retinol and activities of cytochrome P450s (CYP450s) related to retinoid metabolism. Rats were treated with CM extract for 15 d. Plasma concentrations of retinol were measured following oral administration of retinol (45 mg/kg). Basal levels of retinol and retinoic acid in serum and liver were also measured. 7-Ethoxyresorufin-O-deethylase activity, phenacetin-O-deethylase activity, and 7-pentoxyresorufin-O-deethylase activities were used to assay the activities of CYP1A1, CYP1A2, and CYP2B1 in hepatic microsomes of rats, respectively. Protein expressions of the 3 CYP450s were measured by western blot. Our studies demonstrated that CM extract dose-dependently increased basal level of retinol in serum. In pharmacokinetic experiment, CM extract dose-dependently increased plasma concentrations of retinol after oral administration of retinol to rats treated with CM extract. But activities and expressions of CYP1A1, CYP1A2, and CYP2B1 in hepatic microsomes of rats were also induced by CM extract.

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Differential mechanisms for the inhibition of human cytochrome P450 1A2 by apigenin and genistein

Cited by 13 publications

References 20 publications

In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance

In Silico Predictions of Drug – Drug Interactions Caused by CYP1A2, 2C9 and 3A4 Inhibition – a Comparative Study of Virtual Screening Performance

Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: metabolite elucidation and main contributions from CYP1A2 and UGT1A1

Increased Exposure of Vitamin A by Chrysanthemum morifolium Ramat Extract in Rat Was Not via Induction of CYP1A1, CYP1A2, and CYP2B1

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