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In vitro modulatory effects of flavonoids on human cytochrome P450 2C8 (CYP2C8)

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Abstract

The inhibitory effects of five flavonoids with distinct chemical classes (flavones [luteolin], flavonols [quercetin and quercitrin], and flavanones [hesperetin and hespiridin]) on cDNA-expressed CYP2C8 were investigated. CYP2C8 was co-expressed with NADPH-cytochrome P450 reductase in Escherichia coli and used to characterise potency and mechanism of these flavonoids on the isoform. Tolbutamide 4-methylhydroxylase, a high-performance liquid chromatography-based assay, was selected as marker activity for CYP2C8. Our results indicated that the flavonoids inhibited CYP2C8 with different potency. The order of inhibitory activities was quercetin > luteolin > hesperetin > hesperidin > quercitrin. All of these compounds however exhibited mechanism-based inhibition. A number of structural factors were found to be important for inhibition; these include the molecular shape (volume to surface ratio), the number of hydroxyl groups as well as glycosylation of the hydroxyl group. Quercetin was the most potent inhibitor among the flavonoids examined in this study, and our data suggest that it should be examined for potential pharmacokinetic drug interactions pertaining to CYP2C8 substrates in vivo.

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Acknowledgements

This work was supported by a research grant from the International Medical University (Grant no: BMedSc 101/04), Kuala Lumpur, Malaysia.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Sunway Campus, Jalan Lagoon Selatan, 46150, Bandar Sunway, Selangor, Malaysia

    Chin Eng Ong

  2. School of Pharmacy and Health Sciences, International Medical University, 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia

    Chia Yong Pang & Joon Wah Mak

  3. Pharmacogenetics Research Group, Institute for Research in Molecular Medicine, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia

    Rusli Ismail

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  1. Chia Yong Pang
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  2. Joon Wah Mak
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  3. Rusli Ismail
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  4. Chin Eng Ong
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Correspondence to Chin Eng Ong.

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Pang, C.Y., Mak, J.W., Ismail, R. et al. In vitro modulatory effects of flavonoids on human cytochrome P450 2C8 (CYP2C8). Naunyn-Schmiedeberg's Arch Pharmacol 385, 495–502 (2012). https://doi.org/10.1007/s00210-012-0731-5

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  • DOI: https://doi.org/10.1007/s00210-012-0731-5

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