Drug Metabolism and Pharmacokinetics
Online ISSN : 1880-0920
Print ISSN : 1347-4367
ISSN-L : 1347-4367
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Mechanism-based Inactivation of Cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus Constituents
Phisit POUYFUNGAruna PRASOPTHUMSongklod SARAPUSITEkaruth SRISOOKPornpimol RONGNOPARUT
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2014 Volume 29 Issue 1 Pages 75-82

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Abstract

  Human cytochrome P450 CYP2A6 and CYP2A13 catalyze nicotine metabolisms and mediate activation of tobacco-specific carcinogens including 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL). In this study, we found rhinacanthins A, B, and C isolated from Rhinacanthus nasutus potentially inhibited coumarin 7-hydroxylation mediated by reconstituted purified recombinant CYP2A6 and CYP2A13. Rhinacanthins A–C are mechanism-based inactivators of CYP2A6 and CYP2A13 as they cause concentration, time and NADPH-dependent inhibition. Among the three rhinacanthins, rhinacanthin-B possessed highest inhibitory potency against CYP2A13 with apparent KI and kinact of 0.16 µM and 0.1 min−1, respectively, while values of 0.44 µM and 0.12 min−1 were found against CYP2A6. Rhinacanthin-C had least inhibition potency, with apparent KI and kinact of 0.97 µM and 0.07 min−1 for CYP2A6, respectively, and values of 1.68 µM and 0.05 min−1 for CYP2A13. Rhinacanthin-A inhibited CYP2A6 and CYP2A13 with apparent KI values of 0.69 and 0.42 µM, respectively and apparent kinact of 0.18 and 0.06 min−1, respectively. The inhibition of both enzymes by rhinacanthins A–C could not be prevented by addition of trapping agents or reversed by dialysis or potassium ferricyanide. These findings demonstrated that rhinacanthins A–C, which are 1,4-naphthoquinone derivatives, irreversibly inhibited CYP2A6 and CYP2A13 in a mechanism-based inhibition mode.

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© 2014 by The Japanese Society for the Study of Xenobiotics
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