Publication: Mechanism-based inactivation of cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus constituents
Issued Date
2014-01-01
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ISSN
18800920
13474367
13474367
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2-s2.0-84898411740
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Mahidol University
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SCOPUS
Bibliographic Citation
Drug Metabolism and Pharmacokinetics. Vol.29, No.1 (2014), 75-82
Suggested Citation
Phisit Pouyfung, Aruna Prasopthum, Songklod Sarapusit, Ekaruth Srisook, Pornpimol Rongnoparut Mechanism-based inactivation of cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus constituents. Drug Metabolism and Pharmacokinetics. Vol.29, No.1 (2014), 75-82. doi:10.2133/dmpk.DMPK-13-RG-048 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/34601
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Title
Mechanism-based inactivation of cytochrome P450 2A6 and 2A13 by Rhinacanthus nasutus constituents
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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 KIand kinactof 0.16 μM and 0.1 min-1, respectively, while values of 0.44 μM and 0.12 min-1were found against CYP2A6. Rhinacanthin-C had least inhibition potency, with apparent KIand kinactof 0.97 μM and 0.07 min-1for CYP2A6, respectively, and values of 1.68 μM and 0.05 min-1for CYP2A13. Rhinacanthin-A inhibited CYP2A6 and CYP2A13 with apparent KIvalues of 0.69 and 0.42 μM, respectively and apparent kinactof 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. Copyright © 2014 by the Japanese Society for the Study of Xenobiotics (JSSX).