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Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors

التفاصيل البيبلوغرافية
العنوان: Effect of Human Flavin-Containing Monooxygenase 3 Polymorphism on the Metabolism of Aurora Kinase Inhibitors
المؤلفون: Sheila J. Sadeghi, Gianfranco Gilardi, Gianluca Catucci, Andrea Occhipinti, Massimo Maffei
المصدر: International Journal of Molecular Sciences, Vol 14, Iss 2, Pp 2707-2716 (2013)
بيانات النشر: MDPI AG, 2013.
سنة النشر: 2013
المجموعة: LCC:Biology (General)
LCC:Chemistry
مصطلحات موضوعية: phase I, drug metabolism, FMO3, polymorphism, enzyme kinetics, VX-680, PHA-739358, LC-MS, Biology (General), QH301-705.5, Chemistry, QD1-999
الوصف: Aurora kinases were recently identified as a potential target in anticancer therapy and, amongst their available inhibitors, Tozasertib (VX-680) and Danusertib (PHA-739358) have been indicated as possible substrates of human flavin-containing monooxygenase 3 (hFMO3). Here we report the in vitro rate of oxidation of these drugs by wild-type hFMO3 and its polymorphic variant V257M. The conversion of Tozasertib and Danusertib to their corresponding metabolites, identified by LC-MS, by the purified wild-type and V257M hFMO3 show significant differences. In the case of Tozasertib, the V257M variant shows a catalytic efficiency, expressed as kcat/Km, similar to the wild-type: 0.39 ± 0.06 min−1µM−1 for V257M compared to 0.33 ± 0.04 min−1µM−1 for the wild type. On the other hand, in the case of Danusertib, V257M shows a 3.4× decrease in catalytic efficiency with kcat/Km values of 0.05 ± 0.01 min−1µM−1 for V257M and 0.17 ± 0.03 min−1µM−1 for the wild type. These data reveal how a simple V257M substitution ascribed to a single nucleotide polymorphism affects the N-oxidation of relevant anticancer drugs, with important outcome in their therapeutic effects. These findings demonstrate that codon 257 is important for activity of the hFMO3 gene and the codon change V to M has an effect on the catalytic efficiency of this enzyme.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 1422-0067
Relation: http://www.mdpi.com/1422-0067/14/2/2707; https://doaj.org/toc/1422-0067
DOI: 10.3390/ijms14022707
URL الوصول: https://doaj.org/article/56b9cfbc8ba1468896bff8dda07e5aba
رقم الأكسشن: edsdoj.56b9cfbc8ba1468896bff8dda07e5aba
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:14220067
DOI:10.3390/ijms14022707