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Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation

1
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-12843 Prague 2, Czech Republic
2
Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-61300 Brno, Czech Republic
3
Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, V Uvalu 84/1, CZ-150 06 Prague 5, Czech Republic
4
Department of Oncology, 2nd Medical Faculty, Charles University and University Hospital Motol, V Uvalu 84/1, CZ-150 06 Prague 5, Czech Republic
5
Department of Analytical, Environmental and Forensic Sciences, MRC-PHE Centre for Environment and Health, King’s College London, 150 Stamford Street, London SE1 9NH, UK
6
NIHR Health Protection Research Unit in Health Impact of Environmental Hazards at King’s College London in partnership with Public Health England and Imperial College London, 150 Stamford Street, London SE1 9NH, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(14), 3392; https://doi.org/10.3390/ijms20143392
Received: 18 June 2019 / Revised: 7 July 2019 / Accepted: 8 July 2019 / Published: 10 July 2019
(This article belongs to the Special Issue Cell and Molecular Biology of Thyroid Disorders 2.0)
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Abstract

The metabolism of vandetanib, a tyrosine kinase inhibitor used for treatment of symptomatic/progressive medullary thyroid cancer, was studied using human hepatic microsomes, recombinant cytochromes P450 (CYPs) and flavin-containing monooxygenases (FMOs). The role of CYPs and FMOs in the microsomal metabolism of vandetanib to N-desmethylvandetanib and vandetanib-N-oxide was investigated by examining the effects of CYP/FMO inhibitors and by correlating CYP-/FMO-catalytic activities in each microsomal sample with the amounts of N-desmethylvandetanib/vandetanib-N-oxide formed by these samples. CYP3A4/FMO-activities significantly correlated with the formation of N-desmethylvandetanib/ vandetanib-N-oxide. Based on these studies, most of the vandetanib metabolism was attributed to N-desmethylvandetanib/vandetanib-N-oxide to CYP3A4/FMO3. Recombinant CYP3A4 was most efficient to form N-desmethylvandetanib, while FMO1/FMO3 generated N-oxide. Cytochrome b5 stimulated the CYP3A4-catalyzed formation of N-desmethylvandetanib, which is of great importance because CYP3A4 is not only most efficient in generating N-desmethylvandetanib, but also most significant due to its high expression in human liver. Molecular modeling indicated that binding of more than one molecule of vandetanib into the CYP3A4-active center can be responsible for the high efficiency of CYP3A4 N-demethylating vandetanib. Indeed, the CYP3A4-mediated reaction exhibits kinetics of positive cooperativity and this corresponded to the in silico model, where two vandetanib molecules were found in CYP3A4-active center. View Full-Text
Keywords: vandetanib; tyrosine kinase inhibitor; metabolism; cytochromes P450; flavin-containing monoxygenases vandetanib; tyrosine kinase inhibitor; metabolism; cytochromes P450; flavin-containing monoxygenases
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Indra, R.; Pompach, P.; Martínek, V.; Takácsová, P.; Vavrová, K.; Heger, Z.; Adam, V.; Eckschlager, T.; Kopečková, K.; Arlt, V.M.; Stiborová, M. Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation. Int. J. Mol. Sci. 2019, 20, 3392.

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