Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation
Abstract
:1. Introduction
2. Results
2.1. Oxidation of Vandetanib by Human, Rat, Mouse and Rabbit Hepatic Microsomes
2.2. The Effects of CYP and FMO Enzyme Inhibitors on Vandetanib Oxidation in Human Liver Microsomes
2.3. Correlation of CYP- and FMO-Linked Enzyme Activities in Human Hepatic Microsomes with Vandetanib Oxidation to N-Desmethylvandetanib and Vandetanib-N-Oxide
2.4. Oxidation of Vandetanib by Human Recombinant CYP and FMO Enzymes
2.5. Contributions of Individual CYPs to Oxidation of Vandetanib to N-Desmethylvandetanib in Human Livers
2.6. Binding Of Vandetanib to the Active Site of Compound I of Human CYP1A1, CYP2D6 and CYP3A4
3. Discussion
4. Materials and Methods
4.1. Chemicals and Material
4.2. Oxidation of Vandetanib by Hepatic Microsomes and CYP Enzymes
4.3. Identification of Vandetanib Metabolites by Mass Spectrometry
4.4. Inhibition Studies
4.5. Contributions of CYP Enzymes to N-Demethylation of Vandetanib to N-Desmethylvandetanibin in Human Livers
4.6. Molecular Docking of Vandetanib into Compounds I of Human CYP1A1, 2D6 and 3A4
4.7. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
α-NF | α-naphthoflavone |
CYP | cytochrome P450 |
DDTC | diethyldithiocarbamate |
DMSO | dimethyl sulfoxide |
EGFR | epidermal growth factor receptor |
FMO | flavin-containing monooxygenase |
HPLC | high-performance liquid chromatography |
POR | NADPH:CYP oxidoreductase |
RET | rearranged during transfection |
r.t. | retention time |
TIE2 | tyrosine kinase with immunoglobulin and EGF domains-2 |
TK | tyrosine kinase |
TKI | tyrosine kinase inhibitor |
VEGFR-2 | vascular endothelial growth factor receptor |
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Enzymes | Inhibitor a | % of Inhibition | IC50 (μM) |
---|---|---|---|
N-Desmethyvandetanib Formation | |||
CYP | α-Napththoflavone (CYP1A) | 0 | NA b |
Diamantane (CYP2B) | 0 | NA | |
Sulfaphenazole (CYP2C) | 38 ± 4 *** | NA | |
Quinidine (CYP2D) | 20 ± 4 ** | NA | |
DDTC (CYP2A, CYP2E1) | 0 | NA | |
Ketoconazole (CYP3A) | 98 ± 3 *** | 2 ± 0.2 | |
Vandetanib-N-oxide Formation | |||
FMO | Methimazol (FMOs) | 79 ± 4 *** | 6 ± 0.5 |
a No. | b Total CYPs | c POR activity | d Cyt b5 | e CYP1A2 | e CYP2A6 | e CYP2B6 | e CYP2C8 | e CYP2C9 | e CYP2C19 | e CYP2D6 | e CYP2E1 | e CYP3A4 | e CYP4A11 | e FMO | f M1 | f M2 |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
HG03 | 290 | 450 | 380 | 170 | 2000 | 51 | 200 | 1700 | 44 | 110 | 1800 | 6100 | 1600 | g NM | 3.639 | h ND |
HG103 | 340 | 210 | 790 | 310 | 440 | 7.2 | 39 | 2300 | 23 | 65 | 1100 | 2200 | 1600 | 1400 | 1.021 | 0.004 |
HG24 | 260 | 260 | 550 | 1700 | 1500 | 35 | 190 | 3000 | 41 | NM | 2300 | 4000 | 1800 | 1500 | 1.698 | 0.004 |
HG32 | 170 | 330 | 580 | 730 | 520 | 0.68 | 20 | 450 | 4.8 | 46 | 1200 | 2000 | 680 | 920 | 0.870 | ND |
HG42 | 670 | 510 | 500 | 700 | 2200 | 150 | 480 | 1600 | 7,4 | 95 | 1600 | 15000 | 1400 | 2000 | 8.887 | 0.015 |
HG43 | 270 | 210 | 640 | 580 | 770 | 14 | 25 | 1800 | 440 | 4 | 780 | 4600 | 1800 | 920 | 1.830 | ND |
HG74 | 220 | 200 | 600 | 520 | 360 | 13 | 130 | 2100 | 55 | 120 | 1400 | 2700 | 1300 | 1200 | 0.714 | 0.004 |
HG93 | 430 | 320 | 450 | 691 | 350 | 43 | 270 | 2200 | 75 | 49 | 2800 | 2800 | 1800 | 3500 | 0.966 | 0.112 |
HK23 | 380 | 380 | 700 | 960 | 1100 | 24 | 160 | 2100 | 110 | 140 | 2100 | 6800 | 780 | 2500 | 4.137 | 0.008 |
HK27 | 300 | 450 | 730 | 1320 | 1320 | 31 | 180 | 480 | 460 | 130 | 3000 | 4910 | 1110 | 2230 | 1.762 | ND |
HK31 | 580 | 540 | 770 | 1220 | 2160 | 8.1 | 130 | 1690 | 172 | 3,4 | 1660 | 8210 | 2010 | 3020 | 4.124 | 0.015 |
HK34 | 500 | 460 | 890 | 1000 | 1500 | 39 | 220 | 1900 | 45 | 100 | 6000 | 5200 | 1100 | 2700 | 3.193 | ND |
Total CYPs | POR | Cyt b5 | CYP1A2 | CYP2A6 | CYP2B6 | CYP2C8 | CYP2C9 | CYP2C19 | CYP2D6 | CYP2E1 | CYP3A4 | CYP4A11 | FMO | |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
a M1 | 0.786 ** | 0.700 | −0.114 | 0.018 | 0.778 ** | 0.826 *** | 0.747 ** | −0.034 | −0.168 | 0.165 | 0.043 | 0.984 *** | 0.002 | 0.270 |
a M2 | 0.166 | 0.035 | −0.5743 | −0.157 | −0.339 | 0.093 | 0.288 | −0.039 | 0.088 | −0.343 | 0.714 ** | −0.200 | 0.315 | 0.736 ** |
Simulated System | The Most Stable Productive Orientations of the Neutral Form of Vandetanib in the Complex with CYPs | |
---|---|---|
Estimated Free Energy of Binding (kcal/mol) | O(Comp I)-N-CH3Distance [Å]a | |
CYP1A1 (4I8V) | −8.64 | 3.89 |
CYP2D6 (3TDA) | −10.21 | 3.38 |
CYP3A4 (1W0E) | −9.96 | 3.12 |
CYP3A4 (6BD7) | −9.63 | 3.45 |
CYP3A4 (6BD7) + second vandetanib molecule | −9.30 | 2.67 |
CYP Enzyme | Kinetical Characteristics | ||
---|---|---|---|
a VMax | b K0.5 | c Hill Coefficient | |
CYP1A1 | 0.76 ± 0.02 | 35.12 ± 2.75 | NA |
CYP2D6 | 2.16 ± 0.15 | 84.36 ± 18.14 | NA |
CYP3A4 | 6.17 ± 1.32 | 45.02 ± 13.62 | 1.73 ± 0.56 |
CYP3A4+cyt b5 | 34.32 ± 1.59 | 83.65 ± 5.55 | 1.83 ± 0.13 |
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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.; et al. 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. https://doi.org/10.3390/ijms20143392
Indra R, Pompach P, Martínek V, Takácsová P, Vavrová K, Heger Z, Adam V, Eckschlager T, Kopečková K, Arlt VM, et al. Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation. International Journal of Molecular Sciences. 2019; 20(14):3392. https://doi.org/10.3390/ijms20143392
Chicago/Turabian StyleIndra, Radek, Petr Pompach, Václav Martínek, Paulína Takácsová, Katarína Vavrová, Zbyněk Heger, Vojtěch Adam, Tomáš Eckschlager, Kateřina Kopečková, Volker Manfred Arlt, and et al. 2019. "Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation" International Journal of Molecular Sciences 20, no. 14: 3392. https://doi.org/10.3390/ijms20143392
APA StyleIndra, R., Pompach, P., Martínek, V., Takácsová, P., Vavrová, K., Heger, Z., Adam, V., Eckschlager, T., Kopečková, K., Arlt, V. M., & Stiborová, M. (2019). Identification of Human Enzymes Oxidizing the Anti-Thyroid-Cancer Drug Vandetanib and Explanation of the High Efficiency of Cytochrome P450 3A4 in its Oxidation. International Journal of Molecular Sciences, 20(14), 3392. https://doi.org/10.3390/ijms20143392