Publication detail

Oxidation of a tyrosine kinase inhibitor vandetanib by human cytochromes P450 and flavin monooxygenases in vitro and its effect of DNA adduct formation mediated by an anticancer drug ellipticine

INDRA, R. POMPACH, P. TAKÁCSOVÁ, P. VÁVROVÁ, K. HEGER, Z. ADAM, V. ECKSCHLAGER, T. KOPEČKOVÁ, K. STIBOROVÁ, M.

Original Title

Oxidation of a tyrosine kinase inhibitor vandetanib by human cytochromes P450 and flavin monooxygenases in vitro and its effect of DNA adduct formation mediated by an anticancer drug ellipticine

Type

presentation, poster

Language

English

Original Abstract

Vandetanib is a tyrosine kinase inhibitor (TKI) used for treatment of certain tumors of the thyroid gland. It inhibits signalling of epidermal growth, vascular endothelial growth factor or rearranged during transfection. Here, using human hepatic microsomes and recombinant cytochromes P450 (CYPs) and flavincontaining monooxygenases (FMOs) expressed in Supersomes TM, oxidation of vandetanib was studied. The vandetanib metabolites were separated by HPLC and identified by mass spectroscopy. Human hepatic microsomes oxidize vandetanib to N-desmethyl-vandetanib, but not to vandetanib-N-oxide. Of all tested human CYP enzymes, the CYP1A1, 2C8, 2D6, 3A4 and 3A5 enzymes, mainly in the presence of cytochrome b5, oxidize vandetanib to N-desmethylvandetanib. No vandetanib-N-oxide was generated by tested human CYPs. However, FMO enzymes were able to generate this metabolite. Of three human FMOs tested (FMO1, FMO3 and FMO5), FMO1 and FMO3 oxidize vandetanib to vandetanib-N-oxide. FMO1 was more effective than FMO3 in this reaction. The results found in this study approved the knowledge showed by the preliminary studies, suggesting that vande-tanib is oxidized to N-desmethylvandetanib and vandetanib-N-oxide, and specified the efficiencies of individual CYPs and FMOs in the reactions. Moreover, they indicated an essential role of cytochromeb5in oxidation of vandetanib to N-desmethylvan-detanib by CYP3A4. Because this CYP is the most important enzyme activating also another anticancer agent that is effective against certain tumours of the thyroid gland, DNA-damaging drug ellipticine, the effect of vandetanib on metabolic activation of this drug was investigated. An inhibition effect of vandetanib on the most efficient anticancer effects of ellipticine, formation of covalent ellipticine-derived DNA adducts, was found. Cytochrome b5 plays an important role also of this CYP3A4-mediated activity.

Keywords

Vandetanib; kinase inhibitor; thyroid gland; tumor

Authors

INDRA, R.; POMPACH, P.; TAKÁCSOVÁ, P.; VÁVROVÁ, K.; HEGER, Z.; ADAM, V.; ECKSCHLAGER, T.; KOPEČKOVÁ, K.; STIBOROVÁ, M.

Released

31. 7. 2018

Pages from

350

Pages to

350

Pages count

1

URL

https://doi.org/10.1002/2211-5463.12453

BibTex

@misc{BUT163395,
  author="INDRA, R. and POMPACH, P. and TAKÁCSOVÁ, P. and VÁVROVÁ, K. and HEGER, Z. and ADAM, V. and ECKSCHLAGER, T. and KOPEČKOVÁ, K. and STIBOROVÁ, M.",
  title="Oxidation of a tyrosine kinase inhibitor vandetanib by human cytochromes P450 and flavin monooxygenases in vitro and its effect of DNA adduct formation mediated by an anticancer drug ellipticine
",
  year="2018",
  pages="350--350",
  url="https://doi.org/10.1002/2211-5463.12453",
  note="presentation, poster"
}