Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems

Radek Indra; Petr Pompach; Katarína Vavrová; Kateřina Jáklová; Zbyněk Heger; Vojtěch Adam; Tomáš Eckschlager; Kateřina Kopečková; Volker Manfred Arlt; Marie Stiborová

doi:10.1016/j.etap.2019.103310

Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems

Radek Indra, Petr Pompach, Katarína Vavrová, Kateřina Jáklová, Zbyněk Heger, Vojtěch Adam, Tomáš Eckschlager, Kateřina Kopečková, Volker Manfred Arlt, Marie Stiborová^*

^*Corresponding author for this work

Genetic & Environmental Toxicology

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10 Citations (Scopus)

Abstract

We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

Original language	English
Article number	103310
Journal	ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY
Volume	74
DOIs	https://doi.org/10.1016/j.etap.2019.103310
Publication status	Published - 1 Feb 2020

Keywords

Anti-thyroid-cancer drug
Cytochromes P450
Flavin-containing monoxygenases
Metabolism
Tyrosine kinase inhibitor
Vandetanib

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10.1016/j.etap.2019.103310

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Indra, R., Pompach, P., Vavrová, K., Jáklová, K., Heger, Z., Adam, V., Eckschlager, T., Kopečková, K., Arlt, V. M., & Stiborová, M. (2020). Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY, 74, Article 103310. https://doi.org/10.1016/j.etap.2019.103310

@article{c95b722b923e4efbb6e976a8a1433abb,

title = "Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems",

abstract = "We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.",

keywords = "Anti-thyroid-cancer drug, Cytochromes P450, Flavin-containing monoxygenases, Metabolism, Tyrosine kinase inhibitor, Vandetanib",

author = "Radek Indra and Petr Pompach and Katar{\'i}na Vavrov{\'a} and Kate{\v r}ina J{\'a}klov{\'a} and Zbyn{\v e}k Heger and Vojt{\v e}ch Adam and Tom{\'a}{\v s} Eckschlager and Kate{\v r}ina Kope{\v c}kov{\'a} and Arlt, {Volker Manfred} and Marie Stiborov{\'a}",

year = "2020",

month = feb,

day = "1",

doi = "10.1016/j.etap.2019.103310",

language = "English",

volume = "74",

journal = "ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY",

issn = "1382-6689",

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Indra, R, Pompach, P, Vavrová, K, Jáklová, K, Heger, Z, Adam, V, Eckschlager, T, Kopečková, K, Arlt, VM & Stiborová, M 2020, 'Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems', ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY, vol. 74, 103310. https://doi.org/10.1016/j.etap.2019.103310

Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems. / Indra, Radek; Pompach, Petr; Vavrová, Katarína et al.
In: ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY, Vol. 74, 103310, 01.02.2020.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems

AU - Indra, Radek

AU - Pompach, Petr

AU - Vavrová, Katarína

AU - Jáklová, Kateřina

AU - Heger, Zbyněk

AU - Adam, Vojtěch

AU - Eckschlager, Tomáš

AU - Kopečková, Kateřina

AU - Arlt, Volker Manfred

AU - Stiborová, Marie

PY - 2020/2/1

Y1 - 2020/2/1

N2 - We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

AB - We studied the in vitro metabolism of the anti-thyroid-cancer drug vandetanib in a rat animal model and demonstrated that N-desmethylvandetanib and vandetanib N-oxide are formed by NADPH- or NADH-mediated reactions catalyzed by rat hepatic microsomes and pure biotransformation enzymes. In addition to the structural characterization of vandetanib metabolites, individual rat enzymes [cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO)] capable of oxidizing vandetanib were identified. Generation of N-desmethylvandetanib, but not that of vandetanib N-oxide, was attenuated by CYP3A and 2C inhibitors while inhibition of FMO decreased formation of vandetanib N-oxide. These results indicate that liver microsomal CYP2C/3A and FMO1 are major enzymes participating in the formation of N-desmethylvandetanib and vandetanib N-oxide, respectively. Rat recombinant CYP2C11 > >3A1 > 3A2 > 1A1 > 1A2 > 2D1 > 2D2 were effective in catalyzing the formation of N-desmethylvandetanib. Results of the present study explain differences between the CYP- and FMO-catalyzed vandetanib oxidation in rat and human liver reported previously and the enzymatic mechanisms underlying this phenomenon.

KW - Anti-thyroid-cancer drug

KW - Cytochromes P450

KW - Flavin-containing monoxygenases

KW - Metabolism

KW - Tyrosine kinase inhibitor

KW - Vandetanib

UR - http://www.scopus.com/inward/record.url?scp=85076172640&partnerID=8YFLogxK

U2 - 10.1016/j.etap.2019.103310

DO - 10.1016/j.etap.2019.103310

M3 - Article

C2 - 31837525

AN - SCOPUS:85076172640

SN - 1382-6689

VL - 74

JO - ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY

JF - ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY

M1 - 103310

ER -

Cytochrome P450 and flavin-containing monooxygenase enzymes are responsible for differential oxidation of the anti-thyroid-cancer drug vandetanib by human and rat hepatic microsomal systems

Abstract

Keywords

UN SDGs

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