Different inhibitory effects of azole-containing drugs and pesticides on CYP2C9 polymorphic forms: An in vitro study.

Autor: Haidukevich IV; Molecular Biotechnology Department, Institute of Bioorganic Chemistry NASB, Minsk, Belarus., Sushko TA; Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo 108-8639, Japan., Tumilovich AM; Molecular Biotechnology Department, Institute of Bioorganic Chemistry NASB, Minsk, Belarus., Grabovec IP; Molecular Biotechnology Department, Institute of Bioorganic Chemistry NASB, Minsk, Belarus., Usanov SA; Molecular Biotechnology Department, Institute of Bioorganic Chemistry NASB, Minsk, Belarus., Gilep AA; Molecular Biotechnology Department, Institute of Bioorganic Chemistry NASB, Minsk, Belarus; Institute of Biomedical Chemistry, Moscow, Russia. Electronic address: agilep@iboch.by.
Jazyk: angličtina
Zdroj: Toxicology in vitro : an international journal published in association with BIBRA [Toxicol In Vitro] 2018 Aug; Vol. 50, pp. 249-256. Date of Electronic Publication: 2018 Apr 03.
DOI: 10.1016/j.tiv.2018.04.002
Abstrakt: CYP2C9 plays a major role in drug metabolism. It is highly polymorphic and among the variants, CYP2C9*2 and CYP2C9*3 have been known to encode the protein with moderately to markedly reduced catalytic activity. Azole antifungals are among the most frequently used drugs in human pharmacotherapy and represent a widely used class of pesticides to which humans are inevitably exposed. Due to the similarities in CYP organization throughout species, azoles can interact not only with the target fungal CYP51 substrate-binding site but can also modulate the catalytic activity of human cytochrome P450s, including CYP2C9, causing severe adverse effects. In the present study the potency of azole-containing drugs and pesticides to inhibit recombinant wild-type CYP2C9*1 and the allelic variants CYP2C9*2 and CYP2C9*3 was evaluated. Significant differences were found in their affinity to CYP2C9*1, CYP2C9*2, and CYP2C9*3 as well as in the catalytic activity of CYP2C9 allelic variants. Moreover, addition of cytochrome b 5 resulted in a decrease of CYP2C9*3 activity to diclofenac in a concentration-dependent manner. Increasing the knowledge of how azoles influence polymorphic variants of CYP2C9 could help individualize drug treatment, leading to optimization of the selection of drugs and doses for individuals based on genetic information.
(Copyright © 2018 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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