In vitro enantioselective inhibition of key human CYP450 enzymes by the chiral fungicide penconazole

IF 4.2 3区环境科学与生态学 Q2 ENVIRONMENTAL SCIENCES

Environmental toxicology and pharmacology Pub Date : 2025-08-11 DOI:10.1016/j.etap.2025.104790

Maike Felipe Santos Barbetta , Giovanni Stoppa Baviera , Icaro Salgado Perovani , Leandro Oka Duarte , Anderson Rodrigo Moraes de Oliveira

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引用次数: 0

Abstract

Penconazole (PEN) is a chiral triazole fungicide widely used in vineyards. Despite its detection in human urine and documented toxicological effect in non-targeted organisms, data on PEN’s effects in humans is scarce. This study investigated the in vitro inhibitory effects of racemic PEN and its isolated enantiomers on major CYP450 isoforms using human liver microsomes. PEN inhibited all tested CYP450 enzymes, with CYP1A2, CYP2C9, and CYP3A4/5 being the most sensitive (K_i values: 0.73–8.1 µmol L⁻¹). Notably, the R-(+)-PEN enantiomer exhibited stronger inhibition of CYP1A2 and CYP2D6, indicating enantioselective interactions. In vivo extrapolation indicated that PEN could significantly inhibit CYP3A4/5, the primary isoform involved in metabolism of xenobiotics, and should not be overlooked. These findings provide critical insights into human toxicity of PEN and contribute to understanding its toxicological and environment impact, especially from an enantioselective perspective in drug-pesticide interactions.

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手性杀菌剂戊康唑对人CYP450关键酶的体外对映选择性抑制作用。

戊康唑（PEN）是一种手性三唑类杀菌剂，广泛应用于葡萄园。尽管在人类尿液中检测到它并记录了它对非靶向生物的毒理学作用，但关于它对人类的影响的数据很少。本研究利用人肝微粒体研究了外消旋PEN及其分离的对映体对CYP450主要亚型的体外抑制作用。PEN对所有CYP450酶都有抑制作用，其中CYP1A2、CYP2C9和CYP3A4/5最敏感（Ki值：0.73-8.1µmol L⁻¹）。值得注意的是，R-(+)- pen对CYP1A2和CYP2D6表现出更强的抑制作用，表明对映选择性相互作用。在体内外推表明，PEN可以显著抑制CYP3A4/5，这是参与外源代谢的主要亚型，不可忽视。这些发现提供了对人类毒性的重要见解，并有助于了解其毒理学和环境影响，特别是从药物-农药相互作用的对构像选择角度来看。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Environmental toxicology and pharmacology 医学-毒理学

CiteScore

7.00

自引率

4.70%

发文量

185

审稿时长

34 days

期刊介绍： Environmental Toxicology and Pharmacology publishes the results of studies concerning toxic and pharmacological effects of (human and veterinary) drugs and of environmental contaminants in animals and man. Areas of special interest are: molecular mechanisms of toxicity, biotransformation and toxicokinetics (including toxicokinetic modelling), molecular, biochemical and physiological mechanisms explaining differences in sensitivity between species and individuals, the characterisation of pathophysiological models and mechanisms involved in the development of effects and the identification of biological markers that can be used to study exposure and effects in man and animals. In addition to full length papers, short communications, full-length reviews and mini-reviews, Environmental Toxicology and Pharmacology will publish in depth assessments of special problem areas. The latter publications may exceed the length of a full length paper three to fourfold. A basic requirement is that the assessments are made under the auspices of international groups of leading experts in the fields concerned. The information examined may either consist of data that were already published, or of new data that were obtained within the framework of collaborative research programmes. Provision is also made for the acceptance of minireviews on (classes of) compounds, toxicities or mechanisms, debating recent advances in rapidly developing fields that fall within the scope of the journal.