The fungicide tebuconazole modulates the sodium current of human NaV1.5 channels expressed in HEK293 cells

Leisiane Pereira Marques; Artur Santos-Miranda; Julliane Vasconcelos Joviano-Santos; Jorge Lucas Teixeira-Fonseca; Fabiana da Silva Alcântara; Jaqueline Oliveira Sarmento; Danilo Roman-Campos

doi:10.1016/j.fct.2023.113992

The fungicide tebuconazole modulates the sodium current of human Na_V1.5 channels expressed in HEK293 cells

Food Chem Toxicol. 2023 Oct:180:113992. doi: 10.1016/j.fct.2023.113992. Epub 2023 Aug 24.

Authors

Leisiane Pereira Marques¹, Artur Santos-Miranda², Julliane Vasconcelos Joviano-Santos³, Jorge Lucas Teixeira-Fonseca¹, Fabiana da Silva Alcântara¹, Jaqueline Oliveira Sarmento¹, Danilo Roman-Campos⁴

Affiliations

¹ Laboratory of Cardiobiology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
² Department of Physiology and Biophysics, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
³ Post-Graduate Program in Health Sciences, Faculdade Ciências Médicas de Minas Gerais, Belo Horizonte, MG, Brazil.
⁴ Laboratory of Cardiobiology, Department of Biophysics, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil. Electronic address: drcampos@unifesp.br.

PMID: 37633639
DOI: 10.1016/j.fct.2023.113992

Abstract

The fungicide Tebuconazole is a widely used pesticide in agriculture and may cause cardiotoxicity. In our present investigation the effect of Tebuconazole on the sodium current (I_Na) of human cardiac sodium channels (Na_V1.5) was studied using a heterologous expression system and whole-cell patch-clamp techniques. Tebuconazole reduced the amplitude of the peak I_Na in a concentration- and voltage-dependent manner. At the holding potential of -120 mV the IC₅₀ was estimated at 204.1 ± 34.3 μM, while at -80 mV the IC₅₀ was 0.3 ± 0.1 μM. The effect of the fungicide is more pronounced at more depolarized potentials, indicating a state-dependent interaction. Tebuconazole caused a negative shift in the half-maximal inactivation voltage and delayed recovery from fast inactivation of I_Na. Also, it enhanced closed-state inactivation, exhibited use-dependent block in a voltage-dependent manner. Furthermore, Tebuconazole reduced the increase in late sodium current induced by the pyrethroid insecticide β-Cyfluthrin. These results suggest that Tebuconazole can interact with Na_V1.5 channels and modulate I_Na. The observed effects may lead to decreased cardiac excitability through reduced I_Na availability, which could be a new mechanism of cardiotoxicity to be attributed to the fungicide.

Keywords: Cardiac sodium channel; Cardiotoxicity; Fungicide; Sodium current; Tebuconazole.