Studies on the interaction of five triazole fungicides with human renal transporters in cells

Jing Nie; Jiabei Zhou; Yi Shen; Ruimiao Lin; Haihong Hu; Kui Zeng; Huichang Bi; Min Huang; Lushan Yu; Su Zeng; Jing Miao

doi:10.1016/j.tiv.2023.105555

Studies on the interaction of five triazole fungicides with human renal transporters in cells

Toxicol In Vitro. 2023 Apr:88:105555. doi: 10.1016/j.tiv.2023.105555. Epub 2023 Jan 18.

Authors

Jing Nie¹, Jiabei Zhou², Yi Shen², Ruimiao Lin², Haihong Hu³, Kui Zeng³, Huichang Bi⁴, Min Huang⁴, Lushan Yu³, Su Zeng⁵, Jing Miao⁶

Affiliations

¹ Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310052, China; Research Center for Clinical Pharmacy, Zhejiang University, Hangzhou, Zhejiang 310058, China; Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, Zhejiang 310058, China.
² Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
³ Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, Zhejiang 310058, China.
⁴ Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.
⁵ Research Center for Clinical Pharmacy, Zhejiang University, Hangzhou, Zhejiang 310058, China; Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; Cancer Center of Zhejiang University, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou, Zhejiang 310058, China. Electronic address: zengsu@zju.edu.cn.
⁶ Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang 310052, China; Research Center for Clinical Pharmacy, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: miaojing@zju.edu.cn.

PMID: 36669674
DOI: 10.1016/j.tiv.2023.105555

Abstract

The widespread use of triazole fungicides in agricultural production poses a potential risk to human health. This study investigates the interaction of five triazole fungicides, i.e., tebuconazole, triticonazole, hexaconazole, penconazole, and uniconazole with human renal transporters, including OAT1, OAT3, OCT2, OCTN1, OCTN2, MATE1, MATE2-K, MRP2, MDR1, and BCRP, using transgenic cell models. For uptake transporters, triticonazole was the substrate of OAT1 and OAT3 and the inhibitor of OCT2. Tebuconazole and penconazole inhibited OCTN2 (100 μM), while tebuconazole, triticonazole, hexaconazole, penconazole, and uniconazole inhibited MATE1 (100 μM). Tebuconazole and hexaconazole inhibited MATE2-K (100 μM). All five triazole fungicides were not substrates or strong inhibitors of MRP2, MDR1, and BCRP efflux transporters. Penconazole inhibited OCT2 with IC₅₀ = 1.12 μM. Penconazole and uniconazole inhibited MATE1 with IC₅₀ = 0.94 μM and 0.87 μM. Tebuconazole and hexaconazole inhibited MATE2-K with IC₅₀ = 0.96 μM and 1.04 μM, indicating that triazole fungicides may inhibit renal drug transporter activity at low concentrations. Triticonazole was transported by OAT1 and OAT3, and the K_m values of triticonazole were 5.81 ± 1.75 and 47.35 ± 14.27, respectively. Tebuconazole and uniconazole were transported by OAT3, and the K_m values of tebuconazole and uniconazole were 30.28 ± 7.18 and 87.61 ± 31.70, respectively, which may induce nephrotoxicity.

Keywords: ATP-binding cassette; Human renal transporters; Nephrotoxicity; Solute carrier; Triazole fungicides.

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
Fungicides, Industrial* / toxicity
Humans
Membrane Transport Proteins
Neoplasm Proteins
Triazoles / toxicity

Substances

triticonazole
Fungicides, Industrial
ATP Binding Cassette Transporter, Subfamily G, Member 2
Neoplasm Proteins
Membrane Transport Proteins
Triazoles