Toxicology Graduate Program, Toxicology Centre, University of Saskatchewan, Saskatoon, SK S7N 5B3, Canada.
Department of Soil Science, University of Saskatchewan, Saskatoon, SK S7N 5A8, Canada.
Toxicol In Vitro. 2024 Dec;101:105942. doi: 10.1016/j.tiv.2024.105942. Epub 2024 Sep 14.
In this study, we investigated the role of two efflux transporters, p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in the cytotoxicity and intracellular accumulation of the organophosphate pesticide chlorpyrifos (CPF) and its active metabolite, CPF-oxon (CPFO), in a human-derived liver cell line (HepG2) and kidney epithelial cell line (HK-2). The cytotoxicity to CPF and CPFO differed between cell lines where HK-2 had lower IC50 values which could be attributed to lower basal expression and inducibility of metabolizing enzymes, transporters, and nuclear receptors in HK-2 cells. In HepG2 cells, co-exposure of CPF with a specific inhibitor of either P-gp or BCRP enhanced the cytotoxicity of CPF while co-exposure of CPFO with VRP enhanced the cytotoxicity of CPFO, suggesting the role of these transporters in the elimination CPF and CPFO. Inhibition of efflux transporters did not affect the cytotoxicity of CPF and CPFO in HK-2 cells. Co-incubation of CPF with P-gp and BCRP inhibitors increased the intracellular concentration of CPF in HepG2 cells suggesting that both transporters play a role in limiting the cellular accumulation of CPF in HepG2 cells. Our results provide evidence that inhibition of efflux transporters can enhance CPF-induced toxicity through enhanced cellular accumulation and raises additional questions regarding how pesticide-transporter interactions may influence toxicity of mixtures containing pesticides and other environmental chemicals.
在这项研究中，我们研究了两种外排转运蛋白，即 P-糖蛋白（P-gp）和乳腺癌耐药蛋白（BCRP），在有机磷农药毒死蜱（CPF）及其活性代谢物 CPF-氧（CPFO）对人源性肝细胞系（HepG2）和肾上皮细胞系（HK-2）的细胞毒性和细胞内积累中的作用。CPF 和 CPFO 的细胞毒性在细胞系之间存在差异，其中 HK-2 的 IC50 值较低，这可能归因于 HK-2 细胞中代谢酶、转运蛋白和核受体的基础表达和诱导能力较低。在 HepG2 细胞中，CPF 与 P-gp 或 BCRP 的特定抑制剂共同暴露增强了 CPF 的细胞毒性，而 CPFO 与 VRP 共同暴露增强了 CPFO 的细胞毒性，表明这些转运蛋白在 CPF 和 CPFO 的消除中起作用。在 HK-2 细胞中，外排转运蛋白的抑制并不影响 CPF 和 CPFO 的细胞毒性。CPF 与 P-gp 和 BCRP 抑制剂共同孵育增加了 HepG2 细胞中 CPF 的细胞内浓度，表明两种转运蛋白都在限制 CPF 在 HepG2 细胞中的细胞内积累中起作用。我们的结果提供了证据，表明抑制外排转运蛋白可以通过增强细胞内积累来增强 CPF 诱导的毒性，并提出了关于农药-转运蛋白相互作用如何影响含有农药和其他环境化学物质的混合物毒性的其他问题。
