The biological effects of the pesticide and mitochondrial complex I inhibitor tebufenpyrad (TEBU) on liver cells were investigated by combining proteomics and metabolomics. Both cell culture media and cellular lysates were analyzed in dose-response and kinetic experiments on the HepaRG cell line. Responses were compared with those obtained on primary human and rat hepatocytes. A multitude of phase I and II metabolites (>80) mainly common to HepaRG cells and primary hepatocytes and an increase in metabolization enzymes were observed. Synthesis of mitochondrion and oxidative phosphorylation complex constituents, fatty acid oxidation, and cellular uptake of lipids were induced to compensate for complex I inhibition and the decrease in ATP intracellular contents caused by TEBU. Secretion of the 20 S circulating proteasome and overall inhibition of acute inflammation followed by IL-6 secretion in later stages were observed in HepaRG cells. These effects were associated with a decrease in STAT1 and STAT3 transcription factor abundances, but with different kinetics. Based on identified TEBU targets, docking experiments, and nuclear receptor reporter assays, we concluded that liver cell response to TEBU is mediated by its interaction with the PPARγ transcription factor.

结合蛋白质组学和代谢组学研究农药和线粒体复合物I抑制剂噻虫胺(TEBU)对肝细胞的生物学效应。在 HepaRG 细胞系的剂量反应和动力学实验中分析了细胞培养基和细胞裂解物。将反应与在原代人和大鼠肝细胞上获得的反应进行比较。观察到大量 I 期和 II 期代谢物 (>80) 主要在 HepaRG 细胞和原代肝细胞中常见，并且观察到代谢酶增加。诱导线粒体和氧化磷酸化复合物成分的合成、脂肪酸氧化和细胞对脂质的摄取，以补偿复合物 I 的抑制和由 TEBU 引起的 ATP 细胞内含量的减少。在 HepaRG 细胞中观察到 20 S 循环蛋白酶体的分泌和急性炎症的总体抑制，随后是后期的 IL-6 分泌。这些影响与 STAT1 和 STAT3 转录因子丰度的降低有关，但具有不同的动力学。基于已确定的 TEBU 靶标、对接实验和核受体报告分析，我们得出结论，肝细胞对 TEBU 的反应是由其与 PPARγ 转录因子的相互作用介导的。