Ivermectin induces chicken BCRP/ABCG2 expression and function: Involvement of CXR signaling pathway and mRNA stabilization
Ivermectin induces chicken BCRP/ABCG2 expression and function: Involvement of CXR signaling pathway and mRNA stabilization
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DOI：
10.1111/jvp.13090
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发表时间：
2022-08-04
影响因子：
1.3
通讯作者：
Wang, Liping
中科院分区：
文献类型：
--
作者：
Xu, Ziyong;Li, Mei;Wang, Liping
伊维菌素是一种大环内酯类抗寄生虫药，广泛应用于人用和兽用药物。已有研究表明伊维菌素可与P-糖蛋白相互作用，是一种良好的诱导剂和底物，但伊维菌素是否影响鸡BCRP尚不清楚。在这项研究中，我们发现伊维菌素以时间和浓度依赖性的上调方式明显影响鸡原代肝细胞中BCRP的表达。随后的一系列实验表明，BCRP的诱导与伊维菌素增加CXR的表达，促进CXR易位到细胞核，并在转录后水平增强Abcg2 mRNA的稳定性有关。此外，我们观察到伊维菌素也提高了转录后水平的Abcg2 mRNA的稳定性，通过Act-D追逐试验。体内实验结果表明，伊维菌素可诱导鸡重要组织中BCRP和CXR的表达，并降低鸡BCRP的底物氟苯尼考的表观渗透系数。以上结果表明，伊维菌素可通过转录CXR信号通路和转录后mRNA稳定化来诱导鸡BCRP的表达和功能。
Ivermectin is a macrocyclic lactone antiparasitic drug widely used in human and veterinary medicine. Previous studies indicated that ivermectin could interact with P-glycoprotein, being a good inducer and substrate; however, it is unknown whether ivermectin affects BCRP of chicken. In this study, we found that ivermectin distinctly affected the expression of BCRP in a time- and concentration-dependent up-regulatory way in chicken primary hepatocytes. Subsequent series of experiments showed that the BCRP induction is related with the increase of CXR expression and, promoting CXR translocations to the nucleus and enhancing the stability of Abcg2 mRNA at the post-transcriptional level by ivermectin. Furthermore, we observed that ivermectin also enhanced the stability of Abcg2 mRNA at the post-transcriptional level by Act-D chase assay. We got the similar results by in vivo test that ivermectin-induced BCRP and CXR expression in pharmacologically important tissues, and decreased the apparent permeability coefficient of florfenicol (substrate of chicken BCRP). In conclusion, the results indicated that ivermectin could induce chicken BCRP expression and function through the transcriptional CXR signaling pathway and post-transcriptional mRNA stabilization.