Ivermectin induces chicken BCRP/ABCG2 expression and function: Involvement of CXR signaling pathway and mRNA stabilization.

Abstract

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.