Chicken xenobiotic receptor upregulates the BCRP/ABCG2 transporter

The transporter breast cancer resistance protein (BCRP, encoded by ABCG2) influences the bio-availability and elimination of numerous substrate drugs during clinical therapy. The xenobiotic-sensing nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) reportedly regulate func-tional expression of BCRP in mammalian species. How-ever, it is unknown whether chicken xenobiotic receptor (CXR) regulates the expression and activity of BCRP. This study aimed to investigate the role of CXR in regula-tion of BCRP in chicken using in vitro and in vivo models. CXR was expressed in the main drug-metabolizing tissues of chickens, and its expression correlated well with that of the prototypical target genes CYP2H1 and ABCG2. BCRP expression was upregulated, and transporter activity was increased, in chicken primary hepatocytes exposed to the CXR agonist metyrapone. Using RNA interference and ectopic expression techniques to manipu-late the cellular CXR status, we confirmed that ABCG2 gene regulation depended on CXR. In vivo experiments showed that metyrapone induced BCRP in the liver, kidney, duodenum, and jejunum of chickens. Coadminis-tration of metyrapone significantly changed the pharma-cokinetic behavior of orally administered florfenicol (substrate of chicken BCRP), with a lower Cmax (4.62 vs. 7.35 mg/mL, P < 0.01) and AUC0-t (15.83 vs. 24.18 h cent mg/L, P < 0.01) as well as a higher Tmax (0.96 vs. 0.79 h, P < 0.05) and Cl/F (0.13 vs. 0.08 L/h/kg, P < 0.05). Together, our data suggest that CXR is involved in regu-lation of BCRP, and consequently, coadministration of a CXR agonist can affect the pharmacokinetic behavior of an orally administered BCRP substrate.

Automated summary

This study investigates the role of chicken xenobiotic receptor (CXR) in the regulation of breast cancer resistance protein (BCRP). The results show that CXR is involved in the regulation of BCRP gene expression and protein activity in chickens. Activation of CXR by metyrapone upregulates BCRP expression and transporter activity. Co-administration of metyrapone affects the pharmacokinetic behavior of orally administered BCRP substrate.