School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang 212100, China.
Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, PR China.
Poult Sci. 2023 Jan;102(1):102278. doi: 10.1016/j.psj.2022.102278. Epub 2022 Oct 23.
The transporter breast cancer resistance protein (BCRP, encoded by ABCG2) influences the bioavailability 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 functional expression of BCRP in mammalian species. However, 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 regulation 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 manipulate 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. Coadministration of metyrapone significantly changed the pharmacokinetic behavior of orally administered florfenicol (substrate of chicken BCRP), with a lower C (4.62 vs. 7.35 µg/mL, P < 0.01) and AUC (15.83 vs. 24.18 h·mg/L, P < 0.01) as well as a higher T (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 regulation of BCRP, and consequently, coadministration of a CXR agonist can affect the pharmacokinetic behavior of an orally administered BCRP substrate.
转运体乳腺癌耐药蛋白（BCRP，由 ABCG2 编码）在临床治疗过程中影响许多底物药物的生物利用度和消除。据报道，外源性物质感应核受体孕烷 X 受体（PXR）和组成型雄烷受体（CAR）调节哺乳动物物种中 BCRP 的功能表达。然而，尚不清楚鸡外源性物质受体（CXR）是否调节 BCRP 的表达和活性。本研究旨在使用体外和体内模型研究 CXR 在鸡中对 BCRP 表达的调节作用。CXR 在鸡的主要药物代谢组织中表达，其表达与典型靶基因 CYP2H1 和 ABCG2 的表达密切相关。暴露于 CXR 激动剂甲吡酮的鸡原代肝细胞中 BCRP 表达上调，转运体活性增加。使用 RNA 干扰和异位表达技术来操纵细胞 CXR 状态，我们证实 ABCG2 基因调节依赖于 CXR。体内实验表明，甲吡酮诱导鸡肝脏、肾脏、十二指肠和空肠中 BCRP 的表达。甲吡酮共给药显著改变了鸡口服氟苯尼考（鸡 BCRP 的底物）的药代动力学行为，C（4.62 对 7.35 µg/mL，P < 0.01）和 AUC（15.83 对 24.18 h·mg/L，P < 0.01）降低，T（0.96 对 0.79 h，P < 0.05）和 Cl/F（0.13 对 0.08 L/h/kg，P < 0.05）升高。总之，我们的数据表明 CXR 参与 BCRP 的调节，因此，CXR 激动剂的共给药会影响口服 BCRP 底物的药代动力学行为。
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