Chicken xenobiotic receptor upregulates the BCRP/ABCG2 transporter.
Chicken xenobiotic receptor upregulates the BCRP/ABCG2 transporter.
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DOI：
10.1016/j.psj.2022.102278
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发表时间：
2023-01
期刊：
影响因子：
4.4
通讯作者：
Zhang, Yujuan
中科院分区：
文献类型：
--
作者：
Xu, Ziyong;Li, Mei;Lu, Wang;Wang, Liping;Zhang, Yujuan
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，外源感应核受体妊娠X受体（PXR）和组成型雄甾烷受体（CAR）调节哺乳动物BCRP的功能表达。然而，鸡的异种受体（CXR）是否调节BCRP的表达和活性尚不清楚。本研究旨在通过体外和体内模型研究CXR对鸡BCRP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具有良好的相关性。暴露于CXR激动剂metyrapone的鸡原代肝细胞中，BCRP表达上调，转运蛋白活性增加。利用RNA干扰和异位表达技术操纵细胞CXR状态，我们证实了ABCG2基因的调控依赖于CXR。体内实验表明，美替拉酮可诱导鸡的肝脏、肾脏、十二指肠和空肠产生BCRP。美替rapone联合给药显著改变了口服氟苯尼考（鸡BCRP底物）的药代动力学行为，降低了Cmax （4.62 vs. 7.35µg/mL, P < 0.01）和AUC0-t (15.83 vs. 24.18 h·mg/L, P < 0.01)，提高了Tmax （0.96 vs. 0.79 h, P < 0.05）和Cl/F （0.13 vs. 0.08 L/h/kg, P < 0.05）。综上所述，我们的数据表明CXR参与BCRP的调控，因此，CXR激动剂的联合使用可以影响口服BCRP底物的药代动力学行为。
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 Cmax (4.62 vs. 7.35 µg/mL, P < 0.01) and AUC0-t (15.83 vs. 24.18 h·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 regulation of BCRP, and consequently, coadministration of a CXR agonist can affect the pharmacokinetic behavior of an orally administered BCRP substrate.
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