Yamasaki Yuki, Kobayashi Kaoru, Chiba Kan
Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University.
Biol Pharm Bull. 2018;41(6):972-977. doi: 10.1248/bpb.b18-00053.
P-Glycoprotein (P-gp), encoded by the MDR1 (ABCB1) gene in humans and by Mdr1a and Mdr1b genes in rodents, is a member of the superfamily of ATP-binding cassette transporters. Since P-gp is constitutively expressed in numerous tissues and exhibits a broad specificity in substrate recognition, it can play a crucial role in limiting the absorption and distribution of xenobiotics by decreasing their intracellular accumulation. The expression of P-gp is regulated by various nuclear receptors such as pregnane X receptor (PXR). Although the characterization of P-gp induction by PXR ligands is a crucial goal for predicting pharmacokinetics of drugs, findings regarding the induction of P-gp by PXR ligands in vivo are still controversial. In this study, we examined the effect of pregnenolone 16α-carbonitrile (PCN), a murine PXR ligand, on the expression of Mdr1a/1b mRNA and P-gp protein in the intestine, brain and liver of mice. The results showed that PCN increased the expression of both Mdr1a/1b mRNA and P-gp protein in the intestine and the brain. The present study provided the first evidence that P-gp is inducible by PCN in the large intestine. The results also showed that P-gp protein was induced by PCN in the cortex but not in the whole brain. On the other hand, PCN increased the expression of Mdr1a/1b mRNA in the liver, although no increase was observed in the expression of P-gp protein. These results suggested different effect of PCN on the expression of P-gp protein in the intestine, brain and liver of mice.
P-糖蛋白（P-gp）由人类的MDR1（ABCB1）基因以及啮齿动物的Mdr1a和Mdr1b基因编码，是ATP结合盒转运体超家族的成员。由于P-gp在许多组织中组成性表达，并且在底物识别方面具有广泛的特异性，它可以通过减少异生物素的细胞内积累，在限制其吸收和分布方面发挥关键作用。P-gp的表达受多种核受体调控，如孕烷X受体（PXR）。尽管PXR配体诱导P-gp的特性是预测药物药代动力学的关键目标，但关于PXR配体在体内诱导P-gp的研究结果仍存在争议。在本研究中，我们检测了小鼠PXR配体孕烯醇酮16α-腈（PCN）对小鼠肠道、脑和肝脏中Mdr1a/1b mRNA和P-gp蛋白表达的影响。结果表明，PCN增加了肠道和脑中Mdr1a/1b mRNA和P-gp蛋白的表达。本研究首次提供了PCN可在大肠中诱导P-gp的证据。结果还表明，PCN可在皮层而非全脑中诱导P-gp蛋白。另一方面，PCN增加了肝脏中Mdr1a/1b mRNA的表达，尽管未观察到P-gp蛋白表达增加。这些结果表明PCN对小鼠肠道、脑和肝脏中P-gp蛋白的表达有不同影响。
