Effect of Pregnenolone 16α-Carbonitrile on the Expression of P-Glycoprotein in the Intestine, Brain and Liver of Mice

• Published in: Biological & pharmaceutical bulletin Vol. 41; no. 6; pp. 972 - 977
• Main Authors: Yamasaki, Yuki, Kobayashi, Kaoru, Chiba, Kan
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01.06.2018
• Subjects: brain; induction; intestine; liver; P-glycoprotein; pregnane X receptor; P-glycoprotein; pregnane X receptor; induction; intestine; brain; liver
• ISSN: 0918-6158; 1347-5215
• 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.