Department of Pharmaceutics and Medicinal Chemistry, Thomas J Long School of Pharmacy and Health Sciences, University of the Pacific, Stockton, CA, USA.
J Pharm Pharm Sci. 2019;22(1):376-387. doi: 10.18433/jpps30537.
Monocarboxylate transporters (MCT) are proton-coupled integral membrane proteins that control the influx and efflux of endogenous monocarboxylates such as lactate, acetate and pyruvate. They also transport and mediate the clearance of drugs such as valproate and gamma-hydroxybutyrate. CD147 functions as ancillary protein that chaperones MCT1 and MCT4 to the cell membrane. There is limited data on the maturation of MCT and CD147 expression in tissues related to drug distribution and clearance. The objective of the present study was to quantify hepatic MCT1, MCT4, and CD147 mRNA, whole cell and membrane protein expression from birth to sexual maturity.
Liver tissues were collected from male and female Sprague Dawley rats at postnatal days (PND) 1, 3, 5, 7, 10, 14, 18, 21, 28, 35, and 42 (n = 3 - 5). Hepatic mRNA, total and membrane protein expression of MCT1, MCT4, and CD147 was evaluated via qPCR and western blot.
MCT1 mRNA and protein demonstrated nonlinear maturation patterns. MCT1 and CD147 membrane protein exhibited low expression at birth, with expression increasing three-fold by PND14, followed by a decline in expression at sexual maturity. MCT4 mRNA had highest expression at PND 1, with decreasing expression towards sexual maturity. In contrast, MCT4 membrane protein exhibited minimal expression from birth through weaning before a 10-fold surge at PND35, whereupon there was a sharp decline in expression at PND42. There was a significant positive correlation between MCT1 and CD147 whole cell and membrane expression, while MCT4 membrane expression demonstrated a weak negative correlation with CD147.
Our study elucidates the transcriptional and translational maturation patterns of MCT1, MCT4 and CD147 expression, with isoform- dependent differences in the liver. Changes in transporter expression during development may greatly influence drug distribution and clearance in pediatric populations.
单羧酸转运蛋白（MCT）是质子偶联的完整膜蛋白，可控制内源性单羧酸如乳酸盐、醋酸盐和丙酮酸的流入和流出。它们还能转运和介导丙戊酸和γ-羟基丁酸等药物的清除。CD147 作为辅助蛋白，可将 MCT1 和 MCT4 易位到细胞膜。关于与药物分布和清除相关的组织中 MCT 和 CD147 表达的成熟，数据有限。本研究的目的是从出生到性成熟定量检测肝 MCT1、MCT4 和 CD147mRNA、全细胞和膜蛋白的表达。
从出生后第 1、3、5、7、10、14、18、21、28、35 和 42 天（n = 3-5）的雄性和雌性 Sprague Dawley 大鼠的肝组织中收集肝组织。通过 qPCR 和 Western blot 评估 MCT1、MCT4 和 CD147 的肝 mRNA、总蛋白和膜蛋白表达。
MCT1mRNA 和蛋白表现出非线性成熟模式。MCT1 和 CD147 膜蛋白在出生时表达水平较低，PND14 时表达增加三倍，然后在性成熟时表达下降。MCT4mRNA 在 PND1 时表达最高，性成熟时表达逐渐下降。相反，MCT4 膜蛋白从出生到断奶期间表达水平较低，然后在 PND35 时急剧增加 10 倍，随后在 PND42 时表达急剧下降。MCT1 和 CD147 全细胞和膜表达之间存在显著正相关，而 MCT4 膜表达与 CD147 之间存在弱负相关。
本研究阐明了 MCT1、MCT4 和 CD147 表达的转录和翻译成熟模式，肝内各同工型表达存在差异。发育过程中转运体表达的变化可能极大地影响儿科人群的药物分布和清除。
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