Jones Robert S, Parker Mark D, Morris Marilyn E
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA.
Current address is Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA 94080, USA.
Pharmaceutics. 2020 Feb 26;12(3):201. doi: 10.3390/pharmaceutics12030201.
Monocarboxylate transporter 6 (MCT6; ) is a recently studied drug transporter that currently has no annotated endogenous function. Currently, only a handful of compounds have been characterized as substrates for MCT6 (e.g., bumetanide, nateglinide, probenecid, and prostaglandin F (PGF2α)). The objective of our research was to characterize the MCT6-specific transporter kinetic parameters and MCT6-specific in vitro and in vivo interactions of PGF2α. Murine and human MCT6-mediated transport of PGF2α was assessed in MCT6-transfected oocytes. Additionally, endogenous PGF2α and a primary PGF2α metabolite (PGFM) were measured in plasma and urine in Mct6 knockout (Mct6) and wild-type (Mct6) mice. Results demonstrated that the affinity was approximately 40.1 and 246 µM respectively, for mouse and human, at pH 7.4. In vivo, plasma PGF2α concentrations in Mct6 mice were significantly decreased, compared to Mct6 mice (3.3-fold). Mct6 mice demonstrated a significant increase in urinary PGF2α concentrations (1.7-fold). A similar trend was observed with plasma PGFM concentrations. However, overnight fasting resulted in significantly increased plasma PGF2α concentrations, suggesting a diet-dependent role of Mct6 regulation on the homeostasis of systemic PGF2α. Overall, these results are the first to suggest the potential regulatory role of MCT6 in PGF2α homeostasis, and potentially other PGs, in distribution and metabolism.
单羧酸转运蛋白6（MCT6； ）是一种最近被研究的药物转运蛋白，目前尚无注释的内源性功能。目前，只有少数化合物被鉴定为MCT6的底物（例如，布美他尼、那格列奈、丙磺舒和前列腺素F（PGF2α））。我们研究的目的是确定PGF2α的MCT6特异性转运体动力学参数以及MCT6特异性的体外和体内相互作用。在转染了MCT6的卵母细胞中评估了小鼠和人MCT6介导的PGF2α转运。此外，在Mct6基因敲除（Mct6）和野生型（Mct6）小鼠的血浆和尿液中测量了内源性PGF2α和主要的PGF2α代谢物（PGFM）。结果表明，在pH 7.4时，小鼠和人的亲和力分别约为40.1和246 μM。在体内，与Mct6小鼠相比，Mct6小鼠的血浆PGF2α浓度显著降低（3.3倍）。Mct6小鼠的尿液PGF2α浓度显著升高（1.7倍）。血浆PGFM浓度也观察到类似趋势。然而，过夜禁食导致血浆PGF2α浓度显著升高，表明Mct6调节对全身PGF2α稳态具有饮食依赖性作用。总体而言，这些结果首次表明MCT6在PGF2α稳态以及可能在其他前列腺素的分布和代谢中具有潜在的调节作用。
