Monocarboxylate Transporter 6-Mediated Interactions with Prostaglandin F-2 alpha: In Vitro and In Vivo Evidence Utilizing a Knockout Mouse Model

Monocarboxylate transporter 6 (MCT6; SLC16A5) 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-2 alpha (PGF2 alpha)). The objective of our research was to characterize the MCT6-specific transporter kinetic parameters and MCT6-specific in vitro and in vivo interactions of PGF2 alpha. Murine and human MCT6-mediated transport of PGF2 alpha was assessed in MCT6-transfected oocytes. Additionally, endogenous PGF2 alpha and a primary PGF2 alpha 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 mu M respectively, for mouse and human, at pH 7.4. In vivo, plasma PGF2 alpha concentrations in Mct6(-/-) mice were significantly decreased, compared to Mct6(+/+) mice (3.3-fold). Mct6(-/-) mice demonstrated a significant increase in urinary PGF2 alpha concentrations (1.7-fold). A similar trend was observed with plasma PGFM concentrations. However, overnight fasting resulted in significantly increased plasma PGF2 alpha concentrations, suggesting a diet-dependent role of Mct6 regulation on the homeostasis of systemic PGF2 alpha. Overall, these results are the first to suggest the potential regulatory role of MCT6 in PGF2 alpha homeostasis, and potentially other PGs, in distribution and metabolism.