Abstract
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 F2α (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.
Highlights
Monocarboxylate transporters (MCTs) are solute carrier proteins of the SLC16A family, which is comprised of fourteen isoforms [1]
We evaluated the transporter kinetic parameters (Kt, Jmax) using both murine Mct6- and human monocarboxylate transporter 6 (MCT6)-transfected X. laevis oocytes and investigated whether there were any other significant interactions with other PGs
Mct6 Protein Expression Is Stably Expressed in Transfected X. laevis Oocytes
Summary
Monocarboxylate transporters (MCTs) are solute carrier proteins of the SLC16A family, which is comprised of fourteen isoforms [1]. While the well-characterized MCTs 1–4 have been predominantly studied for their roles as lactate-proton symporters and drug targets due to their upregulation in a wide variety of cancers [2,3,4], other isoforms have become more recently characterized within the past decade. Monocarboxylate transporter 6 (MCT6; SLC16A5), was found to be implicated in the transport of a wide variety of drugs (i.e., bumetanide, nateglinide, probenecid, and prostaglandin F2α (PGF2α)), as well as dependent on pH and membrane potential [5,6]. Our lab recently characterized MCT6 s interactions with a series of commonly ingested aglycone flavonoids, suggesting its role in their potential transport and/or drug–diet interactions [7].
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