MONOCARBOXYLATE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 156

7.3.3. Regulation of Transporter Activity
Studies regarding the modulation of transport kinetics of MCTs within the plasma
membrane provide important evidence regarding the regulation of MCT1 activity. Ac-
tivation of cAMP-dependent pathways in rat brain endothelial cells (RBE4) caused
a 40 to 60% reduction in lactate transport. 49 This reduction in lactate transport was
attributed to loss of transporter function in the membrane by either internalization of
the transporter or inactivation of the transporter by protein modification. These re-
sults suggest that phosphorylation of MCT1, CD147, or a closely associated protein
is likely to be involved in the cAMP response. 49 Indeed, MCT1 contains potential
phosphorylation sites, but to date there is no conclusive evidence for direct phospho-
rylation. Aside from CD147, carbonic anhydrase isoform II (CAII) is the only other
protein that has been shown to interact directly with MCT1. Addition of CAII to
Xenopus oocytes expressing MCT1 increased transporter activity three- to fivefold. 50
Interestingly, it was shown that the C-terminus of MCT1 was not important for bind-
ing with CAII to occur, but it was essential for modulation of transporter activity. In
addition to direct protein-protein interactions with MCTs, it is probable that protein
interactions with CD147 may also modulate transporter function. There is evidence for
a “CD147-CD98hc supercomplex” containing several transporters and cell surface
glycoproteins that are tightly associated with each other in the plasma membrane. 51
This complex includes CD147, MCT1, CD98hc, the amino acid transporters LAT1
and ASCT2, and the glycoprotein EpCAM. This complex is coordinately expressed
at the transcriptional level in tumor cells, and due to their close association in the
membrane, it is likely that functional modulation of one of these proteins could alter
the transport activity of other proteins in the complex. 51
7.4. CLINICAL APPLICATIONS AND IMPLICATIONS
FOR DRUG DELIVERY
7.4.1. Substrates
Natural Substrates MCT1-4 and SMCTs 1 and 2 are known to transport a variety
of physiologically relevant substrates, including lactate, pyruvate, and butyrate. Each
of these monocarboxylate transporters exhibits unique kinetic properties. The affinity
for monocarboxylates by MCT1 and MCT4 is very similar across species, while the
affinity for monocarboxylates by MCT2 varies greatly between rodents and humans
(Table 7. 1). Rat MCT2 was characterized as the high-affinity pyruvate carrier because
of its low K m value, 0.08 mM. 52 MCT2 also has a relatively high affinity for lactate,
but major differences exist between human, rat, and hamster transporters. While
rat MCT2 has a K m of 0.74 mM for lactate, human and hamster MCT2 have a
roughly 10-fold higher K m of 6.5 and 8.7 mM, respectively. 52 , 53 The differences in
transporter kinetics between species can make it difficult to form conclusions about
the physiological role of MCTs in rodents compared to that of humans. Cross-species
studies of MCT kinetics are absent for MCT3, SMCT1, and SMCT2. Therefore,
species comparisons are not possible.