MONOCARBOXYLATE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 159

it does not contain reactive isothiocyanate groups and may be less toxic to cells dur-
ing long-term exposure. 87 A recent report suggests that bumetanide is transported by
MCT6. 6 However, because the physiological substrate for MCT6 is not known, it is
conjecture whether this drug inhibits the normal function of this transporter.
In addition to the MCT inhibitors that interact directly with the transporter it-
self, pCMBS irreversibly inhibits MCT transport through modification of CD147.
Inhibition of monocarboxylate transport by pCMBS results from the modification of
disulfide bridges within the IgG-like domains of CD147, thus disrupting the interac-
tion between the transporter and CD147 at the cell surface. 44 DEPC may also inhibit
transport by MCTs through an indirect mechanism. 54 Whether any of the compounds
within these four inhibitor categories act on SMCTs is unknown, but the identification
of SMCT-specific inhibitors will surely provide valuable information as to the overall
contribution of these transporters to monocarboxylate transport.
Of all the inhibitors described previously, only the PPDs appear to be MCT specific;
the remainder are less specific and may inhibit other transporter families. 83 The PPDs
are known to be highly specific for MCT1 and to a lesser extent for MCT2. Although
most of these inhibitors are not isoform specific, their affinities for the various MCT
isoforms vary significantly (Table 7.2). Most of the MCT inhibitors identified are com-
petitive, and therefore the high-affinity MCT2 is most sensitive, while the low-affinity
MCT4 is least sensitive to the classical MCT inhibitors. The most potent inhibitors

TABLE 7.2. Inhibitors of MCTs

Transporter Source Expression System Substrate IC 50 ( M) a

Rat 53

α

MCT1 Oocyte -CHC 425

Phloretin 28

Benzobromaron 22

Quercetin 14

DIDS 1100 22

DBDS N.A.

pCMBS N.A.

MCT2 Rat 53 Oocyte α -CHC 24

Phloretin 14

Benzobromaron 9.0

Quercetin 5.0

DIDS N.A.

DBDS N.A.

Rat 54 MCT3 Yeast DEPC 400

Rat 22 MCT4 Oocyte α -CHC 350

Phloretin 40

DIDS 500

Human 6 0.08 b MCT6 Oocyte Bumetanide

a N.A., not available.
b K m value (mM).