The Cell - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 35

Monocarboxylate Transporters
The monocarboxylate transporters (MCTs) belong to the SLC16 gene family and
comprise 1 base sequence-related isoforms. The transporters exhibit wide tissue
expression. In humans, MCT1 are involved with lactate flux and are expressed in
almost every tissue. In contrast, sodium-dependent MCTs expression is specific to
certain tissues and displays high substrate specificity. MCT1, MCT2, MCT, and
MCT have been shown to transport monocarboxylates such as lactate, pyruvate,
butyrate, and the ketone bodies—hydroxybutyrate and acetoacetate. MCT facili-
tates flux of thyroid hormones T and T. TAT1 is a transporter of neutral amino
acids. These transporters gain importance because they are expressed in the gut and
are involved in improved uptake and bioavailability of drugs absorbed from the gas-
trointestinal tract. Their presence in various barriers like blood-brain barrier, blood-
testis barrier, and blood-placental barrier opens up a vista for the delivery of drugs
that do not cross the barrier as such [11,11] .
Nucleoside Transporters: Centrative Nucleoside Transporters
and Equilibrative Nucleoside Transporters
Endogenous nucleosides are key precursors of nucleic acid synthesis. Nucleosides
exhibit low membrane permeability because of their hydrophilic character. To allow
the movement of these nucleosides, two types of transporters come into play—
concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transport-
ers (ENTs). They help to regulate adenosine signaling at the receptor sites.
Concentrative Nucleoside Transporters
Mammalian CNTs comprise 1 transmembrane passes and are Na  -coupled transporters
using the intracellularly directed Na  gradient to transport substrates into cells. CNT1
and CNT2 are sodium specific, but CNT can utilize both H  and Li  for coupling.
CNT1, CNT2, and CNT exhibit substrate specificity for nucleosides and their analogs.
Equilibrative Nucleoside Transporters
ENT1 and ENT2 are transporters that utilize the concentration gradient as the driv-
ing force for the movement of nucleosides. The intracellular breakdown of nucleo-
sides promotes influx of the nucleosides; higher intracellular concentrations of free
nucleoside promote the efflux. ENT is found to be associated with lysosomes with
maximal activity near pH 5.0, signifying either a proton-nucleoside cotransport
mechanism or specificity of ENT operation at lysosomal pH.
These transport mechanisms are under strict transcriptional and post-transcriptional
regulation. Various hormones and other chemicals may exert control over them, medi-
ating through cellular signaling mechanisms. The uptake of nucleosides is to fulfill the
requirement of nucleosides in tissues lacking de novo biosynthetic pathways. Their
therapeutic importance is because several anticancer drugs are nucleoside analogs and