MAMMALIAN OLIGOPEPTIDE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 119

that unlike PepT1 and PepT2, the dipeptide glycylsarcosine (Gly-Sar) is not a sub-
strate for hPHT1. Taken together, these data are indicative of both the overlapping
specificity, in terms of valacyclovir, as well as the functionally distinct specificity of
these transporters. Nevertheless, there is still much to elucidate concerning the affinity
and substrate specificity of these peptide transporters.

6.4. REGULATION

Oligopeptide transporter research has predominantly been focused on delineating the
functional characteristics of each transporter isoform. Although considerable research
is still needed in this area, particularly with undercharacterized isoforms such as
PHT1, our focus must now shift toward developing a greater appreciation of their
molecular characteristics. In particular, understanding the underlying mechanisms of
oligopeptide transporter regulation by various physiological and exogenous stimuli is
integral to comprehending their role as mediators of nutritional and pharmacological
substrate absorption. Clearly, alterations in oligopeptide transporter expression could
potentially result in significant changes that affect the PK/PD phenomena of peptide-
based drug substrates. PepT1 has been the most widely studied isoform and has been
shown to be regulated via a number of different mechanisms under varying conditions.
Studies on the regulation of other POT members (PepT2, PHT1, and PHT2) and PT1
are scarce at best. Factors such as diet, development phase, hormonal influences,
pathological conditions (diabetes, intestinal disorders), and various pharmacological
agents have all been demonstrated to regulate PepT1 expression and are also discussed
in various reviews. 13 , 118 - 121 Some of these factors are discussed in greater detail below.
However, it is evident that additional studies are required to better elucidate the pre-
and posttranscriptional changes that the oligopeptide transporters undergo following
various stimuli.

6.4.1. Dietary Regulation

Changes in PepT1 expression due to dietary influences are relatively well established.
Erickson et al. demonstrated that a high-casein diet induced a parallel 1.5- to twofold
increase in both the PepT1 and rat PT1 mRNA expressions in the middle and dis-
tal regions of the rat small intestine when contrasted with low-casein diet control. 69
No apparent change was observed in the proximal region of the rat small intestine,
leading to the suggestion that the middle and distal regions may be the most sensitive
to dietary fluctuations. Shiraga et al. further investigated the molecular mechanisms
of PepT1 expressional changes in the Caco-2 cell model. 122 Incubation of cells with
dipeptides (Gly-Sar, Gly-Phe, Phe-Val, Lys-Phe, and Asp-Lys) and individual amino
acids (phenylalanine, arginine, and lysine) resulted in activation of the PepT-1 gene
promoter. Subsequent induction of the PepT1 mRNA was caused by transcriptional
activation through an AP-1 binding site and an amino acid-response element present
at the − 295 and − 277 nucleotides relative to the transcription start site in this region.