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...

Control Of Bile Acid Transport And Metabolism

In addition to their role as physiological detergents, bile acids possess crucial regulatory properties which allow them to control their own transport and metabolism within the enterohepatic circulation through multiple feedforward and feedback mechanisms. Hepatocytes and enterocytes possess numerous signaling pathways that are activated or modulated by bile acids, and ultimately serve to maintain intracellular concentrations of potentially toxic bile acids at a constant level. An important...

Pglycoprotein Gene Polymorphisms And Their Implications In Drug Therapy And Disease

Changes in Pgp expression and function would be expected to alter the absorption, plasma concentration, tissue distribution, and excretion of its drug substrates. Pgp polymorphisms might thus influence the outcome of drug treatment. Variations in the nucleotide sequence of the Pgp gene can affect both expression and function of the transporter. The first polymorphism to be reported in the human MDR1 gene was the G2677T variant, which results in the amino acid change A893S. Since then, about 30...

Mct And Smct Transporter Expression

Tissue Distribution and Subcellular Localization of MCTs In humans, MCT1 is expressed nearly ubiquitously in almost every tissue in the body and serves as the carrier for lactate flux across the plasma membrane of most cells. In the case of polarized cells such as the choroid plexus and intestinal epithelium, MCT1 is coexpressed with another MCT, but trafficking mechanisms segregate the MCTs to opposite sides of the cell (apical and basolateral). This asymmetric distribution may...

Clinical Applications And Implications For Drug Delivery

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...

Clinical Significance Of Nucleoside Transporters

The clinical significance of nucleoside transporters can be viewed in several aspects. First, a number of anticancer nucleoside analogs rely on nucleoside transporters to enter cells to reach their cellular targets. As such, the expression level of nucleo-side transporters on the target cells is an important determinant for intracellular drug bioavailability, and consequently, responsiveness to therapy. Second, if a drug is a substrate for nucleoside transporters, the distribution of these...

Mct6

A N.A., not available. bKm value (mM). a N.A., not available. bKm value (mM). are the flavonoids phloretin and quercetin. The hystidyl-selective reagent diethyl pyrocarbonate (DEPC) is the only compound known to inhibit MCT3. Treatment with hydroxylamine did not reverse the inhibition therefore, the authors concluded that DEPC inhibition was caused by modification of lysine or arginine residues.54 Interestingly, MCT3 was found to be insensitive to the classical MCT inhibitors, such as...

Enterohepatic Bile Acid Transporters In Liver Disease

Chronic cholestatic liver diseases such as primary biliary cirrhosis and primary sclerosing cholangitis are characterized by an impairment of bile formation or of bile flow. Altered expression or function of bile acid transporters can be either a cause or a consequence of cholestasis, thus leading to hepatotoxicity due to accumulation of bile acids and cholephilic toxins in hepatocytes. Among the genes encoding transporters that are involved in bile acid transport or bile formation are several...

Molecular And Structural Characteristics

Adrenal Vasculature

Members of the POT superfamily share a common topological map consisting of 12 putative a-helical transmembrane domains with intracellularly localized N- and C-termini.13'22'23 Two characteristic protein signatures of the POT family members have been identified, known as the PTR2 family signatures (1) and (2) A FIGURE 6.1. Potential parallel or competing pathways available for oligopeptide and peptide-based drug permeation and their potential intracellular fates across cellular barriers....

References

P-glycoprotein structure and evolutionary homologies. Cytotechnology 12 1-32. 2. Lincke CR, Broeks A, The I, Plasterk RH, Borst P. 1993. The expression of two P-glycoprotein pgp genes in transgenic Caenorhabditis elegans is confined to intestinal cells. EMBO J 12 1615-1620. 3. Ruetz S, Gros P. 1994. Phosphatidylcholine translocase a physiological role for themdr2 gene. Cell 77 1071-1081. 4. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. 1987. Cellular...

Oct1 Knockout Mice

Oct 1 - - knockout mice were shown to be viable and fertile, showing no obvious physiological abnormalities compared with their wild-type littermates, suggesting that Octl is dispensible for normal physiology.64 However, significant differences were observed in the disposition of organic cations in these mice. For example, when administered the typical organic cation, TEA, Octl - - mice showed significantly approximately fivefold reduced uptake of TEA into the liver, the site of highest OCT1...