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Membrane, basolateral localization in MDCK Some expression also found in mitochondria Plasma membrane Basolateral localization in MDCK Widely distributed (skeletal muscle, heart, pancreas, brain, kidney, placenta, prostate, small intestine, lung, thymus, etc.) ENT family (Continued) hENT3 Gene name adenosine, inosine, guanosine, thymidine, uridine Nucleobase adenine Nucleoside analogs cladribine, cordycepin, tubercidine, fludarabine, zebularine, AZT, ddC, ddl Biogenic amines serotonin,...

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...

Physiological Roles Of Nucleoside Transporters

Mammalian cells acquire purines and pyrimidines via two pathways, de novo biosynthesis and salvage pathways. The primary physiological function of ENTs and CNTs in mammalian cells is to facilitate cellular uptake of natural nucleosides, derived from the diet or produced by tissues such as the liver, for nucleotide synthesis in the salvage pathways.1'3-5 This function is particularly important for cells that lack de novo biosynthetic pathways, such as leukocytes, erythrocytes, bone marrow, and...

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...

Regulation Of Pglycoprotein Expression

Cells adapt to the presence of toxic xenobiotics in their environment by up-regulation of drug efflux pumps, such as Pgp, which provides them with a long-term survival advantage. The MDR1 gene is activated, and a stable MDR phenotype induced, after short-term exposure of cells to a variety of environmental insults. This response is of fundamental importance in the case of emergence of MDR in tumor cells exposed to anticancer drugs. MDR1 expression may be up-regulated by two mechanisms an...

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...

Bile Acid Transporters

Kullak-Ublick University Hospital Zurich, Division of Clinical Pharmacology and Toxicology, Zurich, Switzerland 9.1. Overview of the Enterohepatic Circulation of Bile Acids 9.2. Chief Transporters in the Enterohepatic Circulation of Bile Acids 9.3. Enterohepatic Bile Acid Transporters in Liver Disease 9.4. Control of Bile Acid Transport and Metabolism 9.5. Nuclear Receptors as Transcriptional Regulators of Bile Acid Homeostasis 9.5.1. FXR The Master Regulator of...

Molecular And Structural Characteristics

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....

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...

Mechanism Of Action Of Pglycoprotein

Much remains to be understood about how Pgp transports (or flips) drugs and how coupled ATP hydrolysis powers transport. Transport can be broken down into several steps entry of substrates into the binding pocket within the cytoplasmic leaflet, conformational changes in Pgp driven by ATP binding hydrolysis, and release of drug to either the outer leaflet or the extracellular aqueous phase. Many different experimental approaches, including various biochemical and spectroscopic techniques, have...

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...

Pglycoprotein As A Hydrophobic Vacuum Cleaner Or Drug Flippase

Pgp substrates are typically hydrophobic and are expected to partition into the membrane. The substrate-binding sites of Pgp appear to be contained within its TM regions, and drugs gain access to these sites after partitioning into the lipid bilayer (Figure 10.2a).34 The idea that the transporter acts as a vacuum cleaner for hydrophobic molecules present in the membrane was first suggested by Higgins and Gottesman149 and has found widespread acceptance. In intact cells, Pgp substrates entering...

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...

Substrate Specificity Of Pglycoprotein And Nature Of The Drugbinding Site

Pgp displays a remarkable ability to interact with, and transport, a large variety of compounds, ranging from chemotherapeutic drugs to peptides. Most preferred substrates are amphipathic and relatively hydrophobic, although some are not colchicine, for example, is quite water soluble . Pgp substrates range in size from large complex molecules such as paclitaxel and vinblastine to smaller drugs such as daunorubicin and doxorubicin. Pgp also interacts with linear and cyclic peptides and...