Pinocytosis mechanism

Duncan R, Pratten MK. Pinocytosis mechanism and regulation. In Dean RT, Jessup W, eds. Mononuclear Phagocytes Physiology and Pathology. Amsterdam Elsevier Biomedical Press, 1985 27-51. 

Materials may be absorbed by a variety of mechanisms. Depending on the nature of the material and the site of absorption, there may be passive diffusion, filtration processes, faciHtated diffusion, active transport and the formation of microvesicles for the cell membrane (pinocytosis) (61). EoUowing absorption, materials are transported in the circulation either free or bound to constituents such as plasma proteins or blood cells. The degree of binding of the absorbed material may influence the availabiHty of the material to tissue, or limit its elimination from the body (excretion). After passing from plasma to tissues, materials may have a variety of effects and fates, including no effect on the tissue, production of injury, biochemical conversion (metaboli2ed or biotransformed), or excretion (eg, from liver and kidney). 

Pinocytosis is a type of endocytosis that is responsible for the transport of large molecules such as proteins and colloids. Some cell types (e.g., endothelial cells) employ this transport mechanism extensively, but its importance in drug action is uncertain. 

Uptake of protein by hepatocytes can occur via one of two mechanisms (a) receptor-mediated en-docytosis or (b) non-selective pinocytosis, again with subsequent protein proteolysis. Similarly, a proportion of some proteins are likely degraded within the target tissue, as binding to their functional cell surface receptors triggers endocytotic internalization of the receptor ligand complex (Figure 4.7). 

Phagocytosis is an important mechanism for the organism to rid itself of bacteria and pathogenic material, as well as cell debris and remnants of apoptosis. However, it can also provide a route for the uptake of pollutant particulate material. It is seen to be especially important in the incorporation of airborne particulate material, which often has serious health consequences (see Section 6.4). In terrestrial invertebrates, food is obtained either from particulate matter in the soil or from molecules dissolved in interstitial water. Most of these organisms have extracellular digestion, with nutrients and foreign material being absorbed by one or more of the routes available for transport across membranes, such as diffusion, channels or pinocytosis. There have been few studies to establish which route is taken. 

The cellular uptake of AS-ODN is an energy-dependent process and takes place in a saturable and sequence-independent manner [120,121]. The exact mechanism of uptake remains controversial. From in vitro experiments, some authors have proposed that the uptake is endocytic and mediated by membrane receptor proteins. The receptor responsible for the cellular uptake of AS-ODNs was reported to consist of both a 30-kDa protein [122] and an 80-kDa membrane protein [121]. However, other workers have argued that AS-ODN binding to membrane proteins is relatively non-specific and is mostly charge associated, consistent with adsorptive endocytosis or fluid-phase pinocytosis [101]. As a result of these conflicting reports, it is unlikely that in vitro data can be safely extrapolated to what occurs in the intact organism. 

Two other types of specialized transport mechanisms, pinocytosis and phagocytosis, may also account for the transmembrane movement of some macromolecules (2). In these complex processes, the cell engulfs a droplet of extracellular fluid or a particle of solid material such as a bacterium. The droplet or particle is completely surrounded by a portion of the cell membrane and the resulting vesicle becomes detached and moves into the cell cytoplasm. 

The first and third routes are important in relation to pharmacokinetic mechanisms. The aqueous pores are too small in diameter for diffusion of most drugs and toxicant, although important for movement of water and small polar molecules (e.g., urea). Pinocytosis is important for some macromolecules (e.g., insulin crossing the blood-brain barrier). 

Substances ingested into cells by any of these three mechanisms either are stored in vesicles inside the cell or are degraded by intracellular enzymes, and only certain cells are capable of either process. The endothelial cells of capillaries are capable of pinocytosis. Neutrophils and macrophages (specific types of white blood cells) are capable of phagocytosis. Phagocytosis, endocytosis, and pinocytosis are slow and inefficient when compared to the other processes by which substances enter cells. 

Although relatively little is known regarding the mechanisms of membrane transport in cyclophyllidean larvae, it should be pointed out that pinocytosis has been shown, albeit indirectly, to take place in the bladder of T. crassiceps (188, 880, 881). 

Inulin synthesis in the tubers occurs in the vacuoles of storage parenchyma cells. Kaeser (1983) proposed a model for the transport of sucrose into the central vacuole that involves the formation of vesicles within the cytoplasm that contain sucrose and inulin synthesis enzymes. The vesicles transfer their contents into the vacuole via two possible mechanisms (1) the cytoplasmic vesicle fuses with the tonoplast and through pinocytosis releases its contents into the vacuole, or (2) vesicles originating from plasmalemma invaginations are tied off into the vacuole, resulting in... 

All the above transport mechanisms are only applicable to the absorption of small molecules, less than approximately 500 Da. There is evidence that larger molecules can be absorbed with low efficiency due to endocy tosis. Endocy tosis is defined as the internalization of plasma membrane with concomitant engulfment of extracellular material and extracellular fluid. The process can be divided into two types, pinocytosis and phagocytosis. 

Advantages of nanostructure-mediated drug delivery include the ability to deliver drug molecules directly into cells and the capacity to target tumors within healthy tissue [50]. The mechanisms of cellular uptake of external particulates include calthrin- and caveoli-mediated endocytosis, pinocytosis, and phagocytosis. However, phagocytosis may not play a role in the uptake of nanoscale particles because of the small size of such particles. 

Cell-surface receptors are involved in both phagocytosis and pinocytosis. At least four distinct mechanisms of pinocytosis have been characterized macropinocytosis, clathrin-mediated endocytosis, raft/caveolae-mediated endocytosis, and clathrin-and caveolae-independent endocytosis (1). Selected receptor-mediated aspects of these mechanisms are outlined below. 

Three processes are involved in transcellular transport across the intestinal epithelial cells simple passive trans-port, passive diffusion together with an efflux pump, and active transport and endocytosis. Simple passive transport is the diffusion of molecules across the membrane by thermodynamic driving forces and does not require direct expenditure of metabolic energy. In contrast, active transport is the movement of molecules across the mem-brane resulting directly from the expenditure of metabolic energy and transport against a concentration gradient. Endocytosis processes include three mechanisms fluid-phase endocytosis (pinocytosis), receptor-mediated endocytosis, and transcytosis (Fig. 6). Endocytosis processes are covered in detail in section Absorption of Polypeptides and Proteins, later. 

Iron-dextran complexes are soluble, nonionic and suitable for injection for the treatment of anaemia the complex is stable on storage in the pH range 4-11. More recently aminoethyldextran-methotrexate complexes have been prepared, the object being to influence uptake of the dmg selectively into tumour cells. Attachment of the dmg to the macromolecule allows selective uptake into malignant cells, as such cells are more active than normal cells in pinocytosis, the mechanism by which macromolecules are taken into many cells. 

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