Epithelial membrane

Figure 41-14. The transcellular movement of glucose in an intestinal cell. Glucose follows Na+ across the luminal epithelial membrane. The Na+ gradient that drives this symport is established by Na+ -K+ exchange, which occurs at the basal membrane facing the extra-ceiiuiarfiuid compartment. Glucose at high concentration within the ceii moves "downhill" into the extracel-iuiarfiuid by fadiitated diffusion (a uniport mechanism).

The hypothesis of the participation of those cholesterol transporters (NPCILI and ABCAl) in the carotenoid transport remains to be confirmed, especially at the in vivo human scale. If the mechanism by which carotenoids are transported through the intestinal epithelial membrane seems better understood, the mechanism of intracellular carotenoid transport is yet to be elucidated. The fatty acid binding protein (FABP) responsible for the intracellular transport of fatty acids was proposed earlier as a potential transporter for carotenoids. FABP would transport carotenoids from the epithelial cell membrane to the intracellular organelles such as the Golgi apparatus where CMs are formed and assembled, but no data have illustrated this hypothesis yet. 

Primary and secondary products, and end-products of lipid peroxidation have all been shown to accumulate in senile cataracts (Babizhayev, 1989b Simonelli et al., 1989). Accumulation of these compounds in the lenticular epithelial membranes is a possible cause of damage preceding cataract formation. In senile cataracts there is also extensive oxidation of protein methionine and cysteine in both the membrane and cytosol components (Garner and Spector, 1980), while in aged normal lenses a lesser extent of oxidation was confined to the membrane. The authors therefore suggested that oxidation of membrane components was a precataract state. 

Okabe H., Okubo T. and Ochi Y. (1996). Expression of an epithelial membrane glycoprotein by neurons arising from the human olfactory plate through development. 

Cereijido M, CA Robbins, DD Sabatini. (1987). Polarized epithelial membranes produced in vitro. In JF Hoffman, ed. Membrane Transport Processes. New York Raven Press, pp 443-456. 

SD Klyce. (1973). Relationship of epithelial membrane potentials to corneal potential. Exp Eye Res 15 567-575. 

For the evaluation of a possible relationship between the molecular structure of a potential candidate and its transport abilities to cross the epithelial membrane of the gut, the mechanism or route of transport must be known [1,4]. This is due to the structural requirements for the transcellular route being different from the paracellular route. During the lead optimization phase - when many mechanistically based studies are performed - the cell culture-based models can also be used with great confidence. 

Fig. 7.1. The intestinal permeability of drugs in vivo is the total transport parameter that may be affected by several parallel transport mechanisms in both absorptive and secretory directions. Some of the most important transport proteins that may be involved in the intestinal transport of drugs and their metabolites across intestinal epithelial membrane barriers in humans are displayed.

Arsenates rapidly penetrated mucosal and serosal surfaces of epithelial membranes. 

Substances can be transported across epithelial membranes by simple passive diffusion, carrier-mediated diffusion, and active transport, in addition to other specialized mechanisms, including endocytosis. 

The proteins coded for by these genes in vertebrates are G protein-coupled receptors (GPCRs). They are linear chains of amino acids that span the olfactory epithelial membrane in which they are embedded seven times. They act by transmitting the odorant signal to specific olfactory G proteins, Goif. 

Epithelial Membrane Antigen (EMA)/Milk Fat Globule Protein (MEG)... 

Pinkus, G. S. and Kurtin, P. J. (1985) Epithelial membrane antigen—A diagnostic discriminant in surgical pathology immunohistochemical profile in epithelial, mesenchymal, and hematopoietic neoplasms using paraffin sections and monoclonal antibodies. Hum. Pathol. 16, 929-940. 

Figure 2.2 Secretion of bile acids and biliary components. Bile acids (BA) cross the hepatocyte bound to 3a-hydroxysteroid dehydrogenase and are exported into the canaliculus by the bile-salt export protein (BSEP). Phosphatidylcholine (PC) from the inner leaflet of the apical membrane is flipped to the outer layer and interacts with bile acids secreted by BSEP. BA, PC, together with cholesterol from the membrane form mixed micelles that are not toxic to epithelial membranes of the biliary tree. Aquaporins (AQP) secrete water into bile.

An alternative method which could be used to establish the fraction of protein that actually reaches the alveoli is the so-called co-aerosohzation. If a protein is aerosolized from a solution that also contains another low molecular weight substance (deposition marker), it can be assumed that the fractions of protein and deposition marker reaching the alveoli will be the same. The deposition marker should be a substance with a known alveolar epithelial membrane passage (e.g. tobramycin or a decapeptide) which does not undergo absorption after oral administration. The fraction of the deposition marker that is deposited in the alveoli can be established from plasma (and urine) measurements of the deposition marker. The maximum fraction of protein that can pass the alveolar membrane whl then be known. The ratio between the deposited fraction and the fraction that has been absorbed into the systemic circulation (as can be estabhshed form plasma or urine analysis) will provide an estimation of the protein passage across the alveolar membrane. 

Epithelial Membrane Transport An introduction, 191, 1 determination of paracellular shunt conductance in epithelia, 191, 4. 

Figure 6.1 Schematic representation of the intestinal membrane structure. The singlet arrow in the figure illustrate the permeation pathways, (a) Villous structure of intestine. Unstirred water layer is adjacentto villi, (b) Permeation pathways of compounds across the intestinal epithelial membrane. (Adapted from [14] and modified from Bentham Science Publishers, Ltd.)...

The presence of folds and villi structures on the surface area is not taken into account for the in vivo effective intestinal membrane permeability (Pefr when extrapolated from a perfusion experiment, a smooth tube is usually assumed). In humans, the fold expansion (FE) of the surface area is about threefold, and villi expansion (VE) is about 10-fold [7]. In the case of high epithelial membrane permeability (Pep) absorption occurs at the top of the villi before diffusing down the villi channels, whereas low Pep compound may diffuse down the villi channels to the crypts (Figure 6.1). Therefore, accessibility (Acc) to the surface depends on Pep and diffusion coefficient [7, 8]. The effective membrane permeability can be expressed as ... 

Figure 6.2 Relationship between the epithelial membrane permeability and the effective intestinal membrane permeability in humans. Based on [6] an recalculated including fold expansion and UWL effect.

The intestinal wall is covered by a mucus layer. This mucus layer prevents direct contact of the lumenal contents with the epithelial membrane. Mucus can be attached onto the lipid membrane by the aid of agar and hydrophilic filter scaffold [64, 65]. This allows the simultaneous assessment of dissolution and permeation. Food effects were adequately predicted using this method. Lofts son et al. used a cellophane membrane as a surrogate for the mucus layer [66]. 

Aqueous diffusion occurs within the larger aqueous compartments of the body (interstitial space, cytosol, etc) and across epithelial membrane tight junctions and the endothelial lining of blood vessels through aqueous pores that—in some tissues—permit the passage of molecules as large as MW 20,000-30,000. See Figure 1-5A. 

Nicotine (log D = 0.45 at pH 7.4) very rapidly enters the CNS, but this is believed to involve facilitated transport (Spector and Goldberg, 1982). Facilitated or active mechanisms are often suspected when transport seems not to follow the pH partition concepts, and can be proved by showing an energy requirement to exist, or that the carrier can become saturated, or that transport is competitively inhibited by a substance of similar structure. Special mechanisms exist for the transport of essential nutrients into the body, e.g. through the gastro-epithelial membrane, or for the selective disposal of excess electrolytes and polar metabolites from the body, e.g. 

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