Epithelial absorptive cells

The human Bu-binder intrinsic factor is a glycoprotein of ca. 44kDa, with a high binding constant (in 1 1 complexes) for vitamin B12 (1) and other cobalamins. The intrinsic factor is secreted by cells of the gastric mucosa and specifically binds cobalamins and carries them to the ileum. There the ileum receptor protein accepts the corrinoid from the intrinsic factor complex and transports it further across the intestinal epithelial absorptive cell. The cobalamins then appear to be bound to transcobalamin II and transported in the blood in this way to membrane-bound transcobalamin/corrin receptor proteins of the specific cells. ... 

Fig. 3 Schematic depiction of intestinal epithelial absorptive cells. (Illustration by Leigh A. Rondano, Boehringer Ingelheim Pharmaceuticals, Inc.)...

The digestion products of triacylglycerols retain their association with bile acids and lipase and combine with other lipids to form small aggregates called micelles that are suspended within the ingesta. The micelles bump into the brush border of the enterocytes (columnar epithelial absorptive cells of the intestinal wall) into which the digestion products pass by diffusion. 

Gres, M. C. et al. (1998). Correlation between oral drug absorption in humans, and apparent drug permeability in TC-7 cells, a human epithelial intestinal cell line Comparison with the parental Caco-2 cell line. Pharm. Res. 15(5) 726-733. 

A deep layer rich in mucus and the origin of which is to be found in the conjunctival calyciform cells. This mucus is in relation with the apical epithelial cells via the glycocalyx. This interface between the lacrymal secretion and the epithelium influences the quality of the corneal surface. Indeed, the stability of the lacrymal secretion and the epithelial absorption of its metabolites both depend on the mucin and the apical expansions of the epithelial cells [2]. 

It is well established today that drug absorption through the alimentary canal walls is a complex event, which involves, in many cases, parallel or sequent microprocesses at the apical membrane of the absorptive cell (enterocyte) or between them (paracellular absorption). In addition to the various types of diffusion processes across the enterocyte membrane, numerous specific proteins—transporters and efflux pumps—are involved in the intricate drug absorption process. In the following sections the various epithelial tissues of the different organs of the GI tract will be looked at briefly. A review of major drug absorption mechanisms across epithelial cells, as they are customary today will follow. 

As mentioned above, the villi of the small intestine (Figure 1.2) house a dynamic, self-renewing population of the epithelial cells that includes absorptive cells (enterocytes), secretory cells, and endocrine cells. The thin lining (height 25 p,M height of the microvilli is 1.5 pM) of the columnar enterocytes is the only barrier between the intestinal lumen and the muscularis mucosa, which represents, in this context, the entire body interior. The entire epithelial lining of the intestine replaces itself every 3-5 d [128], It is the enterocyte and its neighboring cells where absorption processes occur and it will therefore be the focus of the mechanistic discussions below. 

The mucus layer also bathes the cilia of ciliated epithelial surface cells and provides a stimulus for ciliary motility (i.e., ciliary beating). The cilia consist of microtubules with a 9 + 2 configuration (nine pairs of peripheral microtubules and two central microtubules) that beat rhythmically to rapidly move mucus from the anterior to the posterior portion of the nasal cavity. To successfully cross the nasal permeability barrier, peptide drugs must penetrate the mucus layer and cross the epithelial cell layer, and do so in a limited time, because mucociliary clearance will limit the time of exposure of the peptide to the absorptive surface [19-21,27-29], Typically, drugs or inspired particles that are delivered nasally are removed via mucociliary clearance, with a clearance time of approximately 15 min in humans however, this transit time can vary from person to person and can be impacted by the addition of mucoadhesive agents to the formulation [30-37],... 

Tub Buuiuuru absorptive pathways fur the absorption of food, most drugs, and, to a minor extent, proteins and peptides have been described above. Membranous epithelial cells are much less numerous than absorptive cells, but they are of special interest since they have structural properties that could be favorable for protein absorption. 

Q13 Osteomalacia and osteoporosis are complications of celiac disease. The mineral in bone is mainly calcium phosphate a supply of calcium is therefore needed for bone growth and replacement. Calcium is absorbed by active mechanisms in the duodenum and jejunum, facilitated by a metabolite of vitamin D. It is also passively absorbed in the ileum and specific calcium binding proteins are present in the intestinal epithelial cells. Loss of absorptive cells and calcium binding proteins markedly decreases calcium uptake and limits its availability for bone growth and repair. 

The surface epithelium of the colonic mucosa undergoes continual renewal, and complete replacement of epithelial cells occurs every 4 to 8 days. Cell replication normally takes place within the lower third of crypts, the tubular glands located within the intestinal mucosa. The cells then mature and differentiate to either goblet or absorptive cells as they migrate toward the bowel lumen. The total number of epithelial cells remains relatively constant as the number of cells migrating from the crypts is balanced by the rate of exfoliation of cells from the mucosal surface. This two-phase process is... 

The relative importance of each of these contributions to pool C is likely to be different in epithelial cells located at different points along the villus-crypt axis. The fact that cholesterol derived from synthesis and from the uptake of LDL is critically important for membrane formation and differentiation is suggested by the finding that 70-80% of total mucosal sterol synthetic activity and LDL transport activity are localized to the immature cells of the lower villus and crypt regions in both the proximal and distal intestine. In the mature absorptive cells of the upper villus in the jejunum, where most sterol absorption takes place, the rate of cholesterol synthesis appears to be suppressed. In the absence of fat absorption, cholesterol newly synthesized in these cells apparently is sloughed into the lumen and not reabsorbed. However, with active triglyceride absorption cholesterol synthesis in these cells is increased and a portion of this sterol appears in the intestinal lymph. Only under this condition does pool B apparently supply sterol for lipoprotein formation. 

A FIGURE 6-4 Principal types of epithelium. The apical and basolateral surfaces of epithelial cells exhibit distinctive characteristics, (a) Simple columnar epithelia consist of elongated cells, including mucus-secreting cells (in the lining of the stomach and cervical tract) and absorptive cells (in the lining of the small intestine), (b) Simple squamous epithelia, composed of thin cells, line the blood vessels (endothelial cells/endothelium) and many body cavities, (c) Transitional epithelia, composed of several layers of cells with different shapes, line certain cavities subject to expansion and contraction (e.g., the urinary bladder). 

Fig. 27.12. Na -dependent and facilitative transporters in the intestinal epithelial cells. Both glucose and fructose are transported by the facilitated glucose transpxrrters on the luminal and serosal sides of the absorptive cells. Glucose and galactose are transported by the Na -glucose cotransporters on the luminal (mucosal) side of the absorptive cells.

The origin and fate of the intestinal epithelial cells have been traced using radioautography. The absorptive cell proliferates in the crypts of Lieberkiihn. The new cells migrate toward the apex of the villi where they are extruded. Cellular proliferation and cellular extrusion are not rigidly linked for example, irradiation blocks cellular proliferation but doesn t affect cellular extrusion, and the villi atrophy. In sprue the reverse occurs cellular proliferation persists, but cellular extrusion seems to be accelerated. 

The lanthaninn teehnique was used to study the epithelial permeability in the rat small intestine (Madara and Trier 1982). Dense lanthanum precipitates in TJ and paracellular spaces were restricted to a subpopulation of villous goblet cells and were not found between villous absorptive cells. These TJ were also permeable to barium, but not to macromolecular tracers such as microperoxidase, eytochrome c and horseradish peroxidase. It was also shown that palmitoylcamitine (PCC) opens TJ in a monolayer of Caco-2 colon carcinoma cells this phenomenon appears to be responsible for the significant enhancement of the absorption of hydrophilic drugs across intestinal mucosa caused by PCC and other long-chain acylcamitines (Hochman, Fix et al. 1994).In an experiment on rats, it was demonstrated that immobilisation stress induced a significant (but reversible) increase in epithelial permeability to the lanthanum tracer (Mazzon, Stumiolo et al. 2002). 

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