The Intestinal Absorptive Cell

In an effort to answer both questions, we will examine in some detail the intestinal absorptive cell, which ordinarily is not considered a secretory cell, but which does produce a secretory product. During intestinal fat absorption, chylomicra are produced and released from the absorptive cells in a manner similar to secretory products in other cell types. 

Intestinal absorptive cells are simple columnar, highly polarized cells (Fig. 4). The luminal plasma membrane is modified to form numerous fingerlike projections, the microvilli, which markedly increase the total absorptive surface of the cell. Directly beneath the microvillous border is an area relatively devoid of cellular organelles, but containing numerous filaments extending from the microvilli into the cytoplasm. This region is termed the terminal web zone of the cell. Below the terminal web area is the apical cytoplasm, which extends to the level of the nucleus and Golgi complex. The apical cytoplasm, in the fasted 

A relatively close association exists between elements of the SER and RER with the Golgi complex. Frequently, RER profiles are seen adjacent to the outermost Golgi saccules of the forming face. These profiles display a peculiar configuration, with ribosomes absent on the 

The biochemical and physiological events in the transport of fat are well known (Borgstrom, 1962 Senior, 1964). Free fatty acids and monoglycerides, which result from the intraluminal digestion of triglycer- 

Obviously, the synthesis of new membrane is not sufficient to keep pace with its conversion to SER vesicles thus, a gradual reduction in quantity of RER occurs as fat absorption continues. 

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Fig. 5 Diagrammatic sketch of the intestinal absorptive cell. (Modified from Ref. 8.)...

Thus, in summary, it may be concluded that much of the cholesterol synthesized in the intestine is apparently used for local purposes. Under circumstances where there is no triglyceride absorption taking place essentially no newly synthesized sterol of intestinal origin can be detected in the lymphatic outflow from the gut. During active triglyceride absorption, however, the rate of sterol synthesis increases markedly in the intestinal absorptive cells, and a portion of this newly synthesized cholesterol is incorporated into chylomicrons and other intestinal lipoproteins and delivered into the lymph. Thus, both the rate of sterol synthesis by the intestine and the rate of entry of this sterol into the body pools is partially dictated by the rate of triglyceride absorption. 

Dobbins, W. O., 1966, An ultrastructural study of the intestinal mucosa in congenital j8-lipoprotein deficiency with particular emphasis upon the intestinal absorptive cell. 

In addition to its role in regulating calcium homeostasis, vitamin D is required for the intestinal absorption of calcium. Synthesis of the intracellular calciumbinding protein, calbindin, required for calcium absorption, is induced by vitamin D, which also affects the permeability of the mucosal cells to calcium, an effect that is rapid and independent of protein synthesis. 

Based on the limitations of using human subjects, simple alternative in vitro models were developed to investigate mechanisms involved in the intestinal absorption process of a compound of interest and to screen the relative bioavailability of a compound from various food matrices. However, the data generated from in vitro approaches must be taken with caution because they are obtained under relatively simplified and static conditions compared to dynamic physiological in vivo conditions. Indeed, the overall bioavailability of a compound is the result of several complex steps that are influenced by many factors including factors present in the gastrointestinal lumen and intestinal cells as described later. Nevertheless, these in vitro approaches are useful tools for guiding further smdies in humans. 

This in vitro approach thus has a great potential for studying the intestinal absorption processes of carotenoids and other pigments. It is important to note the existence of several clones isolated from the parent Caco-2 cell line that can be used for studying... 

In this model, no attempt is made to reproduce the in vivo physiochemical conditions occurring in the lumen of the human small intestine during digestion. This cell culture model only provides information about the intestinal absorption and metabolism processes of the compound. Using this cell culture system in con-... 

Madara JL, D Barenberg, S Carlsson. (1986). Effects of cytochalasin D on occluding junctions of intestinal absorptive cells Further evidence that the cytoskeleton may influence paracellular permeability and junctional charge selectivity. J Cell Biol 102 2125-2136. 

The peculiar thing in hereditary haemochromatosis (HH) is that the intestinal mucosal cell behaves essentially like an iron deficient cell. Iron absorption is always high if related to the body s iron needs. In HH subjects with normal plasma ferritin values, both mucosal uptake and mucosal transfer of iron often exceed values found in patients with uncomplicated iron deficiency (Marx, 1979b). In fact the situation with respect to iron absorption in mature intestinal mucosal cells, as depicted in Figure 9.4(b), is identical to that in iron deficiency, except for the difference in plasma iron saturation. It was already known that mucosal cells in HH contain no ferritin, explaining the high mucosal transfer of iron (Francanzani... 

Wenzel, U., B. Meissner, F. Doring, and H. Daniel. PEPTl-mediated uptake of dipeptides enhances the intestinal absorption of amino adds via transport system b(0, +), J. Cell. Physiol. 2001, 386, 251-259... 

Wils, P., Warnery, A., Phung-Ba, V., Scherman, D., Differentiated intestinal epithelial cell lines as in vitro models for predicting the intestinal absorption of drugs, Cell Biol. Toxicol. 1994, 30, 393-397. 

Following oral administration, the intestinal absorption of Li+ occurs primarily in the small intestine and the subsequent movement of Li+ into the blood stream is a passive process, via a paracellular route, with very little Li+ accumulating in the intestinal cells [51,52]. The excretion of Li+ is almost entirely by the kidneys with only very small amounts (<1%) being excreted in the feces, sputum, sperm, and sweat. The elimination half-life of Li+ is approximately 20-30 hours. 

Many drugs have been recognized to cross the intestinal epithelial cells via passive diffusion, thus their lipophilicity has been considered important. However, as described above, recent studies have demonstrated that a number of drug transporters including uptake and efflux systems determine the membrane transport process. In this chapter, we provide an overview of the basic characteristics of major drug transporters responsible not only for absorption but also for disposition and excretion in order to delineate the impact of drug transport proteins on pharmacokinetics. 

Figure 23.3 Drug transporters in the intestinal epithelial cells. PEPT1 is the most characterized transporter for intestinal drug absorption. The basolateral peptide transporter, which is not identified at the molecular level, also plays important roles. OATP-B, OCTN2 and MRP3 may be responsible for the intestinal absorption of some drugs. On the contrary, ABC transporters such as P-gp located at brush-border membranes mediated the efflux of drugs from intestinal epithelial cells, contributing to the low bioavailabihty of drugs such as the immunosuppressive agent, tacrolimus.

The intestinal absorption of dietary cholesterol esters occurs only after hydrolysis by sterol esterase steryl-ester acylhydrolase (cholesterol esterase, EC 3.1.1.13) in the presence of taurocholate [113][114], This enzyme is synthesized and secreted by the pancreas. The free cholesterol so produced then diffuses through the lumen to the plasma membrane of the intestinal epithelial cells, where it is re-esterified. The resulting cholesterol esters are then transported into the intestinal lymph [115]. The mechanism of cholesterol reesterification remained unclear until it was shown that cholesterol esterase EC 3.1.1.13 has both bile-salt-independent and bile-salt-dependent cholesterol ester synthetic activities, and that it may catalyze the net synthesis of cholesterol esters under physiological conditions [116-118], It seems that cholesterol esterase can switch between hydrolytic and synthetic activities, controlled by the bile salt and/or proton concentration in the enzyme s microenvironment. Cholesterol esterase is also found in other tissues, e.g., in the liver and testis [119][120], The enzyme is able to catalyze the hydrolysis of acylglycerols and phospholipids at the micellar interface, but also to act as a cholesterol transfer protein in phospholipid vesicles independently of esterase activity [121],... 

Poor intestinal absorption of a potential drug molecule can be related to poor physicochemical properties and/or poor membrane permeation. Poor membrane permeation could be due to low paracellular or transcellular permeability or the net result of efflux from transporter proteins including MDRl (P-gp) or MRP proteins situated in the intestinal membrane. Cell lines with only one single efflux transporter are currently engineered for in vitro permeability assays to get suitable data for reliable QSAR models. In addition, efforts to gain deeper insight into P-gp and ABC on a structural basis are going on [131, 132]. 

To meet the need of conducting HTS for ADME-Tox properties, many slow and expensive in vivo ADME assays are now being replaced by in vitro cell models. For intestinal absorption, Caco-2 cell lines and Madin Darby canine kidney (MDCK) cell lines are widely used to predict the absorption rate of candidate drug compounds across the intestinal epithelial cell barrier. A number of models for Caco-2 cell permeability and MDCK cell permeability have been reported that predict the oral absorption properties of drugs, mostly limited to small organic molecules. Caco-2 and MDCK permeability are related to "A" and "D" in the ADME-Tox. 

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