Enterocyte cells membranes

The third mucosal layer is that lining the entire length of the small intestine and which represents a continuous sheet of epithelial cells. These epithelial cells (or enterocytes) are columnar in shape, and the luminal cell membrane, upon which the microvilli reside, is called the apical cell membrane. Opposite this membrane is the basal (or basolateral) plasma membrane, which is separated from the lamina propria by a basement membrane. A sketch of this cell is shown in Fig. 5. The primary function of the villi is absorption. 

From the above, it is clear that the gut wall represents more than just a physical barrier to oral drug absorption. In addition to the requirement to permeate the membrane of the enterocyte, the drug must avoid metabolism by the enzymes present in the gut wall cell as well as counter-absorptive efflux by transport proteins in the gut wall cell membrane. Metabolic enzymes expressed by the enterocyte include the cytochrome P450, glucuronyltransferases, sulfotransferases and esterases. The levels of expression of these enzymes in the small intestine can approach that of the liver. The most well-studied efflux transporter expressed by the enterocyte is P-gp. 

Fig. 22.4. Model of aciclovir and Val-aciclovir transport. The prodrug Val-aciclovir is taken up at the apical cell membrane via the di/tri-peptide transporter, hydrolyzed intracelIularly in the enterocyte, with basal exit of valine and aciclovir. (Adapted from Smith et a. [78].)...

Absorption of cholesterol in the small intestine contributes to maintaining whole-body cholesterol homeostasis, yet the mechanisms of absorption have not been completely defined. For many years it was believed that cholesterol, a normal component of cell membranes, simply diffused through the brush border membrane of enterocytes (Grundy, 1983 Westergaard and Dietschy, 1974). However, the discovery of specific transporters, receptors,... 

Simionescu N (1983) Cellular aspects of transcapillary exchange. Physiol Rev 63 1536-1579 Simons K, Ikonen E (1997) Functional rafts in cell membranes. Nature 387 569-572 Snoeck V, Goddeeris B, Cox E (2005) The role of enterocytes in the intestinal barrier function and antigen uptake. Microbes Infect 7 997-1004 Sugiyama Y, Kato Y (1994) Pharmacokinetic aspects of peptide delivery and targeting importance of receptor-mediated endocytosis. Drug Dev Ind Pharm 20 591-614 Takano M, Yumoto R, Murakami T (2006) Expression and function of efflux transporters in the intestine. Pharmacol Therap 109 137-161... 

Final hydrolysis of di- and oligosaccharides is carried out by surface enzymes of the small intestinal epithelial cells, called the brush border, a term that comes from the appearance of the enterocytes, in which the luminal plasma membrane is enlarged by a regular array of projections called microvilli. The enzymes are not secreted into the lumen, but are embedded in the cell membrane, many of these enzymes can protrude into the intestinal lumen up to 10 gm, as they are attached to the plasma membrane by an anchoring polypeptide that has no role by itself in the hydrolysis. 

A second member of the ceruloplasmin family multicopper oxidases with six BCB domains was recently identified as the causative agent of sex-linked anemia (sla) in mice (Vulpe et al., 1993). It was named hephaes-tin and shown to be expressed mostly in the small intestine and the colon, where it is presumably involved in gastrointestinal iron uptake. Hephaes-tin displays a high level of sequence identity to ceruloplasmin and differs from it only by an additional C-terminal transmembrane domain, which anchors the protein to the cell membrane. A 582-nucleotide in-frame deletion in the mRNA for hephaestin sla mice has been identified compared to normal animals. The mice with such a mutation are unable to release iron from enterocytes (intestinal epithelial cells) into the circulation, which results in severe anemia. The GPI-anchored form of ceruloplasmin could potentially also mediate similar cellular iron efflux in the central nervous system. There is a transferrin-independent iron uptake system that requires Fe(III) to be reduced to Fe(II) at the cell surface for uptake to occur (DeSilva et al., 1996). Ceruloplasmin would oxidize Fe and prevent its uptake by this mechanism. Briefly, the role of ceruloplasmin is most likely to prevent excessive intracellular iron accumulation by tightly controlling iron efflux and inhibiting its uptake. 

Carrier-mediated transport involves interaction of the drug with a specific transporter or carrier, in which drug is transferred across the cell membrane or entire cell and then released from the basal surface of the enterocyte into the circulation. The process is saturable and utilized by small hydrophilic molecules. Drugs that are shown to be transported by this mechanism include p-lactam antibiotics, cephalosporins, and ACE inhibitors. 

Figure 9.7 Intestinal peptide transport. Peptides are taken upinto enterocytes together with H+ ions. The proton gradient is maintained via an Na + /H+ antiport system in the apical cell membrane. The Na+ gradient is guaranteed by the Na + /I<+-ATPase in the basolateral cell membrane.

Brush-border surface hydrolysis of oligosaccharides and disaccharides (e.g., sucrose, lactose, and trehalose) to their monomers by specific oligosaccharidases that are integral to the cell membrane of the enterocyte and... 

Transport of amino acids into cells is mediated by specific membrane-bound transport proteins, several of which have been identified in mammalian cells. They differ in their specificity for the types of amino acids transported and in whether the transport process is linked to the movement of Na+ across the plasma membrane. (Recall that the gradient created by the active transport of Na+ can move molecules across membrane. Na+-dependent amino acid transport is similar to that observed in the glucose transport process illustrated in Figure 11.28.) For example, several Na+-dependent transport systems have been identified within the lumenal plasma membrane of enterocytes. Na+-independent transport systems are responsible for transporting amino acids across the portion of enterocyte plasma membrane in contact with blood vessels. The y-glutamyl cycle (Section 14.3) is believed to assist in transporting some amino acids into specific tissues (i.e., brain, intestine, and kidney). 

The binding of enterotoxin (produced by several bacterial species) to another type of guanylate cyclase found in the plasma membrane of intestinal cells causes diarrhea. For example, one form of traveler s diarrhea is caused by a strain of E. coli that produces heat stable enterotoxin. The binding of this toxin to an enterocyte plasma membrane receptor linked to guanylate cyclase triggers excessive secretion of electrolytes and water into the lumen of the small intestine. 

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