Gastrointestinal epithelium cells

Methotrexate acts by inhibition of dihydrofolate reductase, the enzyme requisite for the reduction of dihydrofolic acid (3) to 5,6,7,8-tetrahydrofolic acid (4). In turn, (4) is a precursor to a series of enzyme cofactors (5-7) essential for the transfer of one carbon unit necessary for the biosynthesis of purines and pyrimidines and hence, ultimately, DNA. As an inhibitor of dihydrofolate reductase, methotrexate kills cells during the S phase of the cell cycle, when the cells are in the log phase of growth. Unfortunately, this cytotoxicity is non-selective, and rapidly proliferating normal cells, e.g., gastrointestinal epithelium cells and bone marrow, are dramatically affected as well. In addition, recent use of high dose methotrexate therapy with leucovorin rescue has led to additional clinical problems arising from a dose-related nephrotoxic metabolite, 7-hydroxy methotrexate (8). Finally, the very polar nature of methotrexate renders it virtually impenetrable to the blood-brain barrier, which can necessitate direct intrathecal injection in order to achieve therapeutic doses for the treatment of CNS tumours. 

The intrinsic barrier of the gastrointestinal epithelium is characterized by intercellular junctions at the apical (luminal) side of differentiated epithelial cells, the so-called tight junctions (TJ), and the maintenance of epithelial integrity based on the balance between cellular proliferation and cell death, as described above. Barriers against drug absorption by the intracellular and paracellular routes, their modulation, and maintenance will be discussed in the following, with the focus on the intestinal epithelium. 

Groh, V., Bahram, S., Bauer, S., Herman, A., Beauchamp, M., and Spies, T. (1996). Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc. Natl. Acad. Sci. USA 93, 12445-12450. 

Secondary Deficiency. Low plasma Cp levels caused by a lack of incorporation of Cu into the molecule during synthesis are much more common than primary deficiency. Secondary deficiency may be due to dietary Cu insufficiency (including malabsorption), inability to release Cu " " from the gastrointestinal epithelium into the circulation, or inability to insert Cu into the developing Cp molecule. In all cases, apoCp (noncopper containing) is stiU synthesized by the hepatic parenchymal cells. However, as mentioned previously, most apoCp is cataboHzed intracellularly before release into the plasma, and plasma apoCp has a much shorter half-life than does holoCp. Levels may also be low in blood loss or in gastrointestinal or renal protein-losing syndromes. 

Drugs can cross the intestinal epithelial barrier in a number of ways. They may permeate either through the cell (transcellular) or between adjacent cells (para-cellular). Enterocytes have tight intercellular junctions that restrict paracellular transport to small hydrophilic molecules.7 These cells possess active and facilita-tive transporters for nutrients, as well as an array of efflux transporters [e.g., P-glycoprotein (P-gp) and related transporters] and enzymes (e.g., cytochrome P450 type 3A4) that restrict transcellular absorption. Transcytotic transport of macromolecules is possible, but compounds are often destroyed in lysosomes. With the exception of M-cells, transcytosis is not considered a major mechanism of the transcellular pathway for absorption of macromolecules across gastrointestinal epithelium.6... 

Cytokeratins (CKs) are a family of intracytoplasmic intermediate filament proteins present in almost all epithelia. Expression of each CK molecule depends on cell type and differentiation status, and therefore specific CKs can be used as markers to identify particular types of epithelial tumors (Table 16.5). CK7 is found in a wide variety of epithelia including the columnar and glandular epithelium of the lung, cervix, and breast, as well as in the bile duct, collecting ducts of the kidney, urothelium, and mesothelium, but not in most gastrointestinal epithelium, hepatocytes, proximal and distal tubules of the kidney, and squamous epithelium. In contrast, CK20 shows relatively restricted expression and is present in gastrointestinal epithelium, Merkel cells of the epidermis, and urothelium. 

Young RH, Prat J, Scully RE. Ovarian Sertoli-Leydig cell tumors with heterologous elements. I. Gastrointestinal epithelium and carcinoid A clinicopathologic analysis of 36 cases. Cancer. 1982 50 2448-2456. 

Potten CS, Wilson JW, Booth C (1997) Regulation and significance of apoptosis in the stem cells of the gastrointestinal epithelium. Stem Cells 15 82-93... 

Tumor cells acquire resistance to methotrexate as the result of several factors, which include the deletion of a high-afQnity, carrier-mediated transport system for reduced folates, an increase in the concentration of dihydrofolate reductase, and the formation of a biochemically altered reductase with reduced affinity for methotrexate. To overcome this resistance, higher doses of methotrexate need to be administered. The effects of methotrexate may be reversed by the administration of leucovorin, the reduced folate. This leucovorin rescue prevents or reduces the toxicity of methotrexate, which is expressed as mouth lesions (stomatitis), injury to the gastrointestinal epithelium (diarrhea), leukopenia, and thrombocytopenia. 

Lipid solubility of the drug is the determining factor for the penetration of cell membranes. Therefore, the passage of many drug molecules across the membranes of the skin, oral cavity, bile, tissue cells, kidneys, central nervous system and the gastrointestinal epithelium is very much related to the lipid solubility of the drug molecule. 

The requirement that the chelating agent and its iron(III) chelate not Interfere with cellular biochemistry must be considered. Drugs which can pass through the gastrointestinal epithelium are also likely to penetrate other cell membranes. A drug which is suitable for oral administration may therefore have undesir-abel side effects unless its lipophilic character is rapidly... 

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