Tight junctions toxins

Hecht G, C Pothoulakis, JT LaMont, JL Madara. (1988). Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J Clin Invest 82 1516-1524. 

Fasano, A., and S. Uzzau. 1997. Modulation of intestinal tight junctions by zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model. J Clin Invest 99 1158. 

Fasano, A., et al. 1995. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest 96 710. 

Fasano, A. 2000. Regulation of intercellular tight junctions by zonula occludens toxin and its eukaryotic analogue zonulin. Ann NY Acad Sci 915 214. 

Fasano, A., and J.P. Nataro. 2004. Intestinal epithelial tight junctions for enteric bacteria-derived toxins. Adv Drug Deliv Rev 56 795. 

Fasano A, Baudry B, Pumplin D, et al. (1991) Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci USA 88 5242-5246 Fasano A, Uzzau S, Fiore C, Mararetten K (1997) The enterotoxic effect of Zonula Occludens toxin on rabbit small intestine involves the paracellular pathway. Gastroentrology 112 839-846... 

Various substances (tauroUthocholate, ethinyl oestradiol, drugs, toxins) cause increased retention of cholesterol in cellular membranes. As a result, the permeabihty of hepatocellular membranes, including the tight junctions, is decreased. Hypothermia and hypoxia also disturb membrane fluidity. The osmotic pressure gradient, necessary for biliary secretion, is no longer maintained because of decreased membrane permeability. 

Cholera toxin and E. call heat-labile toxin ADP-ribosylate the a-subunit of trimeric G-proteins (Gj) so that they are unable to hydrolyze GTP (Casey and Gilman, 1988 Neer and Claphan, 1988). As a result, the adenylate cyclase stays in a persistently active state. The toxin is taken up from the apical pole of the enterocytes, whereas the adenylate cyclase is located at the basolateral side. Since membrane glycolipids such as the toxin receptor (ganglioside GMi) tend not to cross tight junctions, it is unlikely that the toxin reaches the basolateral side by lateral diffusion. Most likely it enters the cytosol and diffuses to the target which is also located at the cytosolic side of the membrane. 

This physiological barrier exists to provide protection from the entry of toxins, bacteria, and viruses from the apical side to the basolateral side, and it allows the passage of selective molecules and cells. The intercellular junctions can be divided into three different regions (1) tight junctions zonula occludens), (2) adherens junctions (zonula adherens), and (3) desmosomes. The intercellular junctions form an 80-nm-long tortuous path between the two adjacent cells that runs the entire lateral side of the cell, as discovered by transmission electron microscopic studies.4... 

Some drug absorption enhancers are capable of loosening tight junctions (zonula occludens) and thereby facilitate paracellular absorption of drug molecules and improve the bioavailability of active pharmaceutical ingredients with low membrane permeability. The penetration enhancers include chelating agents [e.g., ethylenediaminetetraacetic acid), toxins [e.g., zonula occludens toxin), plant-derived materials [e.g., aloe vera gel), and cationic polymers. Polycationic lipophilic-core dendrons, which form lipophilic ion-pairs with heparin, were studied as a system for oral delivery of heparin. ... 

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