Clostridium difficile cytotoxin inhibits protein synthesis in fibroblasts and intestinal mucosa.
The pathophysiology of Clostridium difficile colitis is thought to be mediated by release of toxin A, an enterotoxin, and toxin B, a cytotoxin. We compared the differential effects of toxin B on protein synthesis in IMR-90 fibroblasts and in hamster esophagus, stomach, gallbladder, small intestine, and cecum in organ culture. Toxin B in low concentrations stimulated (p less than 0.001) incorporation of [3H]leucine into fibroblast proteins, whereas at higher dosages it inhibited incorporation (p less than 0.001). This biphasic effect was independent of cell rounding and was not caused by a change in uptake of precursor. Purified toxin B had no effect on protein synthesis in a cell-free rabbit reticulocyte translation system, indicating that inhibition of protein synthesis in intact fibroblast monolayers and intestinal explants is a consequence of toxin B effect on some other cellular target. Toxin B significantly inhibited protein synthesis in hamster cecal explants in a dose-dependent fashion. Again, this inhibition was not mediated by altered precursor uptake. Toxin B significantly inhibited in vitro protein synthesis in hamster terminal ileum, cecum, and sigmoid colon, but not in esophagus, gallbladder, stomach, or duodenum. These results suggest that toxin B-mediated inhibition of protein synthesis may be a generalized toxic effect in tissue culture cells and intestinal epithelium. Inhibition of protein synthesis in the distal intestinal epithelium may contribute to the pathophysiology of colitis caused by this organism.
D002432:Cecum / Q000187:drug effects; D003013:Clostridium; D003603:Cytotoxins / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008168:Lung / Q000187:drug effects; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors*
D003603:Cytotoxins; D011506:Proteins; D007930:Leucine