| Autor: |
Sigthorsson, Gudmundur, Tibble, Jeremy, Mahmud, Taher, Bjarnason, Ingvar |
| Předmět: |
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| Zdroj: |
Inflammopharmacology; 2000, Vol. 8 Issue 1, p31-41, 11p, 1 Diagram, 2 Charts, 1 Graph |
| Abstrakt: |
There is irrefutable evidence that cyclooxygenase-1 (COX-1) inhibition by itself is not the only factor in the development of the gastrointestinal damage of NSAIDs. One suggestion is that the 'topical' effect of NSAIDs is an important initiating factor in their toxicity ('ion trapping hypothesis'), but the biochemical mechanisms are unknown. We made an integrated approach to elucidate the biochemical basis of the 'topical' toxicity of NSAIDs. Assay of specific intestinal subcellular organelle marker enzymes following indomethacin shows that only brush border and mitochondria are affected. Electron microscopy shows mitochondrial changes characteristic of uncoupling of mitochondrial oxidative phosphorylation (or inhibition of the respiratory chain) following NSAIDs. In vitro studies show that the mitochondrial effects relate to the acidity (pKa) of the NSAID, which is also crucial for their binding (inhibition) to the COX enzymes. We attempted to dissociate the two effects. Enantioners (R and S) of flurbiprofen have a differential effect on COX inhibition. We show that both enantiomers are associated with changes in mitochondrial morphology, increase in intestinal permeability and inflammation, but only the S-enantiomer (which decreases intestinal mucosal prostaglandin levels) is associated with intestinal ulceration. In a separate set of experiments we show that the uncoupler, dinitrophenol, altered intestinal mitochondria, increased intestinal permeability and inflammation, but caused no ulcers. Parenteral aspirin, which does not have a 'topical' effect, decreased intestinal mucosal prostaglandin levels significantly but was not associated with any other pathophysiogical alterations. Given together, the two drugs were associated with the same damage as indomethacin. These studies show a clear dissociation of the 'topical' and COX inhibitory effects of NSAIDs. We suggest that the 'topical' effect of NSAIDs is instrumental in initiating the intestinal damage of conventional NSAIDs and that inhibition of COX modifies this response leading to severe inflammation and ulcers. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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