title: Indomethacin enhances bile salt detergent activity: relevance for NSAIDs-induced gastrointestinal mucosal injury.
abstract: Gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs) is partly independent from cyclooxygenase inhibition, possibly related to increased intermixed micellar-vesicular (nonphospholipid-associated) bile salt concentrations thought to be responsible for bile salt cytotoxicity. We evaluated the effects of indomethacin on bile salt cytotoxicity with complementary in vitro and ex vivo systems. In the erythrocyte model, indomethacin alone did not induce hemolysis. In contrast, indomethacin enhanced and phospholipids decreased hemolysis induced by hydrophobic taurodeoxycholate (TDC). Hydrophilic tauroursodeoxycholate (TUDC) enhanced rather than decreased TDC-induced hemolysis in the presence of indomethacin. Indomethacin did not affect intermixed micellar-vesicular bile salt concentrations or compositions. Indomethacin also increased TDC-induced lactate dehydrogenase release in CaCo-2 cells and bile salt-induced rat colonic mucosal injury, and prevented potential protective effects of TUDC in these systems. Our data show that indomethacin enhances bile salt-induced cytotoxicity without affecting intermixed micellar-vesicular bile salt concentrations or compositions. These findings may be relevant for gastroduodenal injury during NSAID therapy.
authors.affiliation: Gastrointestinal Research Unit, Department of Gastroenterology, University Medical Center Utrecht, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Petruzzelli
authors.forename: A
authors.initials: A
authors.lastname: Moschetta
authors.forename: W
authors.initials: W
authors.lastname: Renooij
authors.forename: M B M
authors.initials: MB
authors.lastname: de Smet
authors.forename: G
authors.initials: G
authors.lastname: Palasciano
authors.forename: P
authors.initials: P
authors.lastname: Portincasa
authors.forename: K J
authors.initials: KJ
authors.lastname: van Erpecum
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D004195:Disease Models, Animal; D004347:Drug Interactions; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000473:pathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D008297:Male; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001647:Bile Acids and Salts; D013655:Taurochenodeoxycholic Acid; D007213:Indomethacin