title: Membrane permeabilization by non-steroidal anti-inflammatory drugs.
abstract: The cytotoxicity of non-steroidal anti-inflammatory drugs (NSAIDs) is involved in the formation of NSAID-induced gastric lesions. The mechanism(s) behind these cytotoxic effects, however, is not well understood. We found here that several NSAIDs tested caused hemolysis when employed at concentrations similar to those that result in cytotoxicity. Moreover, these same NSAIDs were found to directly permeabilize the membranes of calcein-loaded liposomes. Given the similarity in NSAID concentrations for cytotoxic and membrane permeabilization effects, the cytotoxic action of these NSAIDs may be mediated through the permeabilization of biological membranes. Increase in the intracellular Ca(2+) level can lead to cell death. We here found that all of NSAIDs tested increased the intracellular Ca(2+) level at concentrations similar to those that result in cytotoxicity. Based on these results, we consider a possibility that membrane permeabilization by NSAIDs induces cell death through increase in the intracellular Ca(2+) level.
authors.affiliation: Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Tomisato
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Tanaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Katsu
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kakuta
authors.forename: Kenji
authors.initials: K
authors.lastname: Sasaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hoshino
authors.forename: Mayuko
authors.initials: M
authors.lastname: Aburaya
authors.forename: Daiwei
authors.initials: D
authors.lastname: Li
authors.forename: Tomofusa
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Keitarou
authors.initials: K
authors.lastname: Suzuki
authors.forename: Kazumi
authors.initials: K
authors.lastname: Yokomizo
authors.forename: Tohru
authors.initials: T
authors.lastname: Mizushima
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006168:Guinea Pigs; D008081:Liposomes / Q000737:chemistry; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D008081:Liposomes; D002118:Calcium