Membrane permeabilization by non-steroidal anti-inflammatory drugs.
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.
Tomisato
Wataru
W
Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan.
Tanaka
Ken-ichiro
K
Katsu
Takashi
T
Kakuta
Hiroki
H
Sasaki
Kenji
K
Tsutsumi
Shinji
S
Hoshino
Tatsuya
T
Aburaya
Mayuko
M
Li
Daiwei
D
Tsuchiya
Tomofusa
T
Suzuki
Keitarou
K
Yokomizo
Kazumi
K
Mizushima
Tohru
T
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*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D008081:Liposomes; D002118:Calcium