Interactions of sulindac and its metabolites with phospholipid membranes: an explanation for the peroxidation protective effect of the bioactive metabolite.
Non-steroidal anti-inflammatory drugs (NSAIDs) treat inflammatory processes by inhibition of cycloxygenase (COX). However, their action against lipid peroxidation can be an alternative pathway to COX inhibition. Since inflammation and lipid peroxidation are cell-surface phenomena, the effects of NSAIDs on membrane models were investigated. Peroxidation was induced by peroxyl radical (ROO*) derived from AAPH and assessed in aqueous or lipid media using fluorescence probes with distinct lipophilic properties: fluorescein; HDAF and DPH-PA. The antioxidant effect of sulindac and its metabolites was tested and related with their membrane interactions. Drug-membrane interactions included the study of: drug location by fluorescence quenching; drug interaction with membrane surface by zeta-potential measurements; and membrane fluidity changes by steady-state anisotropy. Results revealed that the active NSAID (sulindac sulphide) penetrates into the lipid bilayer and protects the membrane against oxy-radicals. The inactive forms (sulindac and sulindac sulphone) present weaker interactions with the membrane and are better radical scavengers in aqueous media.
Santos
Fernando
F
REQUIMTE, Departamento de Química Física, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
Teixeira
Lígia
L
Lúcio
Marlene
M
Ferreira
Helena
H
Gaspar
Diana
D
Lima
José L F C
JL
Reis
Salette
S
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D002463:Cell Membrane Permeability; D004305:Dose-Response Relationship, Drug; D005454:Fluorescence Polarization; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008081:Liposomes; D008560:Membrane Fluidity / Q000187:drug effects; D008956:Models, Chemical; D010545:Peroxides / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005456:Fluorescent Dyes; D016166:Free Radical Scavengers; D008081:Liposomes; D010545:Peroxides; D010743:Phospholipids; D013467:Sulindac; C049375:perhydroxyl radical; C025462:sulindac sulfide; C025463:sulindac sulfone