title: Interactions of sulindac and its metabolites with phospholipid membranes: an explanation for the peroxidation protective effect of the bioactive metabolite.
abstract: 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.
authors.affiliation: REQUIMTE, Departamento de Química Física, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
authors.forename: Fernando
authors.initials: F
authors.lastname: Santos
authors.forename: Lígia
authors.initials: L
authors.lastname: Teixeira
authors.forename: Marlene
authors.initials: M
authors.lastname: Lúcio
authors.forename: Helena
authors.initials: H
authors.lastname: Ferreira
authors.forename: Diana
authors.initials: D
authors.lastname: Gaspar
authors.forename: José L F C
authors.initials: JL
authors.lastname: Lima
authors.forename: Salette
authors.initials: S
authors.lastname: Reis
mesh_terms: 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
chemical_list: 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