title: Amiodarone inhibits tocopherol-mediated human lipoprotein peroxidation.
abstract: It is unknown whether lipoprotein tocopherol-mediated peroxidation (TMP) is influenced by peculiar drug physicochemical properties such as hydrophobicity. Thus, we studied the effect of the extremely hydrophobic agent amiodarone on human non-HDL TMP. The drug, albeit devoid of specific radical-scavenging effects, inhibited TMP at therapeutic concentrations and with an efficiency similar to that of the physiological co-antioxidant ascorbic acid, showing indeed an IC(50) of 5microM. A comparable efficiency was observed with human LDL, and with a pure LDL-VLDL mixture. TMP was also inhibited by other hydrophobic cationic amphiphiles without radical-scavenging activity, namely desethylamiodarone, chlorpromazine, clomipramine, promethazine, promazine, verapamil, bromhexine, propranolol, mepivacaine, metoprolol, tramadol and ranitidine, whose anti-TMP potency was far lower than that of amiodarone and related to drug hydrophobicity degree. Further, TMP was strongly inhibited by butylhydroxytoluene, a lipophilic radical scavenger. Hydrophobic acidic (diclofenac, indomethacin, ibuprofen and ketoprofen) or neutral (n-hexane, anthracene, o-xylene and toluene) compounds could not instead inhibit TMP, indicating a stringent requirement for drug basicity in the pharmacological inhibition of TMP. Amiodarone effectiveness was lowered by lipoprotein alpha-tocopherol enrichment, suggesting some drug-alpha-tocopherol interaction and less lipid pharmacological protection at higher alpha-tocopheroxyl radical generation. Drug anti-TMP activity may so be related to electrostatic and hydrophobic interactions with lipoprotein alpha-tocopherol and lipid moiety, resulting in decreased radical phase transfer and lipid propensity to undergo radical-driven peroxidation. In conclusions, primarily drug basicity and then hydrophobicity are solely relevant to TMP inhibition. Amiodarone, at therapeutic concentrations, has anti-TMP properties, which could occur in the clinical setting.
authors.affiliation: Dipartimento di Medicina e Scienze dell'Invecchiamento and Centro di Scienze dell'Invecchiamento-Fondazione Università G. d'Annunzio, Facoltà di Medicina e Chirurgia, Chieti, Italy. piersd@tiscalinet.it
authors.forename: Domenico
authors.initials: D
authors.lastname: Lapenna
authors.forename: Giuliano
authors.initials: G
authors.lastname: Ciofani
authors.forename: Sante Donato
authors.initials: SD
authors.lastname: Pierdomenico
authors.forename: Matteo
authors.initials: M
authors.lastname: Neri
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Giamberardino
authors.forename: Franco
authors.initials: F
authors.lastname: Cuccurullo
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D008074:Lipoproteins / Q000378:metabolism*; D024505:Tocopherols / Q000037:antagonists & inhibitors*
chemical_list: D016166:Free Radical Scavengers; D008074:Lipoproteins; D000638:Amiodarone; D024505:Tocopherols