title: Selective inhibition of phospholipases by atiprimod, a macrophage targeting antiarthritic compound.
abstract: Azaspiranes are cationic amphiphilic compounds that are active in a number of models of autoimmune disease and transplantation. Repeated administration of cationic amphiphiles induces phospholipid accumulation in a variety of species. The present study was conducted to explore the mechanism of phospholipid accumulation in rats caused by treatment with the novel azaspirane, SK&F 106615 (atiprimod). Atiprimod inhibited the activities of partially purified phospholipases A(2) and C, but not D, in a noncompetitive manner in vitro. Treatment of rats for 28 days with 10 mg/kg/day of atiprimod increased the contents of arachidonate-containing molecular species within plasmalogen subclasses of hepatic phosphatidylcholine and phosphatidylethanolamine. In contrast, diacyl-linked species were not affected, indicating a selective effect upon an hepatic plasmalogen-selective phospholipase A(2). Taken together, the data suggest that the beneficial effects of atiprimod in autoimmune diseases may involve inhibition of phospholipase A(2) and C activities. Further, the data suggest that atiprimod is a selective inhibitor of plasmalogen-selective phospholipase A(2) in vivo.
authors.affiliation: Department of Toxicology, SmithKline Beecham Pharmaceuticals, Collegeville, Pennsylvania, 19426, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Handler
authors.forename: A
authors.initials: A
authors.lastname: Badger
authors.forename: C A
authors.initials: CA
authors.lastname: Genell
authors.forename: A M
authors.initials: AM
authors.lastname: Klinkner
authors.forename: S
authors.initials: S
authors.lastname: Kassis
authors.forename: C R
authors.initials: CR
authors.lastname: Waites
authors.forename: P J
authors.initials: PJ
authors.lastname: Bugelski
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001667:Binding, Competitive; D066298:In Vitro Techniques; D016676:Macrophages, Alveolar / Q000378:metabolism*; D008297:Male; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010740:Phospholipases / Q000037:antagonists & inhibitors* / Q000145:classification; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013141:Spiro Compounds / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D013141:Spiro Compounds; C099015:azaspirane; D016718:Arachidonic Acid; D010740:Phospholipases