title: Paraquat-induced phosphatidylserine oxidation and apoptosis are independent of activation of PLA2.
abstract: Paraquat is a pneumotoxin that causes lung injury by enhancing oxidative stress; however, the cellular responses to these redox events are undefined. We previously showed that paraquat produced selective peroxidation of phosphatidylserine that preceded apoptosis in 32D cells. We now report that the phospholipase A2 (PLA2) inhibitor quinacrine can attenuate phosphatidylserine oxidation and also block paraquat-induced apoptosis. Therefore, we investigated the potential for PLA2 to mediate apoptosis after paraquat. We found that, in contrast to quinacrine, the PLA2 inhibitors manoalide, aristolochic acid, and arachidonyl trifluoromethylketone failed to prevent paraquat-induced apoptosis. Moreover, no evidence of PLA2 activation was observed within 7 h after paraquat exposure. Finally, quinacrine failed to inhibit basal and 4-bromo-A-23187-induced release of [3H]arachidonic acid at concentrations that protected paraquat-induced apoptosis. We conclude that paraquat-induced phosphatidylserine oxidation and apoptosis occurred in the absence of PLA2 activation and that quinacrine protected phosphatidylserine and cell viability after paraquat in a PLA2-independent manner.
authors.affiliation: Department of Pharmacology, School of Medicine, University of Pittsburgh, Pennsylvania 15261, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Fabisiak
authors.forename: V E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Y Y
authors.initials: YY
authors.lastname: Tyurina
authors.forename: V A
authors.initials: VA
authors.lastname: Tyurin
authors.forename: J S
authors.initials: JS
authors.lastname: Lazo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007377:Interleukin-3 / Q000502:physiology; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology*; D010718:Phosphatidylserines / Q000378:metabolism*; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054467:Phospholipases A2; D011796:Quinacrine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007377:Interleukin-3; D010718:Phosphatidylserines; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D010269:Paraquat