Effects of organometals on cellular signaling. I. Influence of metabolic inhibitors on metal-induced arachidonic acid liberation.
Organic lead and tin compounds stimulate an increase of free arachidonic acid (AA) in HL-60 cells. This fatty acid is involved in numerous health problems and physiological mechanisms. Three major pathways result in a liberation of AA from membrane phospholipids and there is evidence that G-proteins serve as couplers within all three pathways. Therefore we investigated the influence of pertussis toxin (PT) on the organometallic-induced AA liberation. The effect of all studied compounds (organotin and organo-lead) was diminished by PT. We conclude that the organometals activate PLA2 to some extent via a PT-sensitive pathway. The ionophor A 23187 (1-10 microM) led to an increase of free AA by raising the intracellular Ca2+ level. One of the postulated ways of AA release is via Ca2+ channel activation; phospholipases are Ca2+ dependent. Thus, we examined the necessity of free intracellular Ca2+ for the organometallic effect. The Ca2+ chelator EGTA inhibited the increase of free AA induced by organometals. This is true also for verapamil, a Ca2+ channel blocker. Quinacrine, which is thought to be an inhibitor of phospholipase A2 (PLA2), prevented the AA liberation from membrane phospholipids induced by organometals. This could be due to the inhibition of PLA2, but it could also be the result of an inhibited Ca2+ influx.
Käfer
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Kernforschungszentrum Karlsruhe, Institute of Toxicology, Germany.
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D016718:Arachidonic Acid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002450:Cell Communication / Q000187:drug effects*; D003470:Culture Media; D004533:Egtazic Acid / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D009942:Organometallic Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D037342:Pertussis Toxin; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D011796:Quinacrine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D003470:Culture Media; D009942:Organometallic Compounds; D010566:Virulence Factors, Bordetella; D016718:Arachidonic Acid; D004533:Egtazic Acid; D014700:Verapamil; D037342:Pertussis Toxin; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine; D002118:Calcium