EFFECTS OF ORGANOMETALS ON CELLULAR SIGNALING .1. INFLUENCE OF METABOLIC-INHIBITORS ON METAL-INDUCED ARACHIDONIC-ACID LIBERATION

Organic lead and tin compounds stimulate an increase of free arachidon ic acid (AA) in HL-60 cells. This fatty acid is involved in numerous h ealth problems and physiological mechanisms. Three major pathways resu lt in a liberation of AA from membrane phospholipids and there is evid ence that G-proteins serve as couplers within ail three pathways. Ther efore we investigated the influence of pertussis toxin (PT) on the org anometallic-induced AA liberation. The effect of all studied compounds (organotin and organo-lead) was diminished by PT. We conclude that th e organometals activate PLA(2) to some extent via a PT-sensitive pathw ay. The ionophor A 23187 (1-10 mu M) 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+ depen dent. Thus, we examined the necessity of free intracellular Ca2+ for t he organometallic effect. The Ca2+ chelator EGTA inhibited the increas e of free AA induced by organometals. This is true also for verapamil, a Ca2+ channel blocker. Quinacrine, which is thought to be an inhibit or of phospholipase A(2)(PLA(2)), prevented the AA liberation from mem brane phospholipids induced by organometals. This could be due to the inhibition of PLA(2), but it could also be the result of an inhibited Ca2+ influx.