Inhibition of human phospholipase C by aurothiomalate and (triethylphosphine) gold complexes.
The effect of several gold complexes on the activity of phospholipase C from human blood platelets was studied in vitro. Aurothiomalate and auranofin--2 agents used for the chrysotherapy of rheumatoid arthritis--, gold chloride, (triethylphosphine)gold chloride, and 5 newly synthesized (triethylphosphine)gold complexes dose-dependently inhibited the enzyme with IC50 values between 0.8 mumol/l ((triethylphosphine)gold chloride) and over 100 mumol/l (auranofin). None of the compounds affected phospholipase A2 from human polymorphonuclear leukocytes at concentrations up to 100 mumol/l. Inhibition of phospholipase C by (triethylphosphine)gold chloride, aurothiomalate, and compound 3 was not significantly different at substrate concentrations of 20 and 100 mumol/l phosphatidylinositol, suggesting that these gold complexes do not inhibit phospholipase C by competing with the substrate. After confirming the Ca2+ dependence of the human platelet phospholipase C by demonstrating inhibition by the Ca2+ chelators EDTA and EGTA--but no inhibition by the Zn2+ chelator 1,10-phenanthroline--the inhibition of the enzyme by (triethylphosphine)gold chloride, aurothiomalate, and compound 3 was studied at 3 different concentrations of Ca2+ in the range of 0.2 to 2 mmol/l. Inhibition by (triethylphosphine)gold chloride was not affected by changes of Ca2+, whereas inhibition by aurothiomalate and compound 3 was markedly suppressed by increasing the Ca2+ concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Research Department, Ciba-Geigy Ltd., Basel, Switzerland.
F
F
Märki
J L
JL
Stanton
D018501:Antirheumatic Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002118:Calcium / Q000502:physiology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006052:Gold Sodium Thiomalate / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008623:Mercaptoethanol / Q000494:pharmacology; D050607:Organogold Compounds; D009942:Organometallic Compounds / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010720:Phosphines; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors*
D018501:Antirheumatic Agents; D050607:Organogold Compounds; D009942:Organometallic Compounds; D009943:Organophosphorus Compounds; D010720:Phosphines; D006052:Gold Sodium Thiomalate; C016797:triethyl phosphine gold; D008623:Mercaptoethanol; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D002118:Calcium