The toxic effects of organometals on the lands cycle in HL‐60 cells

Abstract The concentration of free fatty acids within cells is mainly dependent upon the following enzyme activities: liberation by phospholipase A 2 (PLA 2 ), activation of free acids by acyl‐CoA‐synthetase and re‐esterification by lysophospholipid acyltransferase (LAT). In many cell types, especially those of the haematopeotic system, this deacylation‐reacylation cycle (‘Lands cycle’) plays an important role in the regulation of free fatty acid concentration, above all that of arachidonic acid. We have shown here that heavy‐metal compounds affect this cycle mainly at two points and thereby lead to an increase of free fatty acids. On the one hand, organometals cause an inhibition of the reacylation of lysophospholipids; and on the other, the induction of PLA 2 activity produces the same result. All compounds investigated such as methylmercury chloride (MeHgCl), diethyltriethyl‐, and trimethyl‐lead chloride (Et 2 PbCl 2 , Et 3 PbCl, Me 3 PbCl) as well as trimethyltin chloride (Et 3 SnCl) and di‐ t ‐butyltin dichloride ( t ‐Bu 2 SnCl 2 ) show at least one of these effects. In the case of Et 3 PbCl, the use of PLA 2 ‐inhibitors or pertussis toxin causes a drastic decrease in the amount of arachidonic acid liberated. These experiments demonstrate that the organometallic compounds inhibit the reacylation and/or stimulate the deacylation of fatty acids that are involved in many important biological or pathological mechanisms. The results suggest that in differentiated HL‐60 cells the organometal compounds stimulate the Lands cycle by increasing the activity of the PLA 2 , possibly via a signal‐transduction mechanism, and this effect is intensified via an inhibition of reesterification.