THE STRUCTURE OF ORGANOMETALS DETERMINES CYTOTOXICITY AND ALTERATION OF CALCIUM HOMEOSTASIS IN HL-60 CELLS

There is increasing concern about the degradation and metabolisation a s well as the biochemical mechanisms of action of organometallic compo unds, They are known to be immunotoxic and/or neurotoxic, Because of t heir different toxic capacities, the development of a reliable correla tion between molecular parameters and biochemical effects, which could be helpful in risk assessment, was an aim of this study. The tested o rganolead and -tin compounds decrease the viability of human cells in culture in a time- and concentration-dependent manner. Parabolic QSAR( 1) models yield an adequate correlation between toxicity expressed as LC(50) and structural parameters like ionic molecular weight (MW(ion)) or total surface area (TSA). Two main chemical attributes of the orga nometals are probably responsible for such a parabolic relationship: t he hydrophobic side chain and the polar metal atom. Furthermore, all t ested organometal compounds evoke a persistent increase of the cytosol ic free calcium concentration [Ca2+](i). This effect is mainly due to an influx from the extracellular space. Further results suggest that C a2+ enters the cell via opened calcium channels. Based on the essentia l role of Ca2+ within cellular signalling, the perturbation of calcium homeostasis appears to be an important event in final cell killing by organometals and it is most likely that other biochemical mechanisms, e.g. activation of phospholipase A(2), are possibly mediated by an in crease of [Ca2+](i).