Calcium and thiol roles in cells exposed to organotins

All organotins are toxic and easily move along the trophic chain with an impact on aquatic biocenoses. Their lipophilicity is critical for bioaccumulation and cellular mechanism of action, the latter varies according to the number and type of organic moiety present. Most of their toxic effects are irreversible, dose- and time-dependent, and are conventionally divided in calcium-dependent and calcium-independent. In calcium-dependent mechanisms, organotins induce increasing of the cytosolic calcium ion concentration. This takes part in a multifactorial apoptotic process, involving a decrease of calcium-ATPase activity, cytosol calcification and endonuclease activation. We have proposed a direct interaction between butyltins and calmodulin, probably hydrophobic in nature (between the aliphatic chains of butyltins and hydrophobic pouches of calcium-activated calmodulin) which leads to a complex formation preventing the regulative activity of calmodulin on the calmodulin-dependent calcium-ATPase. Moreover, in invertebrate haemocytes, co-exposition to exogenous calmodulin reverses the calcium-ATPase inhibition. Depolymerisation of cytoskeletal components also occurs. In ascidian haemocytes, microfilaments assemble in clusters around the peripheral cytoplasm and microtubules reveal extensive disaggregation and disperse in the cytoplasm, whereas the microtubule organising centre remains visible. In calcium-independent mechanisms, organotins impair mitochondrial oxidative phosphorylation and several thiol-containing and GSH-dependent enzymes. In ascidian haemocytes, interaction with detoxicant ones, like glutathione S-transferase and glutathione peroxidase, makes exposed organisms more vulnerable to oxidative stress. We do consider that the two proposed mechanisms of toxicity are linked and synergistic in triggering the cascade of secondary events which lead to cell toxic activities and death. Cytoskeletal protein depolymerisation may be due to both cytosolic calcium increase and extensive oxidation of their thiol groups. Moreover, the increase in cytosolic calcium is provoked by an interaction with GSH, since the presence of high amount of cytosolic GSSG causes stimulation of calcium-releasing property of the InsP3 receptor. This work was supported by grants of Co.Ri.La.