Thimerosal: a versatile sulfhydryl reagent, calcium mobilizer, and cell function-modulating agent.

Abstract

An overview of the literature concerning the effects of thimerosal is presented. Because of its antibacterial effect, thimerosal is used for a variety of practical purposes such as antiseptic and preservative. In biomedical studies, thimerosal is used as a sulfhydryl reagent, and as a calcium-mobilizing agent. The ability of thimerosal to act as a sulfhydryl group is related to the presence of mercury. Relatively little study has been devoted to the mechanism of the reaction of thimerosal with the sulfhydryl group; the sulfhydryl reactive capacity is mostly concluded on the basis of inactivation of the effect by dithiothreitol (DTT). Thimersal causes a release of calcium from intracellular stores in many cells types; this is followed by an influx of extracellular calcium. Both InsP3- and ryanodine-sensitive calcium stores may be affected. Studies with permeabilized cells or organelles show that the effect of thimerosal on calcium is dependent on the concentration: low concentrations of thimerosal stimulate calcium release, high concentrations are inhibitory. This dependence is not found in intact cells. Thimerosal may activate or inhibit a number of cell functions. These are often related to the ability to release calcium or with the sulfhydryl reactivity. In platelets, thimerosal causes aggregation, increase of arachidonic acid metabolism, and exocytotic release of serotonin. In neutrophils, thimerosal causes, besides an increase of cytosolic free calcium, an increase of formyl-methionyl-leucyl-phenylalanine (fMLP)-activated leukotriene release, and a modulation of chemotactic migration and exocytosis. At low concentrations, thimerosal induces chemotactic migration of neutrophils, in the absence of other chemoattractants. The effect is also observed with thiosalicylic acid, indicating that the stimulation of migration was due to the thiosalicylic acid moiety of the thimerosal molecule. At higher concentrations, thimerosal causes inhibition of fMLP-activated migration. Low concentrations of thimerosal, but not of thiosalicylic acid, induced exocytotic enzyme release from neutrophils. High concentrations of thimerosal inhibited fMLP-activated exocytosis. The results point to an involvement of calcium mobilization and calcium influx of activation, and reaction with sulfhydryl groups for inhibition.