Inhibition of iodide transport in thyroid cells by dysidenin, a marine toxin, and some of its analogs.

Dysidenin, a hexachlorinated tripeptide-like molecule extracted from the sponge Dysidea herbacea, has lethal effects on fishes and some marine organisms. In an in vitro screening study, this molecule appeared to be a strong inhibitor of iodide transport in dog thyroid slices. Ouabain blocks iodide transport by inhibiting the Na+/K+ ATPase, which sustains the Na+ gradient needed to drive iodide transport. Dysidenin and ouabain block iodide transport with the same kinetics but not by the same mechanisms; dysidenin, unlike ouabain, did not inhibit 86Rb+ uptake or increase its efflux. Inhibitors of chloride channels or carriers did not reduce the T/M value of 131I-, with the exception of phloretin, a relatively nonspecific anion transport blocker. Monesin (or Na+ ionophores) but not dysidenin clearly increased 22Na+ efflux in tracerpreloaded thyroid slices treated with ouabain. This suggests that dysidenin does not act as a chloride channel inhibitor or a Na+ ionophore. Increasing the iodide concentration in the medium decreased the inhibition by dysidenin, suggesting a pseudocompetitive type of effect. To study the structure-activity relationship of dysidenin, several hydrolytic products and synthetic derivatives have been prepared. The data obtained showed that the inhibition is sensitive to stereochemical effects and that the trichloromethyl terminus of the molecule is recognized by the binding site. The presence of only one trichloromethyl terminus is sufficient to exert the inhibitory effect.