Evidence that an iodolactone mediates the inhibitory effect of iodide on thyroid cell proliferation but not on adenosine 3',5'-monophosphate formation.

Iodolactone (6-iodo-8,11,14-eicosatrienoic-delta-lactone), an iodinated derivative of arachidonic acid, was found to be synthesized in rat thyroid slices; however, the physiological role of this compound is still unknown. We tried to detect iodolactone in isolated porcine thyroid follicles and investigated the effects of in vitro synthesized iodolactone on epidermal growth factor-induced thyroid cell proliferation and TSH-induced cAMP formation. In vitro synthesis of iodolactone was performed with lactoperoxidase-catalyzed iodination of arachidonic acid in the presence of trace amounts of [125I]- and [3H]arachidonic acid. After purification by silica gel chromatography, HPLC of the reaction products revealed one main peak containing trace amounts of both [125I]- and [3H]arachidonic acid. With gas chromatography-mass spectrometry (GC-MS) a molecular mass of 391 m/z, corresponding to the derivatization product of iodolactone, was found. An ethanol-chloroform extract of isolated thyroid follicles preincubated with KI (10 microM) and arachidonic acid (1 microM) revealed peaks in HPLC and GC comparable with those of in vitro synthesized iodolactone. This indicates the ability of thyroid follicles to form iodolactone. Iodolactone (0.1-1.0 microM) dose-dependently inhibited epidermal growth factor-induced thyroid cell growth. This growth-inhibiting effect of iodolactone was 50-fold more pronounced than the inhibitory effect of KI (4 X 10(-5) microM) on thyroid cell proliferation. In contrast to the effect of iodide, the inhibitory effect of iodolactone on thyroid cell growth could not be abolished by methimazole (1 mM). Basal as well as TSH (0.5 U/liter)-induced cAMP formation were not changed by iodolactone. These experiments suggest a physiological role of iodolactone as a mediator of the known inhibitory effect of iodide on thyroid growth.