Biomedical subjects

A Dugrillon

Publications and source records attributed to A Dugrillon.

6 recordsLinked to original sources

PubMed1996

Evidence that iodolactones are the mediators of growth inhibition by iodine on the thyroid.

Different iodolipids have been identified within the last decades in thyroid cells exposed to iodine in vitro as well as in vivo. Iodolipids have been supposed to be involved in thyroid autoregulation, but no specific compounds could be found. A new approach was stimulated by the finding that rat thyroid lobes were able to iodinate arachidonic acid and docosahexaenoic acids in vitro. Meanwhile 6-iodo-5 hydroxy-eicosatrienoic acid (delta-iodolactone) has been identified in human thyroid tissue, but only after treating the patients with high doses of iodine before thyroidectomy, whereas in untreated endemic goiter this delta-iodolactone could not be found. In rats treated with iodolactones, methimazole induced goiter formation could be prevented. In human and porcine thyroid cells in vitro, delta-iodolactone inhibited epidermal growth factor (EGF) induced proliferation in 50-fold lower concentrations than iodide itself. Furthermore it could be demonstrated that only the IP3-, but not the cAMP generation in porcine thyroid cells could be inhibited by this compound. Also a structure specifity for delta-iodolactones for the biological activity could be shown. We will summarize and discuss these important new findings on the role of iodolactones on thyroid growth.

Animals↗

PubMed1995

delta-Iodolactones decrease epidermal growth factor-induced proliferation and inositol-1,4,5-trisphosphate generation in porcine thyroid follicles--a possible mechanism of growth inhibition by iodide.

delta-Iodolactone (6-iodo-8,11,14-eicosatrienoic delta-lactone, delta-IL), an iodinated derivative of arachidonic acid, has been shown to be synthesized in thyroid tissue and to inhibit thyroid cell proliferation. It is discussed as a potential mediator of the autoregulatory pathway of iodide in cyclic adenosine-3',5'-monophosphate (cAMP)- and thyrotropin (TSH)-independent growth. We therefore further localized the action of iodide and of delta-IL in isolated porcine thyroid follicles. Epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) dose dependently stimulated thyroid cell proliferation, which could be inhibited by staurosporin (0.1-10 nmol/l). Iodide (2.5-40 mumol/l) as well as delta-IL (0.5-2 mumol/l) also dose dependently inhibited EGF- and TPA-induced proliferation. As the calcium ionophor A23187 (100 pmol/l) completely abolished the inhibitory effects of iodide and of delta-IL, this may indicate a mechanism of delta-IL at or proximal to the calcium-dependent activation of protein kinase C. The growth inhibitory effect was restricted to delta-iodolactones when delta-IL was compared to 6-iodo-8,11,14,17-eicosatetraenoic delta-lactone and 5-iodo-7,10,13,16,19-docosapentaenoic gamma-lactone. It could not be prevented with propylthiouracil and therefore deiodination and a different iodide action is unlikely. Inositol-1,4,5-trisphosphate (IP3) and cAMP were measured in extracts from isolated porcine thyroid follicles stimulated with EGF (10 ng/ml) or TSH (1.0 U/l) revealing comparable kinetics in IP3 generation, while cAMP formation was only stimulated by TSH. delta-Iodolactone (2 mumol/l) only decreased EGF-induced IP3 formation, whereas TSH-induced IP3 and cAMP formation was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Identification of delta-iodolactone in iodide treated human goiter and its inhibitory effect on proliferation of human thyroid follicles.

There is evidence that iodoarachidonates are mediators of iodide in thyroid autoregulation, however, their occurrence in vivo has not yet been demonstrated. We therefore tried to identify delta-iodolactone (5-Hydroxy-6-iodo-8,11,14-eicosatrienoic delta-lactone, IL-delta) in thyroid tissue from a patient with Graves' disease treated with high doses of iodide. Lipids were extracted from thyroid tissue, purified by reversed phase chromatography and analyzed by gas chromatography--tandem mass spectrometry (GC-MSMS). The retention time in gas chromatography and fragmentation pattern in tandem mass spectrometry were determined with biochemically synthesized non-deuterated and deuterated IL-delta. According to retention time (13.44 min) and specific fragments (m/z 303, m/z 259) the occurrence of IL-delta could be demonstrated in the extract of iodide treated goiter. In vitro, potassium iodide (40 microM) as well as IL-delta (1.0 microM) significantly inhibited the proliferation of human thyroid follicular cells induced by phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate). These results demonstrate for the first time that Il-delta is present in iodide treated human thyroid. As cell proliferation is under negative control of IL-delta, a crucial role in thyroid involution following iodide treatment may be possible.

Arachidonic Acids↗

PubMed1992

The role of iodine and thyroid cell growth.

The autoregulatory effects of iodide on thyroid growth and function are discussed to be mediated by iodinated derivatives of essential fatty acids (EFA), esp. iodolactones. We now reevaluated the effect of iodide on proliferation of isolated porcine thyroid follicles by determination of cell counts and investigated the effects of pretreatment of the follicles with arachidonic acid (AA, C 20:4 n6) in comparison to docosahexaenoic acid (DHA, C22:6 n3). Growth experiments were performed in multi-well culture plates and cell counts were determined after 6 d of incubation. EGF (5 ng/ml) significantly stimulated thyroid cell proliferation (151 +/- 6%; Mean +/- SD vs. basal control, 100 +/- 8%). 2.5 microM of iodide, added 24 h before EGF, had a weak stimulatory effect (168 +/- 9%) whereas higher concentrations of iodide (5-80 microM) exerted significantly dose-dependent inhibitory effects (117 +/- 1% at 80 microM of KI) which could be abolished with 500 microM of methimazole (155 +/- 11% at 80 microM of KI). Isolated porcine follicles showed a rapid uptake of EFA (25 microM) measured by specific tracer activity in the ethanol/acetic acid extracts of follicles (1.60 +/- 0.48 mumol EFA/ml follicle/24 h). Treatment with DHA (100 and 300 microM) significantly enhanced the inhibitory effect of 10 microM of iodide on thyroid follicle proliferation (84 +/- 2% and 45 +/- 4%) in contrast to follicles pretreated with AA (100 +/- 8% and 60 +/- 8%). These results demonstrate the biphasic effect of iodide on thyroid growth which can be abolished by inhibition of iodide organification with methimazole.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

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.

Animals↗

PubMed1990

Evidence that thyroid growth autoregulation is mediated by an iodolactone.

For further investigating the mechanism of the known autoregulation of thyroid follicle growth and function by iodine, we tried to detect iodolactone (6-iodo-8,11,14-eicosatrienoic-delta-lactone) in isolated porcine thyroid follicles and investigated the effects of in vitro synthesized iodolactone on EGF induced thyroid cell proliferation as well as on TSH induced cycli AMP formation. In vitro synthesis of iodolactone was performed with lactoperoxidase catalyzed iodination of arachidonic acid. With gas chromatography-mass spectrometry 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 (10uM) and arachidonic acid (1uM) revealed an identical substrate. This indicates the ability of thyroid follicles to form iodolactone. Iodolactone (0.1-1.0 uM) dose-dependently inhibited EGF induced thyroid cell growth. This growth inhibiting effect of iodolactone was found to be 50-fold more pronounced than the inhibitory effect of KI (4 x 10(-5] 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 (1mM). The basal as well as TSH (0.5 U/l) induced cyclic AMP formation was 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.

Animals↗