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Dugrillon, Gartner, Krawiec, Pisarev
Inhibition of peroxidase and catalase activities and modulation of hydrogen peroxide level by inositol phosphoglycan-like compounds.
Thomasz L, Aran M, Pizarro RA, Ibanez J, Pisarev MA, Converso D, Juvenal GJ, Krawiec L.
Horm Metab Res. 2007 Jan;39(1):14-9.
[abstract only]
"Inositol phosphoglycan-like compounds are produced by the hydrolysis of the membrane bound glycosyl phosphoinositides. Besides being short term mediators of insulin action, they inhibit peroxidases and catalase, increasing the concentration of cellular hydrogen peroxide. Although high concentrations of hydrogen peroxide are toxic, moderate increases of its basal level are signals for different metabolic pathways. The inhibitor, localized in the cytosol of the cell, acts on peroxidases and catalase of the same tissue (homologous action) and of other tissues or organisms (heterologous action). The inositol phosphoglycan-like compound inhibits peroxidases with different prosthetic groups, i.e. containing iron such as: thyroid peroxidase, lactoperoxidase, horseradish peroxidase, soy bean peroxidase; and containing selenium such as glutathione peroxidase and 2-cys peroxiredoxin with no prosthetic group. Besides peroxidases, the inositol phosphoglycan-like compound inhibits catalase, another heme enzyme. The inhibition kinetics demonstrates a noncompetitive effect. The site of action is not the prosthetic group, given that the inhibitor does not produce any effect on the peak in the Soret region in the presence or absence of hydrogen peroxide. In conclusion, the inositol phosphoglycan-like compound is the general inhibitor of peroxidases and catalase involved in the modulation of hydrogen peroxide level that acts in different metabolic pathways as a signal transducer."
Influence of iodide and iodolactones on thyroid apoptosis. Evidence that apoptosis induced by iodide is mediated by iodolactones in intact porcine thyroid follicles.
Langer R, Burzler C, Bechtner G, Gartner R.
Exp Clin Endocrinol Diabetes. 2003 Sep;111(6):325-9.
"Iodine induced thyroid involution is caused by apoptosis rather than necrosis. This effect of iodide on apoptosis of thyroid epithelial cells may be not a direct one but mediated by iodinated derivatives i.e. of polyunsaturated fatty acids, especially of iodolactones, which have previously shown to inhibit thyroid cell proliferation. We studied the influence on apoptosis of iodide (2 microM and 20 microM) and iodolactone (0.05 microM and 0.5 microM), with and without TSH (1 mU/ml), using a well characterized ex vivo- culture system of intact porcine thyroid follicles in three-dimensional culture. Apoptosis and necrosis was evaluated by electron-microscopy. Stimulation with 2 and 20 microM iodide rapidly induced a rate of apoptosis (4 - 6 %) comparable to about 40-fold lower doses of delta-iodolactone (0.05 microM and 0.5 microM). Addition of TSH (1 mU/ml) caused a slight but not significant further increase of the incidence of apoptotic cells. The rate of necrotic thyroid epithelial cells (1 - 2 %) was similar in all experiments. As delta-iodolactone in very low concentrations--comparable to iodide in higher concentrations--not only inhibits growth but also induces apoptosis, it has to be supposed that the effect of iodide is mediated by this iodinated compound. However, further experiments are necessary to confirm this hypothesis. In addition it could be demonstrated, that apoptosis is a very rapid and limited process in intact follicles. This also may explain, why iodine supplementation even in high doses does not lead to thyroid atrophy but only normalisation of thyroid size. These results confirm that apoptosis is an important regulated and limited mechanism in goiter involution."
"Introduction. Apoptosis, programmed or physiological cell death, is an essential process for development and homeostasis of all organ systems. Concerning the thyroid, abnormal apoptotic thyroid follicular cells appear in various diseases of the thyroid like Hashimoto's thyroiditis, Graves' disease, or in proliferating human thyroid tissue like multinodular goiter and neoplastic thyroid tissue. An increased incidence of apoptotic rather than necrotic thyroid epithelial cells has already been shown during goiter development and involution in rats. Also in subacute thyroiditis, apoptotic thyroid follicular cells were detected. Especially in thyroid autoimmune diseases like Hashimoto's thyroiditis and Graves' disease, apoptosis seems to be related to the FAS/FASL pathway. In vitro TGF-B and EGF, high doses of iodide also induce apoptosis of thyroid follicular cells.
"Iodine supplementation not only prevents thyroid enlargement but is also known to reduce thyroid hyperplasia. The inhibitory effect of iodide on thyroid follicular cell growth has been shown to be mediated by iodinated derivatives of polyunsaturated fatty acids (PFA), especially iodolactones. The delta-iodolactones of arachidonic acid and eicosapentaenoic acid inhibit growth-factor-induced porcine thyroid cell proliferation. As it is known that not iodide directly, but iodinated compounds mediate thyroid involution, we now investigated the influence on apoptosis of iodolactone and iodide...."
"The amount of apoptotic cells is limited to about 10% of all cells, implicating a regulatory mechanism preventing apoptosis of too many cells and destruction of follicles. This may be the reason why also in vivo high doses of iodide do not lead to atrophy of the land, but only to an involution to a normal and sufficient size for maintaining the normal function. Within the follicles, not more than a few scattered cells within one follicle underwent apoptosis - apoptotic cells were mainly extruded out of the follicular structure, but not into the follicular lumen. Therefore, the structure of the follicles always was preserved and no leakage or interruption of follicular structure occurred. This also implicates a paracrine communication of follicular cells preventing the destruction of the cell formation."
Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations.
Gartner
R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW.
J Clin Endocrinol Metab. 2002 Apr;87(4):1687-91.
"In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells. Selenium-dependent enzymes also have several modifying effects on the immune system. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases. We performed a blinded, placebo-controlled, prospective study in female patients (n = 70; mean age, 47.5 +/- 0.7 yr) with autoimmune thyroiditis and thyroid peroxidase antibodies (TPOAb) and/or Tg antibodies (TgAb) above 350 IU/ml. The primary end point of the study was the change in TPOAb concentrations. Secondary end points were changes in TgAb, TSH, and free thyroid hormone levels as well as ultrasound pattern of the thyroid and quality of life estimation. Patients were randomized into 2 age- and antibody (TPOAb)-matched groups; 36 patients received 200 microg (2.53 micromol) sodium selenite/d, orally, for 3 months, and 34 patients received placebo. All patients were substituted with L-T(4) to maintain TSH within the normal range. TPOAb, TgAb, TSH, and free thyroid hormones were determined by commercial assays. The echogenicity of the thyroid was monitored with high resolution ultrasound. The mean TPOAb concentration decreased significantly to 63.6% (P = 0.013) in the selenium group vs. 88% (P = 0.95) in the placebo group. A subgroup analysis of those patients with TPOAb greater than 1200 IU/ml revealed a mean 40% reduction in the selenium-treated patients compared with a 10% increase in TPOAb in the placebo group. TgAb concentrations were lower in the placebo group at the beginning of the study and significantly further decreased (P = 0.018), but were unchanged in the selenium group. Nine patients in the selenium-treated group had completely normalized antibody concentrations, in contrast to two patients in the placebo group (by chi(2) test, P = 0.01). Ultrasound of the thyroid showed normalized echogenicity in these patients. The mean TSH, free T(4), and free T(3) levels were unchanged in both groups. We conclude that selenium substitution may improve the inflammatory activity in patients with autoimmune thyroiditis, especially in those with high activity. Whether this effect is specific for autoimmune thyroiditis or may also be effective in other endocrine autoimmune diseases has yet to be investigated."
Autoregulatory Actions of Iodine
Pisarev MA, Gartner R
in Braverman LE, Utiger RD, The Thyroid, 8th ed. 2000, pp 85-90.
"Iodine is not only the main substrate for the thyroid to synthesize thyroid hormones but also directly influences most of the specific functions in the thyroid as well as thyroid cell proliferation. The daily intake of iodine in iodine sufficient areas ranges from about 50 to 1,000 mcg per day, and thyroid function in general remains normal without changes in circulating thyroid-stimulating hormone (TSH). This phenomenon is best explained by autoregulatory processes. Autoregulation may be defined as the ability of the thyroid to regulate its own function and growth depending on the intrathyroidal availability of iodide (and putative iodocompounds) and to modulate the response to thyrotrophic factors."
Presence of a soluble inhibitor of thyroid iodination in primary cultures of thyroid cells.
Bocanera LB, Aphalo P, Pisarev MA, Gartner R, Silberschmidt D, Juvenal GJ, Beraldi G, Krawiec L.
Eur J Endocrinol. 1999 Jul;141(1):55-60.
"Monolayer cultures of thyroid cells lose their iodide organification capacity a few days before the disappearance of thyroid peroxidase (TPO) activity. The present studies were performed in order to clarify this point. The above mentioned difference was due to the presence of an inhibitor in the monolayer thyroid cells culture, given that total homogenate prepared from confluent cells caused a significant inhibition of activity of TPO from fresh tissue. The inhibitor was localized in the 105000g supernatant of the homogenate of the cell culture, but not in a similar preparation obtained from fresh thyroid. It is thermostable, dialyzable and has a molecular weight of less than 2 kDa. Addition of the inhibitor at the end of the reaction of tyrosine iodination failed to alter the results. This fact suggests that the compound does not destroy the iodinated product. The presence of the cytosolic inhibitor was observed in monolayer thyroid cell cultures of different species (bovine, porcine, rat and human) but not in free follicles cultures."
[From iodine deficiency to goiter. Pathophysiology of iron deficiency goiter]
Gartner R, Dugrillon A.
Internist (Berl). 1998 Jun;39(6):566-73. Review. German.
[citation only]
Role of cyclic 3'5' guanosine monophosphate and nitric oxide in the regulation of iodide uptake in calf thyroid cells.
Bocanera LV, Krawiec L, Silberschmidt D, Pignataro O, Juvenal GJ, Pregliasco LB, Pisarev MA.
J Endocrinol. 1997 Dec;155(3):451-7.
"Sodium nitroprusside (SNP) spontaneously produces nitric oxide (NO). In many cell types, this activates the soluble form of the enzyme guanylyl cyclase (GC), resulting in the elevation of cGMP. We herein report the role of NO and cGMP on iodide uptake in primary cultures of calf thyroid cells. Iodide uptake is the limiting step in thyroid hormone biosynthesis and a typical functional parameter. The effect of SNP on this parameter was thus determined. In cells treated with TSH for 72 h, addition of 5 mM SNP for the last 2 h caused a significant inhibition on iodide uptake, with no change in cells not treated with TSH. This action was mimicked by an analogue of cGMP, 8Br-cGMP, and blocked by reduced hemoglobin, thus suggesting that it is mediated by the GC-cGMP pathway. SNP also inhibited the stimulation caused by forskolin or analogues of cAMP, indicating that the effect takes place in this pathway, which would be distal to cAMP generation. The accumulation of radioiodine by thyroid cells is a consequence of the balance between influx and efflux. The studies demonstrate that SNP does not affect iodide efflux, thus revealing that it inhibits the influx."
Regulation of transforming growth factor beta 1 messenger ribonucleic acid expression in porcine thyroid follicles in vitro by growth factors, iodine, or delta-iodolactone.
Gartner R, Schopohl D, Schaefer S, Dugrillon A, Erdmann A, Toda S, Bechtner G.
Thyroid. 1997 Aug;7(4):633-40.
[abstract only]
"Transforming growth factor
beta 1 (TGF beta 1) is an autocrine growth factor for thyrocytes and
is supposed to be the mediator of iodine-induced growth inhibition of
thyroid epithelial cells, but this is still controversial. We further
investigated this hypothesis using intact porcine thyroid follicles ex
vivo in a three-dimensional culture system. In this culture system it
has been shown previously that both iodide as well as
delta-iodolactone, the putative iodocompound mediating thyroid cell
proliferation, inhibit growth of these follicles. We measured the
amount of TGF beta 1 mRNA expression in these follicles after
treatment either with thyrotropin (TSH), epidermal growth factor (EGF),
or transforming growth factor alpha (TGF alpha) for growth stimulation
or with inorganic iodine or delta-iodolactone in concentrations known
to inhibit growth. TGF beta 1-mRNA was detected by Northern blot
analysis. The known major transcript of 2.5 kb was detected in a
steady state level up to 48 hours in untreated thyroid follicles. EGF
and TGF alpha (5 ng/mL each) enhanced TGF beta 1 mRNA about threefold
within 4 and 8 hours. This increase of TGF beta 1 mRNA was slightly
decreased by simultaneous incubation with delta-iodolactone (1 microM)
or iodide (40 microM KI). In contrast, both TSH (1 mU/mL) and
forskolin (16 microM) decreased TGF beta 1 mRNA expression to about
70%, and this effect was abolished when follicles were pretreated with
iodide (40 microM KI) in a concentration known to inhibit TSH action
on cyclic adenosine monophosphate (cAMP) formation and proliferation.
Iodide or delta-iodolactone alone had no significant effect on basal
TGF beta 1 mRNA expression. We conclude that the growth inhibitory
effect of iodide as well as of delta-iodolactone is not mediated
through TGF beta 1 in intact porcine thyroid follicles ex vivo. The
stimulatory effect of EGF and TGF alpha on TGF beta 1 expression might
be related to extracellular matrix modulation during proliferation."
Iodolactones and iodoaldehydes--mediators of iodine in thyroid autoregulation.
Dugrillon A.
Exp Clin Endocrinol Diabetes. 1996;104 Suppl 4:41-5. Review.
[abstract only]
"Within the last decades multiple iodolipid-classes have been identified in thyroid tissue. For a long time they have been supposed to be involved in thyroid autoregulation, but for the time being no specific compounds could be isolated. A new approach was stimulated by the finding that thyroid cells were able to iodinate polyunsaturated fatty acids to form iodolactones and by the identification of alpha-iodohexadecanal (alpha-IHDA) as the major compound of an iodolipid fraction. alpha-IHDA exerts multiple inhibitory effects on adenylate cyclase, NADPH-oxidase and thyroid peroxidase. Therefore, it is speculated as a mediator of the Wolff-Chaikoff-effekt and to be involved in the autoregulation of specific thyroid functions mediated by the cyclic adenosine-3',5'-monophosphate (cAMP)-pathway. Meanwhile 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid delta-lactone (delta-iodolactone) has been identified in human thyroid tissue and it could be demonstrated that this iodoeicosanoid specifically inhibits signal transduction pathways induced by local growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). Therefore, delta-iodolactones seem to act as mediators of iodine, especially in the autoregulation of cAMP-independent thyroid cell proliferation. We will summarize these important new findings and discuss the role of these iodolipids on thyroid cell growth regulation."
Evidence that iodolactones are the mediators of growth inhibition by iodine on the thyroid.
Gartner R, Dugrillon A, Bechtner G.
Acta Med Austriaca. 1996;23(1-2):47-51. Review.
[abstract only]
"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."
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.
Dugrillon A, Gartner R.
Eur J Endocrinol. 1995 Jun;132(6):735-43.
[abstract only]
"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)"
Studies on the goiter inhibiting action of iodolactones.
Pisarev MA, Krawiec L, Juvenal GJ, Bocanera LV, Pregliasco LB, Sartorio G, Chester HA.
Eur J Pharmacol. 1994 Jun 2;258(1-2):33-7.
"The thyroid gland synthesizes 6-delta-iodolactone, a compound shown to inhibit goiter growth in vivo and cell proliferation in culture. The present studies were performed to characterize this effect further with the aim of exploring the possible therapeutic action of iodolactones. Prevention assay: rats were treated simultaneously with a goitrogen, methylmercaptoimidazole, and either 6-delta-iodo-lactone or 14-iodo-omega-lactone, a synthetic derivative, given either i.p. or p. o. Both compounds caused a significant decrease in thyroid weight irrespective of the route of administration, but oral administration was less effective. A dose-response relationship was observed, the minimal effective dose (i.p.) being 3 micrograms/day. Involution assay: goiter was first induced with methylmercaptoimidazole and then the iodolactones were injected. Both compounds caused a significant involution, which was dose-related. Acute (10 days) administration of the iodolactones did not produce significant changes in several serum parameters (total T3 and T4, cholesterol, total protein, urea and acetylcholinesterase). These results give further support to the potential therapeutic application of iodolactones."
Identification of delta-iodolactone in iodide treated human goiter and its inhibitory effect on proliferation of human thyroid follicles.
Dugrillon A, Uedelhoven WM, Pisarev MA, Bechtner G, Gartner R.
Horm Metab Res. 1994 Oct;26(10):465-9.
"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."
Effect of iodoarachidonates on thyroid FRTL-5 cells growth.
Pisarev MA, Bocanera LV, Chester HA, Kleiman de Pisarev DL, Juvenal GJ, Pregliasco LB, Krawiec L.
Horm Metab Res. 1992 Dec;24(12):558-61.
[abstract only]
"Excess iodide inhibits several thyroid parameters, by a putative organic iodocompound. Different iodolipids, including iodinated derivatives of arachidonic acid (IAs), are produced by rat, calf and pig thyroid. The action of two iodolactones, one bearing the iodine atom at the position 6 (IL-d) and the other at position 14 (IL-w) on growth of FRTL-5 cells was studied. KI, IL-w and IL-d exert a dose-related inhibition on FRTL-5 cell proliferation. The first two compounds caused inhibition at 1 microM while IL-d was effective at 10 microM. This inhibitory action of iodolactones (ILs) was not altered by 1 mM methyl-mercaptoimidazol (MMI), indicating that they exert their effect per se. The action of ILw on cell growth was reversible. The growth-stimulating effect of 10 microM forskolin was inhibited by IAs, showing that one possible site of action lies at the cAMP pathway. The present results give further support to our hypothesis about the role of IAs in thyroid growth autoregulation."
The role of iodine and thyroid cell growth.
Dugrillon A, Gartner R.
Thyroidology. 1992 Apr;4(1):31-6. Review.
[abstract only]
"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)"
Further studies on the antigoitrogenic action of iodoarachidonates.
Pisarev MA, Krawiec L, Juvenal GJ, Chester HA, Bocanera LV, Pregliasco LB, Sartorio G.
Thyroidology. 1992 Apr;4(1):27-9.
[abstract only]
"Previous studies have shown that iodoarachidonates (IAs) prevent goiter production in rats. In the present studies we show that both IL-d and IL-w (IAs bearing the iodine atom at the positions 6 and 14, respectively), cause a significant involution of preformed goiter. This effect was evident when IAs were administered either orally or via i.p., although the first one required larger doses to obtain the same degree of inhibition. No changes were observed in serum protein, urea, cholesterol, cholinesterase, T3 or T4. In vitro studies with FRTL-5 cells showed that both IAs inhibit iodide and alpha-AIB uptake, as well as ATPase activity."
Thyroid autoregulation: evidence for an action of iodoarachidonates and iodide at the cell membrane level.
Krawiec L, Chester HA, Bocanera LV, Pregliasco LB, Juvenal GJ, Pisarev MA.
Horm Metab Res. 1991 Jul;23(7):321-5.
[abstract only]
"Iodolipids are the possible mediators of excess iodide in thyroid autoregulation. Previous work from our laboratory has shown that 14-iodo-15-hydroxy-5,8,11 eicosatrienoic acid (I-HO-A) and its omega lactone (IL-w) mimic the inhibitory action of excess iodide upon several parameters of thyroid metabolism. The present experiments were performed in order to study the mechanism of the inhibitory effect of I-HO-A and IL-w on 2-deoxy-D-glucose (DOG) and aminoisobutyric acid (AIB) uptake by calf slices. I-HO-A, IL-w and KI 0.1 mM caused a 33, 31 and 25% inhibition, respectively, of AIB uptake. The presence of 0.1 mM methimazole (MMI) only reversed the effect of KI. The transport of DOG was inhibited by both compounds: I-HO-A caused a 62% decrease, while IL-w produced a 64% inhibition; and MMI failed to relieve their action. On the contrary, the 33% inhibition caused by KI disappeared when MMI was present. Taking into account that AIB and DOG transport across the membrane requires energy, supplied by Na-K-ATPase, changes in its activity were studied. TSH (10 mU/ml) produced a 74% increase in the enzyme activity which was significantly blocked by KI (82%), I-HO-A (100%) and IL-w (100%). Basal enzyme activity was impaired by IL-w (33%), but not by KI. These results were correlated with the decrease of DOG uptake produced by 1 mM ouabain. Tissue specificity effect of iodoarachidonates was demonstrated by the absence of action on DOG transport in kidney and liver. (ABSTRACT TRUNCATED AT 250 WORDS)"
Evidence that an iodolactone mediates the inhibitory effect of iodide on thyroid cell proliferation but not on adenosine 3',5'-monophosphate formation.
Dugrillon A, Bechtner G, Uedelhoven WM, Weber PC, Gartner R.
Endocrinology. 1990 Jul;127(1):337-43.
[abstract only]
"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."
Evidence that thyroid growth autoregulation is mediated by an iodolactone.
Gartner R, Dugrillon A, Bechtner G.
Acta Med Austriaca. 1990;17 Suppl 1:24-6.
[abstract only]
"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."
Thyroid autoregulation. Inhibition of goiter growth and of cyclic AMP formation in rat thyroid by iodinated derivatives of arachidonic acid.
Pisarev MA, Chazenbalk GD, Valsecchi RM, Burton G, Krawiec L, Monteagudo E, Juvenal GJ, Boado RJ, Chester HA.
J Endocrinol Invest. 1988 Oct;11(9):669-74.
[abstract only]
"Thyroid autoregulation has been related to intraglandular content of an unknown putative iodocompund. Data from different laboratories have shown that the thyroid is capable of producing different iodolipids, including iodinated derivatives of arachidonic acid; such as 5-hydroxy-6-iodo-8, 11, 14-eicosatrienoic-delta-lactone (IL-delta). Previous results from our laboratory showed that a semi-purified preparation of iodinated arachidonic acid exerts an inhibitory action in vitro on calf thyroid. In the present studies three purified iodinated derivatives of arachidonic acid were synthesized: IL-delta; 14-iodo-15-hydroxy-5, 8, 11-eicosatrienoic acid (I-OH-A) and its corresponding omega-lactone (IL-omega). Their action on MMI-induced goiter was studied in rats. Administration of MMI to rats during 10 days increased thyroid weight by 124%. This effect was significantly inhibited by the simultaneous injection of 5 micrograms/day of I-OH-A (57% inhibition of MMI action), IL-W (39%), IL-delta (33%) and T3 (95%), while arachidonic acid was without action. No inhibition was found with 1.25 micrograms/day Kl, a dose equivalent to that which could be originated from total dehalogenation of the iodocompounds. These results support the idea that these iodocompounds have an intrinsic biologic activity and that there is a correlation between action and chemical structure. Serum TSH was increased around 15-20 fold after MMI administration. Chronic or acute injection of I-OH-A failed to alter TSH levels, indicating that this iodocompound exerts its action directly on the gland, without altering TSH concentration. (ABSTRACT TRUNCATED AT 250 WORDS)"
Thyroid autoregulation. Inhibitory effects of iodinated derivatives of arachidonic acid on iodine metabolism.
Chazenbalk GD, Valsecchi RM, Krawiec L, Burton G, Juvenal GJ, Monteagudo E, Chester HA, Pisarev MA.
Prostaglandins. 1988 Aug;36(2):163-72.
[abstract only]
"Thyroid autoregulation has been linked to an organified iodocompound. Since several iodolipids are produced by the gland their possible role in thyroid autoregulation was examined. The following pure synthetic compounds were prepared: 1) 14-iodo-15-hydroxy-5,8,11-eicosatrienoic acid (I-OH-A); 2) its omega lactone (IL-omega); 3) 5-hydroxy-6-iodo-8,11,14-eicosatrienoic acid delta lactone (IL-delta). Their action on iodine metabolism was studied. Iodine uptake was measured in calf thyroid slices. At 10(-4)M I-OH-A caused a 64% decrease in the T/M ratio, while IL-omega inhibited it by 36% and IL-delta was without effect. At 10(-5)M the inhibition was 44% for I-OH-A and 19% for IL-omega, while T3 was without action. A possible isotopic dilution effect was excluded, and no change in iodine efflux was observed. The inhibition by I-OH-A of iodide uptake was observed after only 15 min preincubation. This compound also decreased 125I accumulation in rats. In calf thyroid slices, I-OH-A at 10(-4)M, inhibited PB125I formation by 80%, IL-omega by 62% and IL-delta by 37%. T3 and arachidonic acid were without action. I-OH-A also caused a dose-dependent inhibition of TSH-stimulated iodide organification. The present results demonstrate, for the first time, that iodinated derivatives of arachidonic acid inhibit thyroid function and mimic the effect of iodide on thyroid autoregulation."
The inhibition of PB125I formation in calf thyroid caused by 14-iodo-15-hydroxy-eicosatrienoic acid is due to decreased H2O2 availability.
Krawiec L, Chazenbalk GD, Puntarulo SA, Burton G, Boveris A, Valsecchi RM, Pisarev MA.
Horm Metab Res. 1988 Feb;20(2):86-90.
[abstract only]
"Previous work from our laboratory has shown that 14-iodo-15-hydroxy-5,8,11-eicosatrienoic acid (I-HO-A) is a potent inhibitor of iodine organification in calf thyroid slices. The present studies were performed in order to clarify the mechanism of this action. Incubation of thyroid slices with 10(-4)M I-HO-A caused a 47 and 53% decrease in PB125I formation after 30 and 60 min incubation, respectively. In a series of experiments an inverse relationship between the degree of inhibition caused by I-HO-A and total iodine content and basal iodoprotein formation was observed. Chromatographic analysis of the labeled compounds showed a significant decrease in 125I incorporation into MIT, DIT, T3 and total iodolipid. The site of the inhibitory effect of I-HO-A was then sought. TPO was measured by three different methods. When TPO was solubilized from I-HO-A treated slices, no change in enzymatic activity was observed. Moreover, the same lack of action was found when solubilized TPO was incubated with I-HO-A. The production and release of H2O2 into the incubation medium was measured by chemiluminiscence technique. In control slices the values increased during the first 10 min and reached a plateau. Pretreatment of the slices with 10(-4)M KI caused a 51% inhibition, while the same concentration of I-HO-A produced a 59% inhibition. The possibility that I-HO-A might exert its action through a putative protein inhibitor was also explored. Incubation of slices with 10(-5)M I-HO-A caused a 46% decrease in PB125I formation and addition of actinomycin D or puromycin failed to alter this effect. (ABSTRACT TRUNCATED AT 250 WORDS)"