Un rôle physiologique des plasmalogènes: la protection contre le stress oxydatif et l’excès d’iode

Plasmalogens constitute a peculiar class of glycerophospholipids characterized by a unique structural feature: a vinyl ether group on the sn-1 position of glycerol instead of the usual ester function. The specific role of plasmalogens, which are especially abundant in brain and heart, has remained elusive for a long time. The ability of reactive oxygen species such as singlet oxygen to attack vinyl ether groups led to the hypothesis that plasmalogens have an antioxidant function. This is supported by the cleavage of plasmalogens during some forms of oxidative stress and by the hypersensitivity to oxidants of mutant cells deficient in plasmalogen synthesis. In a completely different research area, the main iodolipid of the thyroid gland was identified as 2-iodohexadecanal. This compound is formed via the addition of a peroxidase-generated reactive form of iodine to the vinyl ether group of plasmalogens, followed by cleavage of this group. As 2-iodohexadecanal mimicks the inhibitory effects of iodine on adenylyl cyclase and H2O2 production in the thyroid, it is likely to represent the mediator of these well-known autoregulatory actions which prevent the development of thyrotoxicosis following exposure to excess iodine.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Les métabolites hexachlorés de Dysidea herbacea: dérivés modèles pour la synthèse d’inhibiteurs spécifiques du transport de l’iodure dans les cellules de la glande thyroïde

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The Na+-I- cotransporter of the thyroid: Characterisation of new inhibitors

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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.In VitroJournal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Biosynthesis and metabolism of 2-iodohexadecanal in cultured dog thyroid cells.

2-Iodohexadecanal (2-IHDA) is a major thyroid iodolipid. It mimics the main regulatory effects of iodide on thyroid metabolism: inhibition of H2O2 production and of adenylyl cyclase. The biosynthesis of 2-IHDA and its metabolism have been investigated in cultured dog thyroid cells maintained in a differentiated state by forskolin. Incubation of these cells with [9,10-3H]hexadecan-1-ol or [9,10-3H]palmitic acid labeled several phospholipids, but [9, 10-3H]hexadecan-1-ol was selectively incorporated into plasmenylethanolamine. In the presence of an exogenous H2O2 generating system (glucose oxidase), iodide induced the production of [9,10-3H]2-IHDA from [9,10-3H]hexadecan-1-ol-labeled cells but not from [9,10-3H]palmitic acid-labeled cells. 2-IHDA was also generated during the lactoperoxidase-catalyzed iodination of brain and heart plasmalogens, and of ethyl hexadec-1-enyl ether, a synthetic vinyl ether-containing compound. Taken together, these results show that thyroid 2-IHDA is derived from plasmenylethanolamine via an attack of reactive iodine on the vinyl ether group. 2-Iodohexadecan-1-ol (2-IHDO) was also detected in these studies; it was formed later than 2-IHDA, and thyroid cells converted exogenous 2-IHDA into 2-IHDO in a time-dependent way. The ratio of 2-IHDO/2-IHDA increased with H2O2 production and decreased as a function of iodide concentration. An aldehyde-reducing activity was detected in subcellular fractions of the horse thyroid. No formation of 2-iodohexadecanoic acid could be detected. Reduction into the biologically inactive 2-IHDO is thus a major metabolic pathway of 2-IHDA in dog thyrocytes.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Inhibition of human thyroid adenylyl cyclase by 2-iodoaldehydes.

2-Iodohexadecanal (IHDA), which can be formed upon addition of iodine to the vinyl ether group of plasmalogens, has been identified as a major thyroid iodolipid (Pereira et al. (1990) J. Biol. Chem. 265, 17018-17025). In this study, we have investigated the possibility that it would be a mediator of the inhibitory effect of iodide on thyroid adenylyl cyclase. In human thyroid membranes, IHDA inhibited the adenylyl cyclase activity stimulated by thyrotropin (TSH), GTP-gamma-S or forskolin (FSK), whereas it did not decrease the specific binding of TSH to its receptors. The inhibitory effect on the cyclase reached a maximum after a 1-h-pre-incubation of the membranes with IHDA at 30 degrees C and was poorly reversible. It was also observed following a 4-h incubation with IHDA at 4 degrees C, a condition in which adenylyl cyclase is protected against heat inactivation. IHDA decreased the Vmax of adenylyl cyclase, but had no effect on the Km for ATPMg2-.IHDA also inhibited the FSK-stimulated adenylyl cyclase activity in liver and kidney cortex membranes, but had no effect on the Mg(2+)-ATPase activity of thyroid membranes. The inhibitory effect of IHDA has also been demonstrated in intact cells. As in membranes, IHDA decreased the rise in cAMP induced by TSH in cultured dog thyroid cells and this inhibition was maintained following pretreatment of the cells with pertussis toxin. In order to evaluate the specificity of the IHDA action, various analogs have been synthesized. This study has permitted the identification of two major structural features required for the inhibition of human thyroid adenylyl cyclase; the terminal aldehyde function and an iodine atom at C2, other halogens being ineffective. In conclusion, we have shown that IHDA exerts a direct inhibitory effect at or near adenylyl cyclase; all the properties of this effect characterized so far are identical to those of the adenylyl cyclase inhibition obtained following the exposure of thyroid tissue to iodide.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells.

2-Iodohexadecanal (IHDA) has been identified as a major thyroid iodolipid which can be formed upon addition of iodine to the vinyl ether group of plasmalogens (Pereira et al. 1990). In order to test whether IHDA plays a role in the thyroid autoregulation by iodide, we have investigated its effects on the production of H2O2 by cultured dog thyroid cells. IHDA inhibited the formation of H2O2 in dog thyroid cells stimulated by carbamylcholine (CCHOL). In the presence of BSA, which potentiated its action, the effect of IHDA was maximal after 2 h and had an IC50 around 5 microM. The effect of IHDA was not decreased by methimazole, which abolished the inhibition by iodide. IHDA also inhibited the stimulatory effect of bradykinin, but had only a marginal effect on the production of H2O2 induced by ionomycin or phorbol 12-myristate 13-acetate (PMA). The accumulation of inositol phosphates in CCHOL-stimulated thyroid cells was decreased by IHDA. As evaluated by measurements of 51Cr release and [3H]thymidine incorporation into DNA, IHDA had no adverse effect on thyroid cell viability. Several analogs of IHDA, of which the synthesis is described, have been tested for their inhibitory activity. This allowed the identification of two major structural features required for the biological activity: the carbonyl group at C1 and an halogen atom at C2, with iodine conferring a greater activity than bromine, while chlorine and fluorine were inactive. In conclusion, IHDA inhibits the production of H2O2 in CCHOL-stimulated dog thyroid cells by decreasing the phospholipase C cascade activity. This effect involves both the aldehyde function and the iodine atom. These results suggest that IHDA might be the mediator of some of the regulatory actions of iodide on the thyroid gland.Journal Articleinfo:eu-repo/semantics/publishe