|
|
The Iodine Group | |
|
Home | Orthoiodosupplementation | Body | Disease | Special | Overviews |
||
|
|
Boeynaems, Braekman, Dumont
Synthesis of Analogues of 2-iodohexadecanal, a Regulator of Iodine Metabolism in the Thyroid GlandHugues Van den Bergen, Désiré Daloze, and Jean-Claude Braekman J. Braz. Chem. Soc., Vol. 10, No. 1, 1-12, 1999.
"With the object of performing a structure-activity relationship study, we have synthesized several analogues of 2-iodohexadecanal, a regulator of iodine metabolism in the thyroid gland, differing by the chain length, the nature of the substituent, and/or the terminal functional group."
Biosynthesis and metabolism of 2-iodohexadecanal in cultured dog thyroid cells.Panneels V, Macours P, Van den Bergen H, Braekman JC, Van Sande J, Boeynaems JM. J Biol Chem. 1996 Sep 20;271(38):23006-14.
"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."
Which iodolipids are involved in thyroid autoregulation: iodolactones or iodoaldehydes?Boeynaems JM, Van Sande J, Dumont JE. Eur J Endocrinol. 1995 Jun;132(6):733-4. Review. [citation only]
Inhibition of human thyroid adenylyl cyclase by 2-iodoaldehydes.Panneels V, Van Sande J, Van den Bergen H, Jacoby C, Braekman JC, Dumont JE, Boeynaems JM. Mol Cell Endocrinol. 1994 Dec;106(1-2):41-50.
"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."
Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells.Panneels V, Van den Bergen H, Jacoby C, Braekman JC, Van Sande J, Dumont JE, Boeynaems JM. Mol Cell Endocrinol. 1994 Jun;102(1-2):167-76. [abstract only]
"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."
Inhibition of thyroid NADPH-oxidase by 2-iodohexadecanal in a cell-free system.Ohayon R, Boeynaems JM, Braekman JC, Van den Bergen H, Gorin Y, Virion A. Mol Cell Endocrinol. 1994 Feb;99(1):133-41. [abstract only]
"The major nonpolar iodolipid formed in horse thyroid cells has recently been identified as 2-iodohexadecanal (2-IHDA). We have investigated in vitro the effect of 2-IHDA on the NADPH-oxidase, NADPH-cytochrome c reductase, and thyroid peroxidase (TPO) activities of a porcine thyroid plasma membrane preparation. 2-IHDA inhibited NADPH-oxidase activity, with half-inhibition at 3-5 microM, but it had no effect on NADPH-cytochrome c reductase. It inhibited the TPO-catalyzed iodination of protein, but not iodide oxidation. Hexadecanal also inhibited NADPH-oxidase. Inhibition by the non-iodinated lipid aldehydes depended on the length of their aliphatic chain: dodecanal and tridecanal gave maximal inhibition. Free iodide, 2-iodohexadecanol and palmitic acid all had no inhibitory effect. Washing treated membranes showed that the inhibition of NADPH-oxidase by hexadecanal was fully reversible, whereas that of 2-IHDA and other iodinated or brominated alkanals was irreversible. Thus the interaction between some residues of the thyroid NADPH-oxidase and the lipid aldehyde groups was favored or stabilized by the iodine atom. Modification of primary amine and thiol groups of NADPH-oxidase inhibited its activity. These groups could also be the target of lipid aldehydes. We suggest that 2-IHDA, because it inhibits TPO and more profoundly the H2O2-generating system in thyroid plasma membrane, modulates iodide metabolism in the thyrocyte and may mediate the Wolff-Chaikoff effect."
Identification of a major iodolipid from the horse thyroid gland as 2-iodohexadecanal.Pereira A, Braekman JC, Dumont JE, Boeynaems JM. J Biol Chem. 1990 Oct 5;265(28):17018-25.
"The incorporation of iodide into proteins (PBI) and lipids (LBI) of horse thyroid slices was measured in various conditions. Their dependency on the concentration of extracellular iodide was strikingly different. For PBI the relationship was biphasic with a decrease above 10 microM, likely to correspond to the Wolff-Chaikoff effect. On the contrary, LBI increased as a function of iodide concentration up to 100 microM. Methimazole (MMI) inhibited the incorporation of iodide into both LBI and PBI, but higher concentrations of MMI were required to depress LBI as compared to PBI. The inhibition of active iodide transport by NaCIO4 reduced both PBI and LBI. Chromatography on silica gel resolved almost equal amounts of low and high polarity iodolipids. The main unpolar iodolipid was identified as 2-iodohexadecanal (2-IHDA), on the basis of proton nuclear magnetic resonance spectroscopy, mass spectrometry, and co-elution with authentic 2-IHDA obtained by chemical synthesis in reversed-phase high performance liquid chromatography and gas chromatography. The presence of 2-IHDA was also detected in dog thyroid slices, following incubation with KI (50 microM) and in the rat thyroid, 4 hours after intraperitoneal injection of KI (650 micrograms). An incubation of bovine brain plasmalogens with lactoperoxidase, iodide, and H2O2 generated 2-IHDA. In conclusion, we have identified a major thyroid iodolipid as 2-iodohexadecanal. The biosynthesis of this compound is likely to involve the addition of iodine to the vinyl ether group of plasmalogens."
|
|
Home | Orthoiodosupplementation | Body | Disease | Special Topics | OverviewsThe Iodine Group | Books | Disclaimers | Contact Us | Search
|
||
