-Atrophic gastritis -Gastric cancer -Goitre -Immunity -Iodine -Iodine as antioxidant -Iodine prophylaxis -Cretinism -Neuropsycological Pathologies Official Web Site Dr. Sebastiano Venturi |
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evolutionary story of a primitive antioxidant?
By Sebastiano and Marta Venturi
published in EUROPEAN JOURNAL OF ENDOCRINOLOGY. 1999, 140, Apr.4 :371-372
The thyroid gland is, embryogenetically and phylogenetically, derived from primitive gut, and we may consider the thyroid cells such as primitive gastroenteric cells which, during evolution, migrated and specialized in uptake of iodide, and in storage and elaboration of iodine compounds.
Stomach and thyroid share iodine-concentranting ability, and many morphological and functional similarities, such as cell polarity and apical microvilli, similar organ-specific antigens and associated autoimmune diseases (1), secretion of glycoproteins (thyroglobulin and mucin) and
peptide hormones, the digesting and readsorbing ability and, lastly, similar ability to form
iodotyrosines by peroxidase activity, where iodide acts as electron donor in the presence of H2O2 (2). However, gastric iodide-pump, phylogenetically more primitive than the thyroidal one, has lower affinity for iodide and do not respond to more recent TSH. So, in pregnant mouse, fetal gastric mucosa shows iodine-concentranting ability earlier than fetal thyroid (3). During human total-body 131I-scintiscans, the radioiodine remains on the stomach more than 72 hours. Similar finding has been reported in bovine abomasum, since cows have an efficient iodine recycling system via the gastrointestinal tract which conserves iodine and can protect them against low dietary iodine (4). In primitive reptilian stomach of lizard radioiodine remains more than 8 days (5).
But which is the role of iodide in the pathophysiology of the stomach? Dietary iodides are able
to defend brain cells from lipid peroxidation in rats (6). In normal thyroid hormonogenesis iodide, giving its electron to oxygen, reduce H2O2 by peroxidase activity. The remaining iodine readily iodinates the tyrosine and so neutralizes its own high oxidant power. The antioxidant action of iodide was described also in isolated rabbit eyes (7).
In old works, Stocks (8) and Spencer (9), reported that iodine-deficient goitre constitute a risk for gastric cancer. Recently, we reported (10) that iodine-deficiency (or excess) might represent a risk factor for gastric cancer and atrophic gastritis, by regulating gastric
trophism and by antagonizing (in thyroid cells and in gastric mucosa) the action of several
iodine-inhibitors, such as nitrates, thiocyanates and salt (11), which are well-known risk-factors for gastric carcinogenesis. Furthermore, mammary gland has high ability to concentrate iodide and to form iodoproteins by mammary peroxidase, exclusively during pregnancy and lactation, which are considered protective conditions against breast cancer (12). Recently, we have hypothesized that iodide might have, since primitive Algae and primitive gastral cavity of Porifera, an antioxidant role in iodine-concentranting organs, and particularly in the stomach of the Vertebrates (13)(14). And now this role is experimentally confirmed in Algae by a study
carried out by F.C. Kupper et al.(15).
In fact, three billion years ago, Algae, which contain a high amount of iodine, were the first living cells to produce oxygen, toxic at that time, in terrestrial atmosphere. So, algae cells required a protective antioxidant action in which iodides might have had a specific role.
The thyroid gland is, phylogenetically a modern organ and its function started and was improved from primitive Chordates to more recent Mammalia. Also evolutionistically recent are the T3-receptors in comparison with primitive Thyroxine (T4). In fact T4 is present in fibrous exoskeletal tissues of the lowest animals (Invertebrates)without showing any hormonal action (16). When the primitive marine-animals started to emerge from the sea, rich of iodine, and transfered in iodine-deficient mainland, their terrestrial diet became deficient of iodine and rich of iodine-competitors (nitrates, nitrites, thiocyanates, some glycosides, etc.). Therefore, we believe that, during the evolution to adapt to terrestrial life, these animals learned to use the primitive T4, in the place of the competitivized iodide, in order to transport into the cells this antioxidant trace-element, utilizing the remaining T3, the real active hormone of modern Vertebrates, for metamorphosis and thermogenesis with a new hormonal action through the formation of T3-receptors (16). As inhibitors of lipid peroxidation, by 5’-monodeiodinase activity, T4 and reverse T3 were found to be more effective in this antioxidant activity than vitamin E, glutathione and ascorbic acid (17).
In conclusion, we believe that the evolutionary story of iodide and thyroid might suggest and explain a primitive antioxidant activity of this trace-element. We should point out that extrathyroidal action of iodide might be an important new area for investigation.
1) Roitt I, Brostoff J & Male DK. The autoimmunity. In Immunologia, pp 231-7 (Eds Roitt I, Brostoff J & Male DK). Italian Ed USES ,1988.
2) Banerjee RK, Bose AK, Chakraborty TK, De SK & Datta AG. Peroxidase-catalysed iodotyrosine formation in dispersed cells of mouse extrathyroidal tissues. J Endocrinol 1985 106 2, 159-65
3) Ullberg S & Ewaldsson B. Distribution of radio-iodine studied by whole-body autoradiography. Acta Radiologica Therapy Physics Biology 1964 2 24-32
4) Miller JK, Swanson EW & Spalding GE. Iodine absorption, excretion, recycling, and tissue distribution in the dairy cow. J Dairy Sci. 1975 58 1578-1593
5) Shaham Y & Lewitus Z. Radioiodine metabolism in the thyroid gland of the lizard (Agama Stellio). General and Comparative Endocrinol.1971 17 142-8
6) Katamine S, Hoshino N, Totsuka K & Suzuki M. Effects of the long-term feeding of high-iodine eggs on lipid metabolism and thyroid function in rats. J Nutr Sci Vitaminol 1985 31 339-53
7) Elstner EF, Adamczyk R, Kromer R & Furch A. The uptake of potassium iodide and its effects as an antioxidant in isolated rabbit eyes. Ophthalmologica 1985 191 122-6
8) Stocks P. Cancer and goitre. Biometrika 1924 16 364-401
9) Spencer JGC. The influence of the thyroid gland in malignant disease. Br J Cancer 1954 8 393-411
10) Venturi S, Venturi A, Cimini D, Arduini C, Venturi M & Guidi A. A new hypothesis: iodine and gastric cancer. Europ J Cancer Prevention 1993 2 17-23
11) Wolff J. Transport of iodide and other anions in the thyroid gland. Physiol Rev 1964 44 45-90
12) Eskin BA. Iodine metabolisme and breast cancer. NY Acad Sci 1970 32 911-947
13) Venturi S, Guidi A & Venturi M. I disordini extra-tiroidei da carenza iodica. Qual è il reale fabbisogno di iodio? Le Basi Razionali della Terapia 1996 16 267-75
14) Venturi S, Stanghellini V, Donati FM, Barbara B, Salvioli R & Corinaldesi R. Does dietary iodine prevent gastric cancer? Ital J Gastroenterol Hepatol 1998 30 238
15) Kupper FC, Schweigert N, Ar Gall E, Legendre J-M, Vilter H & Kloareg B. Iodine uptake in Laminariales involves extracellular, haloperoxidase-mediated oxidation of iodide. Plancta 1998 207 :163-171
16) Venturi S. Letter to the Editor.The Thyroid Gland, Clinical and Experimental 1998 1 23
17) Tseng YL & Latham KR. Iodothyronines: oxidative deiodination by hemoglobin and inhibition of lipid peroxidation. Lipids 1984 19 96-102
LETTER TO THE EDITOR:
"Enigma of the function of iodide in primitive algae and in animal extrathyroidal organs: is it an ancient antioxidant?"
Dear Sir,
in relation to the functional role of inorganic iodide in metabolism of algal and animal cells,
we have hypothesized, in previous (1) and recent works (2)(3) that iodide might have a (phylogenetically and evolutionistically) ancient antioxidant role in extrathyroidal iodide-concentrating cells.
Into these cells iodide may act as an electron donor in the presence of H2O2 and peroxidase, and
the remaining iodine readily iodinates the tyrosine (and more slowly, the histidine (4)(5) or some protein and lipid), and so, neutralizes its own high oxidant power (3). In fact, three billion years ago, Algae, which contain a high amount of iodine, were the first living cells to produce oxygen, toxic at that time, in terrestrial atmosphere. So, algae cells required a protective antioxidant action in which iodides might have had a specific role.
Now this hypothesis of the antioxidant role of iodide is experimentally confirmed in Algae by a
recent study carried out by Kupper et al. (6).
We believe that this work, which convalidates our hypothesis, may constitute a fundamental
experimental milestone in the study of the extrathyroidal nonhormonal action of iodine-iodide
in biology and physiology of the cells.
Several extrathyroidal organs in animals, many of which share the same gene expression of sodium-iodide symporter of thyroidal iodide-pump (7), particularly stomach mucosa and lactanting mammary gland, but also salivary glands, thymus, epidermis, choroid plexus, articular and arterial sistems, have a iodide-concentrating ability without showing any hormonal or
biological action (8), and so, Algae, Porifera, Anthozoa (9) and several marine Invertebrates. In human organism extrathyroidal nonhormonal inorganic iodide is about 50-80% of the total
amount of iodine and its role is not known. Besides, direct uptake of inorganic iodine by tumor shows experimentally a suppressive effect on DMBA-induced breast tumors growth in the rat (10).
The antioxidant action of iodide may give a satisfactory explanation of the function of this
trace-element and might be a very important knowledge for preventive purpose.
We should point out that extrathyroidal action of iodide might be an important new area for
investigation.
(1) Venturi S et al (1993) A new hypothesis: iodine and gastric cancer. European Journal of Cancer Prevention. 2 :17-23
2) Venturi S & Venturi M (1998) Does iodine in the gastric mucosa have an ancient antioxidant role? IDD-Newsletter 14, 4 :61-2
(3) Venturi S & Venturi M (1999). Iodide, thyroid and stomach carcinogenesis: evolutionary story of a primitive antioxidant? European Journal of Endocrinology 140, 4 :371-2
(4) Li CH (1945) J Am Chem Soc 67 :1065
(5) Mayberry WE & Hockert TJ (1970). Endocrinology 86 :225..
(6) Kupper FC, Schweigert N, Ar Gall E, Legendre J-M, Vilter H & Kloareg B (1998). Iodine uptake in Laminariales involves extracellular, haloperoxidase-mediated oxidation of iodide. PLANCTA 207 :163-171
(7) Spitzweg C, Joba W, Eisenmenger W & Heufelder AE (1998). Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acid from salivary gland, mammary gland, and gastric mucosa. J Clin Endocrinol Metab 83, 5 :1746-51
(8) Venturi S, Guidi A & Venturi M (1996). I disordini extra-tiroidei da carenza iodica. Qual è il reale fabbisogno di iodio? Le Basi Razionali della Terapia 16 :267-75
(9) Roche J (1952) Biochimie comparée des scléroprotéines iodées des Anthozoaires et des Spongiaires. Experientia 8 :45-56
(10) Funahashi H, Imai T, Tanaka Y, Tobinaga J, Wada M, Morita T & al. (1996) Suppressive effect of iodine on DMBA-induced breast tumor growth in the rat. J Surg Oncol 61, 3 :209-13
"Lo ioduro: un antico antiossidante?"
Di Sebastiano e Marta Venturi
pubblicato in "Il Giornale del Medico" n. 16 del 3 Maggio 1999, Masson Editore
In natura lo iodio esiste come ione ioduro ed in questa forma viene captato dalle cellule viventi del regno animale e vegetale. Negli animali superiori oltre alla tiroide, mostrano capacità iodiocaptante, senza alcuna attività ormonale o biologica conosciuta, diversi organi tra cui: lo stomaco, la mammella, le ghiandole salivari, e inoltre timo fetale,
epidermide, plessi coroidei cerebrali, apparato articolare e arterioso (FIG. 1).
E’ stato accertato che il gene codificante per il Na/I symporter della "pompa dello ioduro" è lo stesso per le cellule di tiroide, stomaco, ghiandole salivari e mammella.
Le cellule tiroidee derivano, embriogeneticamente e filogeneticamente, da quelle iodiocaptanti dello stomaco primitivo, per cui possono essere considerate come cellule gastroenteriche primitive che, durante l’evoluzione, sono migrate e si sono specializzate nella cattura, nell’accumulo e nella elaborazione di composti iodati allo scopo di adattarsi alla vita sulla
terraferma.
Da alcuni anni abbiamo ipotizzato una azione antiossidante dello ioduro, molto antica, che precedette la formazione della tiroide (Europ J Cancer Prev. 1993; 2:17-23).
Tre miliardi di anni fa le alghe, ricchissime di iodio, furono le prime cellule viventi a produrre ossigeno, tossico a quei tempi, nell’atmosfera terrestre. Pertanto le cellule delle alghe necessitavano di una efficace sostanza antiossidante per difendersi dall’ossigeno prodotto nel loro interno. Pochi mesi fa ricercatori francesi del CNRS hanno confermato sperimentalmente sulle alghe l’azione antiossidante da noi ipotizzata (Plancta.1998; 207 :163-171).
Ma qual è il ruolo dello ioduro nella fisiologia e biochimica cellulare degli organi iodiocaptanti?
Come avviene anche nella normale ormonogenesi tiroidea, gli ioduri riducono, tramite perossidasi, cedendo un elettrone, l’ossigeno del H2O2. Il rimanente atomo di iodio si lega rapidamente a residui della tirosina, o anche della istidina o a determinati lipidi, e cosìì neutralizza il suo potente e tossico potere ossidante. Infatti gli ioduri difendono le cellule cerebrali ed epatiche dai danni della perossidazione lipidica nei ratti (J Nutr
Sci Vitaminol. 1985; 31:339-53) e agiscono così anche nell’occhio isolato di coniglio.
Recentemente abbiamo riportato (IDD-Newsletter. 1998; 14, 4 :61-2) che, come per la tiroide, la carenza, o l’eccesso, di iodio nella dieta potrebbero costituire un importante fattore di
rischio per il cancro dello stomaco e per la gastrite cronica atrofica, molto frequenti nell’entroterra delle nostre province di Pesaro, Forlì e Arezzo, che sono le più colpite da cancro gastrico ed anche da gozzo da carenza iodica. La correlazione epidemiologica tra gozzo e cancro gastrico era già stata descritta in vecchi studi dai britannici Stocks e Spencer ed è stata anche da noi, in questi anni, riconfermata. Anche la ghiandola mammaria capta lo ioduro, ma solo durante la gravidanza e l’ allattamento, condizioni, ben conosciute, che proteggono dal cancro mammario. In tali situazioni fisiologiche nelle cellule delle ghiandole mammarie si formano, tramite perossidasi, iodoproteine poi secrete nel latte. La diretta captazione dello ioduro da parte delle cellule tumorali mostra sperimentalmente un effetto soppressivo sulla crescita dei tumori mammari, nei ratti, indotta dall’agente cancerogeno DMBA (J Surg Oncol. 1996; 61, 3 :209-13 ).
Esistono numerosi e poco conosciuti studi che correlano il tumore della mammella alla carenza alimentare sia di iodio (Eskin BA e coll.) che di alghe marine commestibili. Malgrado ciò, l’Italia è, con l’Albania , all’ultimo posto in Europa per consumo di sale iodato. Negli USA, in cui il sale da cucina iodizzato è usato da molti decenni, il gozzo ed il cancro dello stomaco sono quasi scomparsi ed anche il cancro della mammella, da alcuni anni, sta
diminuendo.
Secondo alcuni ricercatori, come per la tiroide, lo iodio avrebbe un ruolo, anche se poco conosciuto, nel regolare il trofismo della mammella (NY Acad Sci. 1970; 32 :911-947) e,
probabilmente, dello stomaco e di altri organi iodio-concentranti.
Alcuni inibitori e competitori della pompa dello ioduro come i nitrati, i tiocianati e il cloruro di sodio, sono infatti ben conosciuti fattori di rischio nella cancerogenesi dello
stomaco.
La ghiandola tiroidea è, filogeneticamente ed evoluzionisticamente, un organo moderno e la sua funzione è iniziata ed è stata perfezionata dai primi cordati ai più recenti mammiferi. Moderni sono anche i recettori nucleari della T3 se paragonati alla più antica e primitiva Tiroxina (T4). Infatti la Tiroxina è, presente nei tessuti fibrosi dell’esoscheletro degli animali inferiori (invertebrati) senza alcuna conosciuta azione
ormonale o biologica (Eur J Endocrinol. 1999; 140, 4 :371-2). Quando alcuni animali marini cominciarono, per la prima volta, ad emergere dall’oceano, ricco di iodio, ed a trasferirsi nella terraferma, povera di iodio, la loro dieta vegetale diventò non solo carente, ma ricca di competitori dello ioduro come i nitrati, nitriti, tiocianati ed alcuni glicosidi. E’
probabile che, durante il processo evolutivo di adattamento alla vita terrestre, questi animali primitivi abbiano imparato ad usare la T4 (non antagonizzata) da prodotto di sostegno dell’esoscheletro (o di scarto) a prezioso trasportatore di ioduro-antiossidante all’interno delle cellule. Infatti, come inibitori della perossidazione lipidica, tramite la 5’-monodeiodasi, la Tiroxina e la reverse-T3 sono state trovate più efficaci per attività antiossidante della vitamina E, del glutatione e dell’acido ascorbico (Lipids. 1984; 19 ,2 :96-102). La rimanente deiodata T3 divenne poi il vero ormone tiroideo dei moderni vertebrati, capace di attivare la metamorfosi e la termogenesi, indispensabili per la vita terrestre, tramite la formazione dei nuovi recettori della T3.
Nell’organismo umano lo ioduro inorganico extratiroideo e non ormonale costituisce circa il 50-80% dello iodio corporeo totale ed il significato del suo ruolo biologico è ancora sconosciuto, anche se i clinici medici fino agli anni ‘50 usavano gli ioduri come farmaci antiaterosclerotici, antiartrosici e proimmunitari, con evidenze cliniche e sperimentali.
La nostra ipotesi di una azione antiossidante di tale oligoelemento offre una possibile risposta che riteniamo importante anche a scopo preventivo.
S. Venturi, A. Venturi, D. Cimini, C. Arduini, M. Venturi, A. Guidi
The authors have hypothesized that iodine-deficiency (I-def) or in some cases iodine-excess (I-excess) is associated with the development of gastric cancer. They report a short review of their own work and general literature on this subject in three fields: (1) epidemiology, where geographical and temporal correlations between territories with I-def (or I-excess) endemic goitre and high GC-death rate are reported; (2) immunology, where the possible correlations between I-def , immune-deficiency and GC are reported; and (3) thyroid gland and stomach correlations, both being embryologically derived from primitive gut and able to concentrate iodine. This ability is impaired by nitrates, thiocyanate, salt and by I-excess, which in fact can cause goitre. In our study I-def goitrous people have shown more atrophic gastritis than normal subjects. These data enable us to hypothesize that I-def or I-excess might constitute a new risk factor for gastric cancer, both by regulating gastric trophism and by antagonizing the action of those I-inhibitors (such as nitrates, thiocyanate and salt) previously studied as risk factors for gastric cancer.
S. Venturi - Coll.: M. Venturi, A. Guidi, F.M. Donati
The aim of this study is to test the hypothesis that iodine deficiency, or, in some cases, iodine excess is a risk factor for gastric cancer. Recent regional and district data on the epidemiology of endemic goitre and gastric cancer in Italy will be correlatad. Gastric cancer trends (until 1997) will be monitored in the populations (district of Montefeltro, Bolzano and Garfagnana) where iodine prophilaxis have been introduced only in recent years (1981-1985). Atrophic gastritis prevalence in Montefeltro district will be reconsidered, and gastric cancer mortality trends in the province of Aosta, where the iodine prophilaxis was interrupted in 1975, will be analysed. The iodine trapping ability of the stomach and the tyroid gland is inhibited by goitrogens, such as nitrate, thiocyanate and salt, previously studied as risk factors for gastric cancer. Previous studies have shown that iodine deficient individuals have more gastric cancer and atrophic gastritis than non deficient subjects; it is believed that iodine is able to regulate gastric trophism and antagonise the action of the above mentioned iodine inhibitors. A paper was published in Eur. J. Cancer Prev., 2:17-23, 1993
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Scintigrafie total-body nell’uomo dopo iniezione intravenosa di I-123 (con emivita di 13 ore) a distanza di 30 minuti (a sn) e di 6, 20 e 48 ore. E’ evidente la elevata captazione di radio-iodio sia tiroidea che delle ghiandole salivari e della mucosa gastrica, nella quale la iodio-concentrazione persiste, nelle scintigrafie con I-131 (con emivita di 8 giorni) fino a 72 ore. Ben visibile anche la cospicua eliminazione reno-vescicale. |
(work in progress 1992-2005)
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