Dr. Sebastiano
Venturi
investigator on Iodine Deficiency Disorders
and Iodine metabolism
|
-Iodine in biology |
Dr. Sebastiano Venturi C.V. |
 |
ROLE OF IODINE IN EVOLUTION AND CARCINOGENESIS OF THYROID, BREAST AND STOMACH
Published in: Advances in Clinical Pathology, 2000, 4, 1 :11-17
S.Venturi, F.M. Donati, M.Venturi, A.Venturi, *L.Grossi and
**A. Guidi
Servizio di Igiene, *Ospedale Civile di Novafeltria and **Direzione Generale
della AUSL n.1 di Pesaro, Regione Marche.
Corresponding address:
Dr. Sebastiano Venturi - via Tre Genghe n. 2;
61016 - PENNABILLI (PU) ; (Italy)
Tel : (+39) 0541 928205 .
Fax : (+39) 0541 928112 .
E-mail : venturi.sebastiano@gmail.com
KEY WORDS : iodine, iodide, antioxidant, evolution,
thyroid, breast cancer, selenium, stomach cancer
SUMMARY
The authors have hypothesized that dietary iodine (deficiency or excess)
is associated with the development of some gastric and mammary cancers,
as it is well-known for thyroid cancer. They report a short review of
their own work and general literature on this correlation and on the antioxidant
function of iodide in stomach, breast and thyroid. Thyroid cells phylogenetically
derived from primitive iodide-concentrating gastroenteric cells which,
during evolution, migrated and specialized in uptake and storage of iodine,
also in order to adapt the organisms from iodine-rich sea to iodine-deficient
land. Mammary cells derived from primitive iodide-concentrating ectoderma
too. Stomach, breast and thyroid share an important iodide-concentrating
ability and an efficient peroxidase activity, which transfers electrons
from iodides to the oxygen of hydrogen peroxide and so protects the cells
from damage caused by lipid peroxidation. The authors suggest that iodide
might have an ancestral antioxidant function in all iodide-concentrating
cells from primitive Algae to more recent Vertebrates. In Italy gastric
cancer is more frequent in farmers and in iodine-deficient populations,
living in mountainous and hilly areas, than in fishermen. In the last
two decades, Italian decrease of gastric cancer seems be correlated more
to the higher dietary consumption of iodine-rich fish rather than to consumption
of fruit and vegetables, which indeed has decreased in Italy.
Iodine is the required element in the diet richest
in electrons . Inorganic iodides are necessary for all living vegetable
and animal cells, but only the Vertebrates have the thyroid gland and
its iodinated hormones. In humans the total amount of iodine is about
30-50 mg and less than 30 % is present in thyroid gland and in its hormones.
About 60-80 % of total iodine is non-hormonal and it is concentrated in
extrathyroidal tissues, but its biological role is still unknown. Recently
we have hypothesized that iodide might have an ancestral antioxidant function
in all iodide-concentrating cells from primitive Algae to more recent
Vertebrates (1-4). Into these cells iodide acts as an electron donor in
the presence of H2O2 and peroxidase (5), the remaining iodine readily
iodinates the tyrosine and (more slowly) the histidine or some specific
lipid (6), and so, neutralizes its own high oxidant power.
IODINE, THYROXINE AND EVOLUTION
Over three billion years ago, Algae, which contain the highest
amount of iodine, were the first living cells to produce oxygen, which
was toxic at that time, in the terrestrial atmosphere. So, algal cells
required a protective antioxidant action in which iodides might have had
this specific role. In fact iodides are greatly present and available
in sea-waters, where algal phytoplankton acts as a biological accumulator
of iodides. Recently our hypothesis of the ancestral antioxidant action
of iodides has experimentally been confirmed in some algae by an important
study carried out by Kuepper et al.(7). Since about 700 million years
ago thyroxine (T4) is present in fibrous exoskeletal scleroproteins of
the lowest invertebrates (Porifera and Anthozoa)(8), without showing any
hormonal action. When some primitive marine vertebrates started to emerge
from the iodine-rich sea and transferred to iodine-deficient fresh water
and finally land, their diet became iodine deficient and also harboured
vegetable iodide-competitors such as nitrates, nitrites, thiocyanates
and some glycosides. Hence these animals needed an efficient thyroid gland
also as reservoir of iodine compounds. Therefore we believe that, during
progressive slow adaptation to terrestrial life, the primitive Chordates
learned to use the primitive, but not antagonized, T4 in order to transport
antioxidant iodide into the cells. So, the remaining triiodothyronine
(T3), the real active hormone, became active in the metamorphosis and
thermogenesis for a better adaptation of the organisms to terrestrial
environment ( fresh water, atmosphere, gravity, temperature and diet ).
The new hormonal action was made possible by the formation of T3-receptors
in the cells of vertebrates. Firstly, about 600-500 million years ago,
in primitive Chordata appeared the alpha T3-receptors with a prevalent
metamorphosing action and then, about 250-150 million years ago, in the
Birds and Mammalia appeared the beta T3-receptors with metabolic and thermogenetic
actions. So, during human embryogenesis alpha T3-receptor genes are expressed
before the beta receptors. Gastric iodide-pump, phylogenetically more
primitive than the thyroidal one, has lower affinity for iodide and does
not respond to more recent TSH (Thyrotropin). In fact, in a pregnant mouse,
fetal gastric mucosa shows iodine-concentranting ability earlier than
fetal thyroid (9). On the other hand, from a biochemical point of view,
as inhibitors of lipid peroxidation, by 5'-monodeiodinase activity (a
seleno-enzyme), T4 and reverse-T3 (but not T3) became and were found to
be more effective in this antioxidant activity than vitamin E, glutathione
and ascorbic acid (10). In fact maternal T4, and not T3, plays a crucial
role in protecting fetal brain from damages caused by hypothyroidism (11).
Virgili et al. (12) reported that treatment with thyroxine protects from
peroxidative intestinal damages, induced by zinc-deficiency in rats .
Dietary iodides are able to defend brain and liver cells from lipid peroxidation
in rats (13).The antioxidant action of iodides has also been described
in isolated rabbit eyes (14). Rieger et. al. (15), Winkler et al.(16)
and Buchberger et al. (17) reported a beneficial and antioxidant action
of iodides in many cronic diseases and in eye cataractogenesis .
IODINE AND SELENIUM
Researchers reported the cooperation between selenium and iodine.
In fact selenium is present in peroxidase enzymes and in type 1 and type
3 deiodinases, which are able to oxidate iodides and the latter enzymes
produce iodides from iodothyronines. Thyroid-peroxidase is an important
selenium-glutathione-enzyme which utilizes iodides in order to transfer
electrons to the oxygen of hydrogen peroxide. Thyroid gland is the richest
tissue in selenium and iodine, whose deficiencies constitute an important
risk factor for thyroid morbility and carcinogenesis (18). Furthermore
there is an interesting chemical gradient of electronegativity, according
to Pauling-scale units, among Oxygen ( 3.44 ), Iodine( 2.66 ), Selenium
(2.55) and Hydrogen (2.20). This gradient might clear up the possible
role of iodides in electron tranfer.
EXTRATHYROIDAL IODIDE-CONCENTRATING ORGANS
( FIGURES 1, 2, 3 )
In the Mammalia several extrathyroidal organs share the same gene
expression of sodium / iodide symporter of thyroidal iodide-pump and particularly
stomach mucosa and lactanting mammary gland (19). Salivary glands, thymus,
epidermis, choroid plexus and articular, arterial and skeletal systems
(20) have iodide-concentrating ability too. But what role does iodide
play in animal cells? We may chronologically differentiate on the basis
of the phylogenesis and embryogenesis three ways of action of iodine :
1) an ancient and direct action, on endodermal fore-gut and stomach and
on ectodermal epidermis, where inorganic iodides probably act as antioxidants.
2) a recent and direct action, on fetal prehormonal thyroid and on salivary
and mammary glands, thymus, ovary and on nervous, arterial and skeletal
systems, where inorganic iodides are active. 3) a recent and indirect
action of the thyroid and its iodinated hormons, on all vertebrate cells,
which makes use of specific organic iodine-compounds: thyroxine (T4) and
triiodothyronine (T3), which act in very small quantities and utilize
T3-receptors. Indeed thyroid hormons contain less than 1 mg of iodine
and less than 1/30 - 1/50 of total iodine amount. We believe that all
these actions of iodine may still take place into the cells of modern
vertebrates (3,4). In fact, Evans et al. (21) reported that 5 mg of potassium
iodide (daily injected) acts as 0.25 micrograms of L-thyroxine in recovering
the impaired functions of many organs of thyroidectomized rats. Thyroid
cells phylogenetically derived from primitive iodide-concentrating gastroenteric
cells which, during evolution, migrated and specialized in uptake of iodides
and storage and elaboration of iodine compounds, in order to adapt to
iodine-deficient terrestrial life. Mammary cells embryologically derived
from primitive iodide-concentrating ectoderma too. The thyroid gland is,
in evolutionary terms, a modern organ and its function started and was
improved from primitive Chordata to more recent Mammalia in which the
thyroidectomy and hypothyroidism might be considered like a sort of phylogenetical
and metabolical regression to a former stage of "reptilian life". In fact,
reptilian features seem to be restored in hypothyroid humans such as a
dry, hairless, scaly, cold skin and a general slowdown of metabolism,
digestion, heart rate, nervous reflexes with lethargic cerebration, hyperuricemia
and hypothermia.
IODINE AND CARCINOGENESIS OF THE THYROID, BREAST AND STOMACH
Human stomach (FIG. 4), breast and thyroid share
an important iodide-concentrating ability and an efficient peroxidase
activity. In a previous paper we reviewed the studies about overall general
extrathyroidal diseases in relation to dietary iodine deficiency (22).
Here we reported a short review of some works on the carcinogenesis of
these organs in relation to dietary iodine deficiency or, in some cases,
excess.
A) Thyroid
Ward and Ohshima (23) and recently also the World Cancer Research
Found and the American Institute for Cancer Research (24) reported that
dietary iodine deficiency and excess are tumor promoters and carcinogens
in the thyroid gland.
B) Mammary gland
Exclusively during pregnancy ( Fig.3) and lactation, which
are considered protective conditions against breast cancer, the mammary
gland has a high, but temporary, ability in concentrating iodides and
also in forming iodoproteins (25) in alveolar and ductular cells by specific
peroxidase (26). Strum (27) reported that when female rats are kept iodide-deficient,
atrophy and necrosis takes place in the mammary gland and areas of dysplasia
and atypia are seen, and in pregnant mice, mammary tumor cells lose their
ability to iodinate (28). Eskin and coworkers reported that iodine deficiency
causes breast dysplasia and cancer in rats and probably in humans (29),
and showed a mammary tumor reduction in rats after iodine treatment (30-31).
Funahashi et al. reported that Japanese edible Wakame seaweed (32) and
also a direct uptake of inorganic iodine by tumor has experimentally a
suppressive effect on DMBA-induced breast tumors growth in the rat (33).
Statistical correlations have been carried out by Ellerker (34), Stadel
(35) and Serra-Majem et al.(36). Recently also Smyth et al. (37) and Giani
et al. (38) reported an epidemiological correlation between thyroid diseases
and breast cancer. Beatson reported an adjuvant use of thyroid extract
in some breast cancers in the "Lancet", as far back as 1896 (39).
C) Stomach
In early statistic works, Stocks (40) and Spencer (41), reported
that iodine-deficient goitre constitute a risk for gastric cancer; and
Diesing reported, in an early work (1911), adjuvant therapy of thyroid-extract
in some gastric tumors (42). Recently, as other researchers on thyroid
cancer stated, we hypothesized that iodine-deficiency (or excess) might
constitute a risk factor for gastric cancer and atrophic gastritis (1-4,
43). This action of iodide on gastric mucosa might be due to antioxidant
activity, and to antagonism against several iodide-inhibitors, such as
nitrates, thiocyanates and salt (44), which are well-known risk-factors
for gastric carcinogenesis. In previous works (1, 22) we reported that
in Italy gastric cancer, thyroid cancer and goitre are statistically correlated
and more frequent in iodine deficient areas, such as in Alpine and Appennines
valleys, and in regions of northern and central Italy compared to southern
Italy where the majority of the population lives in sea-side areas. In
fact Italy has never carried out significant iodine-prophylaxis and, despite
the fact that its inland is an endemic goitre area, only less than 3 %
of kitchen salt is iodized. Gastric cancer is more frequent in farmers
than in fishermen, whose diet is richer in iodine (45). Recently the Italian
National Organization "Istituto Nazionale della Nutrizione", comparing
the years 1980 to 1995, found that Italians, whose gastric cancer mortality
has decreased, have in fact increased their yearly fish consumption (from
8.7 to 14.4 Kg per person) and decreased their consumptions of fruit (from
86.6 to 84.9 Kg per person) and vegetables (from 111.4 to 108.2 Kg per
person) (46). A recent study suggests that, in northern Italy, the consumption
of even small amounts of fish, which is rich in iodine, is a favourable
indicator of the risk of several cancers, especially of the digestive
tract and stomach (47). On the other hand, an excess of dietary iodine
(more than 2 mg) impairs the iodide-pump and the functions of some permanently-concentrating
tissues (thyroid, stomach and salivary glands) causing, in the case of
greater and prolonged quantities, degenerative, necrotic and also neoplastic
lesions, which are well-known in thyroid gland (48). The fact that the
iodine-excess is able to damage the stomach too, should be examined carefully
if we consider that the coastal populations of Japan (49) and China (50),
which have the highest rate of gastric cancer mortality in the world,
frequently eat an excessive and harmful quantity of marine algae (seaweeds),
which are very rich in iodine (up to 200 mg /daily / per person). Several
researchers reported also a general anti-tumor activity of iodine-rich
edible marine algae (in moderate amount) and a favourable activity in
human chemoprevention of oral cancer, not due to the action of retinol
or beta-carotene (51). Noda et al. showed that per-iodate oxidation is
necessary to the anti-tumor activity of algae (52). Recently an inhibition
of vacuolation toxin activity of Helicobacter pylori by iodine was also
reported (52-B). The high iodide-concentration of thymus ( Fig.3)
explains the important role of iodine in immune system. We,
also, reported that iodine deficiency impairs immunity (53) and so might
reduces defence against tumor cells.
In conclusion,
we believe that the knowledge of antioxidant action
and presumed antitumor activity of iodide might be important for preventive
purposes.We should point out that extrathyroidal action of iodide might
be an important new area for investigation .
Figures 1, 2, 3 show the distribution of 131-Iodine in radioautographies of the body of a pregnant mouse, at 1 minute, 1 hour and 24 hours after intravenous injection of radioiodine. It is evident the high iodide-concentrating ability of gastric mucosa and milk gland of the mother and stomach, placenta and thymus of fetuses. (from Ullberg and Ewaldsson,1964; courtesy of Acta Radiologica)
Fig. 4. Sequence of I-123 total-body scintiscans of a woman after intravenous injection of I-123 (half-life: 13 hours); (from left) respectively at 30 minutes, and at 6, 20 and 48 hours. It is evident the highest and rapid concentration of radioiodide in gastric mucosa of the stomach, which persists in I-131 (half-life: 8 days) scintiscans for more than 72 hours. In the thyroid iodine-concentration is more progressive, as in a reservoir (from 1% to 5.8 % of the total injected dose). Mammary gland iodide-concentration is here not evident because this woman was not pregnant or lactating. It is evident a high excretion of radioiodides in urina.
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