Evolution of Dietary Antioxidants: Role of Iodine
Lecture held at the “Thyroid Club” Annual Meeting of Bologna University, Feb. 6, 2007
Sebastiano Venturi and *Mattia Venturi
Servizio di Igiene, ASL n. 1, Regione Marche, Pennabilli (PU) Italy,
and *Department of Oral Science, University of Bologna, Italy
Corresponding address:
Dr. Sebastiano Venturi - via Tre Genghe n. 2; 61016-Pennabilli (PU), Italy
Tel : (+39) 0541 928205 . E-mail: venturis@freeweb.org
KEY WORDS : Antioxidants, antioxidant evolution, evolution, iodine, iodide, thyroxine
ABSTRACT
The authors review the role of inorganic and organic forms of iodine as an antioxidant in evolution
of plants and animals. Iodine is one of the most abundant electron-rich essential element in the diet
of marine and terrestrial organisms. It is transported from the diet to the cells via iodide
transporters. Iodide, which acts as a primitive electron-donor through peroxidase enzymes, seems to
have an ancestral antioxidant function in all iodide-concentrating cells from primitive marine algae
to more recent terrestrial vertebrates. Thyroxine and iodothyronines have an antioxidant activity too
and, through deiodinase enzymes, are donors of iodides and indirectly of electrons. Thyroid cells
phylogenetically derived from primitive gastroenteric cells, which during evolution of vertebrates
migrated and specialized in uptake and storage of iodo-compounds in a new follicular “thyroidal”
structure, for a better adaptation to iodine-deficient terrestrial environment. Finally, some animal
and human chronic diseases, such as cancer and cardiovascular diseases, favored
by dietary antioxidant deficiency, are briefly discussed.
INTRODUCTION
Oxygen is a potent oxidant whose accumulation in terrestrial atmosphere resulted from the
development of photosynthesis over three billion years ago, in blue-green algae (Cyanobacteria),
which were the most primitive oxygenic photosynthetic organisms. In this review, we discuss the
role of iodine in evolutionary strategies of antioxidant defense in plants and animals. A further aim
of this paper is to provide a medical perspective. In fact, the importance of antioxidants as
protective substances against many chronic and degenerative diseases, such as cancer and
cardiovascular diseases has been studied for many years. But the utility of well-known antioxidant
vitamins in some chronic diseases has not been recently supported by statistical data, and their
benefits in cancer prevention have not been recently confirmed by epidemiological data (Bjelakovic
et al. 2004; Hung et al. 2004; Lin et al. 2005; Sato et al. 2005; Tsubono et al. 2005; Morris and
Carson 2003). In the wide range of antioxidants, we have recently hypothesized an “evolutionary
1
hierarchy”, where the most ancient might be more essential than the “modern” ones in the
developing stages of animal and human organisms (Venturi and Venturi 2004, 2006). Deficiency of
iodine, as a primitive antioxidant, seems to cause more damage in developing embryos than some
other “modern” antioxidants. In fact, in pregnant women I-deficiency causes abortions and
stillborns (Dunn and Delange 2001). Molecular iodine (I2) has the chemical capacity to nonspecifically iodinate amino acids, proteins and lipids (Gottardi 1991). The oxidation of iodide by
reactive oxygen species (ROS) like H2O2 has been studied since the early 1920s, and it is a
necessary step to incorporate iodine into bioactive molecules (Bray and Caulkins 1921). These
reactions yield a complex mixture of different iodine species. One factor that contributes to this
complexity is the range of oxidation states associated with iodine species: -1 to +5, e.g. -1 (iodide –
I-); +1 (hypoiodic acid - HOI); +5 (iodate - IO3) as shown in Table 1.
Table. 1. From Gottardi, 1991
Several oxidized iodine species formed from iodide oxidation have the potential to react with both
water and I- (Bray and Caulkins, 1921). The iodine species that exist at a pH 7.4 are: iodide (I-),
triiodide (I3 ), molecular iodine (I2), hypoiodious acid (HOI), hypoiodite ion (OI-) and the iodine
anion (HI2O-). In 1985, Venturi suggested that the antioxidant biochemical mechanism of iodides
was probably one of the most ancient mechanisms of defense from poisonous ROS as shown in
Table 2 and in Table 3.
2 I-  I2 + 2 e- (electrons) = - 0.54 Volt ;
2 I- + Peroxidase + H2O2 + 2 Tyrosine  2 Iodo-Tyrosine + H2O + 2 e- (antioxidants);
2 e- + H2O2 + 2 H+ (of intracellular water-solution)  2 H2O
Table. 2. Proposed antioxidant biochemical mechanism of iodides (From Venturi 1985)
2
2 I- + Peroxidase + H2O2 + Tyrosine, Histidine, Lipids, Carbons 
 Iodo-Compounds + H2O + 2 e- (antioxidants)
Iodo-Compounds: Iodo-Tyrosine, Iodo-Histidine, Iodo-Lipids, Iodo-Carbons
Table. 3. Proposed antioxidant biochemical mechanism of iodides, probably one of the most
ancient mechanisms of defense from poisonous reactive oxygen species (Modified from Venturi
2003).
Petersén et al. (1996), Küpper et al. (1998, 2002) and Gall et al. (2004) suggested that the
production of volatile iodo-compounds by marine algae is a result of the development of
photosynthesis, oxygen production and respiration some 3 billion years ago, and it is due to
adaptation to light in order to reduce the amount of poisonous ROS, such as hydrogen peroxide,
superoxide radicals and hydroxyl radicals.
Increase of Oxygen in Earth’s Atmosphere and its Biological Consequences
The evolution of oxygen-producing cells was probably the most significant event in the history of
life after the beginning of life itself. Oxygen is a potent oxidant whose accumulation into the
atmosphere forever changed the surface chemistry of Earth (Canfield 2005). Lane (2002),
Wiedenheft et al. (2005) and Benzie et al. (2003) suggested that the evolution of oxygenic
photosynthesis marks the dawn of oxidative stress and represents one of the greatest selective
pressures imposed on primordial life. The association of molecular oxygen with abundant ferrous
iron pools produced two major biological consequences. First, life dependent on the redox
properties of Fe(II) had to contend with its oxidation and precipitation as Fe(III). Secondly, life had
to contend with the toxicity of ROS generated by the partial reduction of dioxygen by ferrous iron.
By the start of the Cambrian period 570 million years ago, or somewhat earlier, oxygen levels had
apparently increased enough to permit rapid evolution of large oxygen-utilizing multicellular
organisms. ROS potentially react with lipids, proteins, carbohydrates and DNA and thus interfere
with the functions of cellular membranes, cell metabolism, cellular signaling, cell growth and
3
differentiation. Oxidative stress seems to have been implicated as a causative process in the
development of a vast number of degenerative diseases (Suzuki et al. 1997; Flohe et al. 1997; Yu
1994; Sies 1997). Stone (1988) studied the role of the primitive sea in the natural selection of
iodides as a regulating factor in inflammation. This author reported that iodides have many nonendocrine biologic effects, including a role they play in the physiology of the inflammatory
response. Iodides increase the movement of granulocytes into areas of inflammation and improve
the phagocytosis of bacteria by granulocytes and the ability of granulocytes to kill bacteria.
Early Developments in Antioxidant Defense
During evolution, endogenous protection systems have developed to counteract the deleterious
effects of cellular oxidation. Protective antioxidant enzyme systems consist primarily of superoxide
dismutase, glutathione peroxidase, catalase and peroxiredoxins. In addition to these endogenous
systems, exogenous dietary antioxidants may help to prevent oxidative stress. In particular, mineral
antioxidants present in the primitive sea, as some reduced compounds of Rubidium, Vanadium,
Zinc, Iron, Cuprum, Molybdenum, Selenium and Iodine (I), which play an important role in
electron transfer and in redox chemical reactions. Most of these substances act in the cells as
essential trace-elements in redox and antioxidant metallo-enzymes. Some researchers hypothesized
that the relative composition of many mineral trace-elements of the animal body is similar to the
composition of the primitive sea, where the first forms of life began (Favier 1991). During
evolution, in the last 500-400 million years (My) antioxidants of terrestrial origin developed in
plants as many polyphenols, carotenoids, flavonoids, tocopherols and ascorbic acid. A few of these
appeared more recently, in last 200-100 My, in fruits and flowers of angiosperm plants (Venturi
2004, 2006). In fact Angiosperms (the dominant type of plant today) and most of their antioxidant
pigments evolved during the late Jurassic period. Plants employ antioxidants to defend their
structures against ROS produced during photosynthesis. The human body is exposed to the very
same oxidants, and it has also evolved an effective antioxidant system. Plant-based, antioxidant-rich
4
foods traditionally formed the major part of the human diet, and plant-based dietary antioxidants are
hypothesized to have an important role in maintaining human health. Benzie (2000, 2003) reported
that the estimated daily intake of many selected antioxidants (such as antioxidant vitamins,
polyphenols, carotenoids and flavonoids) decreased quantitatively from palaeolithic to modern
human diet.
Table.4. (Reported from Benzie, 2000)
Iodide/iodine and Iodide/thyroxine: Evolutionary History of a Primitive
Antioxidant
Over three billion years ago, blue-green algae were the most primitive oxygenic photosynthetic
organisms, ancestors of multicellular eukaryotic algae. Algae that contain the highest amount of
iodine (1-2 % of dry weight) and peroxidase enzymes, were the first living cells to produce
poisonous oxygen in the atmosphere (Obinger et al. 1997a, b; Venturi et al. 2000a, b). Therefore
Venturi suggested that algal cells required a protective antioxidant action of their molecular
components, in which iodides, through peroxidase enzymes, seem to have had this specific role
5
(Venturi 1985; Venturi et al. 1987, 1993, 1999). In fact iodides are greatly present and available in
the sea, where algal phytoplankton, the basis of marine food-chain, acts as a biological accumulator
of iodides, selenium (and n-3 fatty acids) (Cocchi and Venturi 2000). The sea is rich in iodine,
about 60 micrograms (g) per liter, since this is where most of the iodine removed and washed
away from the soil accumulated due to rains and the glacial ages (Elderfield and Truesdale 1980)
(Fig. 1).
Figure 1. IODINE and EVOLUTION.
Over three billion years ago, blue-green algae were the first living Prokaryota to produce oxygen
and emit volatile halocarbons and CH3I in the atmosphere. For 700 million years, thyroxine has
been present in fibrous exoskeletal scleroproteins of the lowest invertebrates. About 500-400
million years ago (Mya) some primitive marine fishes began to emerge from the iodine-rich sea and
transferred to iodine-deficient terrestrial fresh waters. 400-300 Mya some vertebrates evolved in
amphibians and reptiles and transferred to I-deficient land. Then, from primitive gastro-intestinal
cells, a new “thyroidal” follicular organ developed, as a reservoir for iodine. In vertebrates, thyroid
hormones became active in the metamorphosis and thermogenesis for a better adaptation to
terrestrial environment. (From Venturi 2004).
The major iodine species in sea waters are iodate and iodide, along with smaller concentrations of
molecular iodine, hypoiodous acid and iodinated organic compounds (Truesdale et al. 1995). Brown
6
algae (seaweeds) accumulate iodine to more than 30,000 times the concentration of this element in
seawater (Colin et al. 2003; Teas et al. 2004). Not much is known, however, on the iodineconcentrating mechanisms and on the biological functions of iodine in algae. Primitive marine
prokaryotes seem to have an efficient active “iodide pump”, ancestor of the pump of multicellular
eukaryotic algae and of mammalian iodide transporters. The mechanism of “iodide-pump” in the
cells is very ancient and lacking of specificity, in fact, it is not able to distinguish iodide from other
anions of similar atomic or molecular size, which may act as “pseudo-iodides”: thiocyanate,
cyanate, nitrate, pertechnate, perchlorate (Wolff 1964). It is hypothesized that 80% of the Earth's
oxygen is produced by planktonic algae, prochlorphytes, cyanobacteria and the free-floating
unicellular microbes inhabiting the sea close to the surface. Up till now only one aspect of halogen
metabolism, the production of volatile halocarbons, seems to have attracted more attention from
researchers, because these compounds, and in particular the iodinated forms, have a significant
impact on the chemistry of the atmosphere, and its ozone shield depletion (Carpenter et al. 1999,
2000). Halogen metabolism in marine algae involves enzymes known as haloperoxidases, which
catalyse the oxidation of halides into hypohalous acids (Vilter et al. 1983; Vilter 1994, 1995;
Gribble 1996; Pedersèn et al. 1996; Dembitsky et al. 2003; Gall et al. 2004). Since iodoperoxidase
of Laminaria seaweeds is more efficient than the bromoperoxidase in the oxidation of iodide (Colin
et al. 2003), this former activity may be more largely responsible for the uptake of iodide from
seawater. There is an increased emission of iodinated halocarbons both from kelp beds at low tide
during day-time (Carpenter et al. 1999, 2000), and from kelp plants incubated under high solar
irradiance, caused by photo-oxidative stress, compared to plants kept in the shade (Gall et al.
2004). The green algae are hypothesized to have been ancestors of terrestrial plants. Recently
Berking et al. (2005) confirmed Venturi’s hypothesis concerning antioxidant iodide and thyroxine
in some marine invertebrates (polyps of the jellyfish Aurelia aurita) which contain iodide ions.
Berking reported that in these invertebrates “the danger to be harmed by iodine is strongly
decreased by endogenous tyrosine which reacts with iodine to form iodiferous tyrosine compounds
7
including thyroxin. Both substances together, iodide and tyrosine, form an efficient oxidant defense
system which shields the tissue against damage by ROS.” Spangenberg (1971) observed that when
polyps of Aurelia are maintained for some weeks in iodide-free surroundings, it is possible to cause
strobilation (metamorphosis) by applying iodine compounds including T4. (Polyps kept in normal
seawater do not respond to strobilation). The interesting observation was that the polyps underwent
strobilation when iodide was applied for 24 hours. But a 24-hour treatment with T4 was not
sufficient. The treatment with T4 must carried out over a longer period of time to induce
strobilation. It appears that T4 can deliver iodide, but this requires time. Recently Heyland and
Moroz (2005) and Heyland et al (2006) reported that the oxidation of iodide to iodine in some
marine invertebrates is a critical step for scavenging ROS, and that the reaction of iodine with
tyrosine residues removes potentially poisonous iodine from the cell. In vertebrates, isolated cells of
extrathyroidal iodide-concentrating tissues can produce protein-bound mono-iodo-tyrosine (MIT),
di-iodo-tyrosine (DIT) and also some iodolipids (Banerjee et al. 1985; Aceves et al. 2005). This
pathway for iodine organification involves iodine incorporation into specific lipid molecules.
Iodolipids have been shown to be regulators of mammalian cellular metabolism. Iodine, reacting
with double bonds of some polyunsaturated fatty acids of cellular membranes, makes them less
reactive with ROS (Cocchi and Venturi 2000). Two iodinated lipids may be iodine autoregulation
mediators: 6-iodo-5-hydroxy-8,11,14-eicosatrienoic acid (delta-iodo-lactone) and 2iodohexadecanal. Delta-iodolactone has been found to be a potent inhibitor of proliferation of
thyroidal and of some non-thyroidal cells (Banerjee et al.1985; Pisarev et al. 1988; Dugrilllon 1996;
Venturi et al. 2000a, b; Cocchi and Venturi 2000; Cann et al. 2000; Aceves et al. 2005). According
to Aceves et al. (2005) the percentage of iodine in cellular homogenate of breast tissue is about 40
% in lipid fraction and 50 % in protein fraction. Aceves also reported that in mammary gland
homogenates from virgin rats, the addition of iodine in their diet significantly decreases lipid
peroxidation. The family of peroxidase enzymes includes mammal, microorganism, plant, algal, and
fungal peroxidases. Some of these peroxidases, known as haloperoxidases, use halide ions (iodide,
8
bromide, and chloride) as natural electron donors, and have an antioxidant function in Cyanobacteria (Obinger et al. 1997, 1999; Venturi and Venturi 1999). Taurog (1999) reported that the
relation between animal and non-animal peroxidases probably represents an example of convergent
evolution to a common enzymatic mechanism. Heyland and Moroz (2005) suggest that exogenous
sources of thyroid hormones (THs) (from food) may have been ancestral, while the ability to
synthesize TH endogenously may have evolved independently in a variety of metazoans, resulting
in a diversity of signaling pathways and, possibly, morphological structures involved in THsignaling. In fact, increasing evidence suggests that THs also function in a variety of invertebrate
species. The evidence of TH effects in invertebrates has been reviewed in Eales (1997) and Heyland
et al. (2005).
Evolution of Iodine from Non-hormonal to Hormonal Functions
Since approximately 700-800 Mya thyroxine (T4) has been also present in fibrous exoskeletal
scleroproteins of the lowest marine invertebrates (sponges, corals) (Roche 1952; Roche and Yagi
1952). Recent studies reported that THs are also present in unicellular planktonic alga (Dunaliella
tertiolecta) and in echinoid larvae (sea-urchin) (Chino et al. 1994; Heyland 2004). These original
sources of animal hormones might have been plants/algae in many cases, and could well have been
independently derived from plants/algae in distinct lineages. The ancestral function of THs could
also have been as feeding deterrents in algae and/or plants and the signaling functions in animals
(Heyland and Moroz 2005; Eales 1997) might, therefore, have been acquired secondarily, perhaps
even through horizontal transfer from their hosts or other co-associated microbes with more ancient
relationships with the host. In waters the iodine concentration decreases step by step from sea-water
to estuary (about 5 g / L) and source of rivers (less than 0.2 g / L in some Triassic mountain
regions of northern Italy), and in parallel, salt-water fishes (herring) contain about 500-800 g of
iodine per kg compared to fresh-water trout about 20 g per kg (Venturi and Venturi 1999; Venturi
et al. 2000a, b, 2003). So, in terrestrial I-deficient fresh waters some trout and other salmonids
9
(anadromous migratory fishes) may suffer thyroid hypertrophy or related metabolic disorders
(Venturi et al. 2000a, b), as do some sharks in captivity. Youson and Sower (2001) reported that
iodide-concentrating ability of the endostyle of sea lamprey was a critical factor in the evolution of
metamorphosis and that the endostyle was replaced by a follicular thyroid, since post-metamorphic
animals needed to store iodine following their invasion of freshwater. According to Manzon and
Youson (1997) in some anadromous migratory fishes (sea lamprey and salmonids), iodine and TH
play a role in initiation of metamorphosis, which is induced by the decline in serum of TH. After
metamorphosis, when these adult marine fishes die in fresh-water after reproducing, they release
their iodides and selenium, and n-3 fatty acids (Venturi et al. 2000a, b), in the environment, where
they have a favorable role in food for life and health of native animals, bringing back upstream from
the sea to I-deficient areas these essential trace-elements (Venturi et al. 2000a, b). In some Ideficient fresh-waters some salmonids may also suffers of “scurvy”, due to dietary vitamin C
deficiency.
Fig. 2 . Cultured salmons in freshwater showing nutritionally induced
spinal curvature (scoliosis and lordosis) by vitamin C deficiency.
If these fishes are housed in I-rich sea-water then this disease improve, presumably because of the
availability of other antioxidants in marine environment (Hardie et al. 1991). For this reason, we
suggested that the antioxidant action of ascorbic acid developed firstly in the plants when, about
500-400 Mya plants began to adapting themselves to mineral (and iodine) deficient estuaries of
10
rivers and land. Some biologists suggested that many vertebrates had developed their metabolic
adaptive strategies in estuary environment (Purves et al. 1998). The role of iodine in marine and
fresh-water fishes has not been completely understood, but it has been reported that I-deficient
fresh-water fishes suffer of higher incidence of infective, parasitic, neoplastic and atherosclerotic
diseases than marine fishes. Farrell et al. (1992) reported the absence of coronary arterial lesions in
some elasmobranch fishes, living in I-rich sea-water. In October 7, 1999, the U.S.A. Committee of
the House and Senate regarding "Marine Research" reported that " The Committee notes the
unusually low incidence of cancer in marine sharks, skates, and rays and encourages basic
research through the study of the immune system of these marine animals and the examination of
bioactive molecules from shark, skate, and ray cells and tissues that have the potential to inhibit
disease processes in humans." Yun et al.(2005) reported that marine vegetation concentrates iodine
for its antimicrobial and antioxidant properties. In the amphibians, environmental iodine is the
essential metamorphosis-factor and has an important role in the spectacular apoptosis on the cells of
larval gills, tail, fins and gastro-intestine, and in adapting and transforming of aquatic animal
(tadpole) to a “more developed” adult terrestrial animal (frog). In fact, programmed cell death, with
nuclear changes and removal by phagocytic macrophages, occurs in a variety of organs, during
amphibian metamorphosis, that is under the control of iodinated TH. Indeed, because of the massive
cell death that occurs during a short period, amphibian organs serve as an ideal model system for
the study of mechanisms underlying programmed cell death (Ishizuya-Oka et al. 2003; Ikuzawa et
al. 2005).
11
Fig. 3. In amphibian metamorphosis iodides and thyroxine have an important
role in the spectacular apoptotic action on the cells of gills, tail and fins, and in
adapting and transforming an aquatic animal (tadpole) into a “more developed”
terrestrial animal (frog).
TH induces apoptosis of larval cells and differentiation of pepsinogen-producing cells in the
stomach of adult form of frog Xenopus laevis (Ishizuya-Oka et al. 2003). Upadhyay et al. (2002)
reported that excess iodine has been observed to induce also apoptosis in thyrocytes and mammary
cells. According to Upadhyay, mitochondria are important in iodination of different proteins;
mitochondria are the central executioner of apoptosis and therefore may play an important role in
carcinogenesis. Mitochondrial proteins from breast tissue are iodinated. Organification of iodine to
proteins requires oxidative enzymes, H2O2 generating system and proteins in the vicinity, conditions
favorable for the iodination of proteins, which exist in mitochondria under normal circumstances.
Upadhyay observed that mitochondria isolated from the tumor (TT) and extra-tumoral tissue (ET)
of human breast display significant uptake of iodine. Mitochondrial proteins were observed to be
predominantly iodinated in ET but not in TT mitochondria. Treatment with iodine showed an
increase in mitochondrial permeability transition of TT and decrease in ET. Iodine induced released
factors other than cytochrome c from tumor mitochondria, which initiated apoptosis in vitro.
Iodine in Terrestrial Organisms
12
When about 500-300 Mya some living plants and animals began to transfer from the sea to rivers
and land, environmental I-deficiency was a challenge to the evolution of terrestrial life (Venturi
2000a). In fishes, plants and animals the terrestrial diet became deficient in many primitive marine
trace-elements, including iodine and selenium. Terrestrial plants slowly optimized the production of
“new” endogenous antioxidants such as ascorbic acid, polyphenols, carotenoids, flavonoids,
tocopherols, some of which became essential “vitamins” in the diet of terrestrial animals (vitamins
C, A, E). According to Coic and Coppenet (1990) and Lamand (1991), iodine and selenium became
no longer necessary to many plants. In a different way, some chordates, about 500 Mya, began to
use also the “new” thyroidal follicles, as reservoir for iodine, and to use the thyroxine in order to
transport antioxidant iodide and triiodothyronine into the peripherical cells. Triiodothyronine (T3),
the biologically active form of thyroid hormone in vertebrates, became active in the metamorphosis
and thermogenesis for a better adaptation to terrestrial fresh-waters, atmosphere, gravity,
temperature and diet (Fig. 1). Extrathyroidal or peripheral TH metabolism is mediated by
deiodinases [type 1 deiodinase (D1), type 2 deiodinase (D2) and type 3 deiodinase (D3)].
Deiodinases deliver from iodothyronines into peripheral cells atoms of iodide without hormonal
action. D3 protein is also expressed by granulocytes and monocarboxylate transporter 8 (MCT8), a
novel very active and specific thyroid hormone transporter is also present at the site of
inflammation. Thyroxine, reverse-T3 and iodothyronines seem to be important as antioxidants and
inhibitors of lipid peroxidation (Oziol et al. 2001; Berking et al. 2005), and more effective than
vitamin E, glutathione and ascorbic acid (Tseng and Latham 1984). Moreover the new terrestrial
diet harbored plant iodide-transport inhibitors such as thiocyanates, cyanates, nitrates and some
glycosides (Wolff 1964; Brown-Grant 1961). Many plant substances that inhibit iodide-transport
seem to have antiparasitic activity (Wolff 1964). In previous work, Venturi et al.(2000a) reported
that, contrary to amphibian metamorphosis, in the mammals the thyroidectomy and
hypothyroidism might be considered like a sort of phylogenetical and metabolical regression to a
former stage of reptilian life. In fact, many disorders, similar to reptilian features, such as a dry,
13
hairless, scaly, cold skin and a general slowdown of metabolism, digestion, heart rate, nervous
reflexes with lethargic cerebration, hyperuricemia, and hypothermia seem to afflict hypothyroid
humans. The new hormonal action was made possible by the formation of T3-receptors (TH-Rs) in
the cells of vertebrates. First, about 500 Mya, in marine chordates, the primitive TH-Rs with a metamorphosing action appeared and then, about 250-350 Mya, in the birds and mammalians, others
more recent TH-Rs with metabolic and thermogenetic actions were formed. TH-R genes are indeed
c-erbA oncogenes, which have been implicated as tumor suppressor genes of non-thyroidal cancers
and are altered in some human gastric and mammary cancer (Wang et al. 2002; Li et al. 2002).
Role of Iodide in Animal Cells
In humans, the total amount of iodine is about 25-50 mg and about 50-70 % of total iodine is nonhormonal and it is concentrated, via NIS, in extrathyroidal tissues (Venturi 2000a, b).
Figure 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 radio-iodide (in white) in gastric mucosa of the stomach,
salivary glands and oral mucosa. In gastric mucosa of the stomach, 131-I (half-life: 8 days) persists
in scintiscans for more than 72 hours. In the thyroid I-concentration is more progressive, as in a
reservoir [from 1% (after 30 minutes) to 5.8 % (after 48 hours) of the total injected dose].
14
Mammary gland iodide-concentration is here not evident because this woman was not pregnant or
lactating. It is evident a high excretion of radioiodide in urina.
In 1996, cloning and molecular characterization of the human NIS have been performed (Dai et al.
1996; Smanik et al. 1996). In the thyroid cells active iodide transport is facilitated by three
transporters: NIS, Pendrin and Apical Iodide Transporter. Expression of all three transporters
appears in extrathyroidal tissues (Burbridge 2005; Rodriguez et al. 2002). Iodine is present, in
different concentration, in every organ and tissue of the human body, not just the thyroid gland. So
far the list of these iodide-concentrating cells includes: white blood cells, salivary and lachrymal
glands, ciliary body of the eye, renal cortex, the pancreas, the liver, gastric, small and large
intestinal mucosa, nasopharynx, choroid plexus, skin, adrenal cortex, mammary gland, placenta,
uterus and ovary (Brown-Grant 1961). What role does iodide play in animal cells? In previous
works Venturi et al. (2000a, b) reported that it is possible to hypothesize on the basis of the
phylogenesis and embryogenesis three ways of action of iodine:
1) An ancient and direct action, on endodermal fore-gut, stomach and on ectodermal epidermis,
where inorganic iodides probably act as antioxidants.
2) A more recent and direct antioxidant action, on salivary glands and mammary glands, thymus,
ovary and on nervous, arterial and skeletal systems.
3) A more recent indirect (but also via non-genomic effects) action of the thyroid and its iodinated
hormones, on all vertebrate cells, which make use of specific iodine-compounds: T4 and T3, which
act in very small quantities and utilize T3-receptors. Indeed thyroid hormones contain less than 1/30
of total iodine amount.
Data from Wolff (1964), Evans et al. (1966), Goethe (1999) and Venturi et al. (1985, 1999, 2000a,
b, 2003) suggest that both these actions of iodine may still have an important place in the cells of
modern vertebrates. Broadhurst et al.(2002) and Cunnane (2005) suggested that early Homo
sapiens, living around the Rift Valley lakes and up the Nile Corridor into the Middle East, received
15
iodine and n-3 fatty acids from littoral food resources. Dobson (1998) suggested that Neanderthal
man suffered I-deficiency disorders caused by inland environment or by a genetic difference of his
thyroid compared to the thyroid of the modern Homo Sapiens. I-deficient humans, like endemic
cretins, suffer physical, neurological, mental, immune and reproductive diseases. Iodine has favored
the evolution of the nervous system for a better adaptation to terrestrial environment as recently
reported by Cunnane (2005), who suggested that “iodine is the primary brain selective nutrient in
human brain evolution.” Cordain et al.(2005) recently reported that the significant changes in diet,
that began with the introduction of agriculture and animal husbandry approximately 10,000 years
ago, occurred too recently on an evolutionary time scale for the human genome to adjust. In
conjunction with this discordance between our ancient, genetically determined biology of huntergatherers and fisher-gatherers human societies and the nutritional patterns of contemporary Western
populations, many of the so-called diseases of civilization have emerged. Cordain suggests that
iodine deficiency was probably one, among other dietary variations, introduced during the Neolithic
and Industrial Periods, which have altered crucial nutritional characteristics of ancestral human diet
(simultaneously fiber and polyunsaturated fatty acid contents). The evolutionary collision of our
ancient genome with the nutritional qualities of recently introduced foods may underlie many of the
chronic diseases of Western civilization.
16
Fig. 5. Daily dietary intake of iodine, according to Food and Nutrition Board, Institute
of Medicine, 2001. Note that an optimal iodine intake of 6.0 mg for breast has been
reported recently by Kessler in °Breast J. 2004, 10:328-36
In 1883, Kocher observed that atherosclerosis, a suspected ROS-caused disease, frequently
appeared following thyroid extirpation and suggested that hypothyroidism may be causally
associated with atherosclerosis. In 1930-50’s, potassium iodide was used empirically in patients
with arteriosclerosis and cardiovascular diseases by European physicians (Cann 2006), and Turner
(1933a, b) reported the efficacy of iodine and desiccated thyroid in preventing the development of
atherosclerosis in rabbits. The antioxidant action of iodides has also been described in brain cells of
rats (Katamine 1985) and in the therapy of some human chronic diseases of cardiovascular and
articular systems (Winkler et al. 2000). Liu (2000a, b) showed that ROS and lipid peroxidations
increase in I-deficient rats and children. Recently, Aceves et al. (2005) and Cann (2006) suggested
that iodides seem to have preventive effects in breast cancer and in cardiovascular diseases. Iodine
seems to support anticarcinogenic defense of the organism. Some data evidenced that iodine can
prevent breast and gastric cancer in humans (Eskin 1970, 1977; Venturi 2000b, 2001; Funahashi et
17
al.1996, 2001; Smyth 2003a, b; Kessler 2004; Szybinski et al. 2004; Abnet et al. 2006 ). Aceves et
al. (2005) reported that “Iodine is a gatekeeper of mammary gland integrity” and proposes that an
iodine supplement should be considered as an adjuvant in breast cancer therapy. In the same Ideficient territories human, animal and plant pathologies by I-deficiency frequently coexist. Many
researchers reported that Tasco-Forage, an (iodine-rich) extract from the brown seaweed
Ascophyllum nodosum, has increased antioxidant activity and immune system in both plants and in
grazing animals ( Saker et al. 2001, 2004; Montgomery et al. 2001; Allen et al. 2001; Fike at al.
2001). The evolutionary adaptation of terrestrial vertebrates to environmental iodine deficiency has
not finished yet (Cabello et al. 2003), and most humans and terrestrial animals still need a dietary
iodine supplementation (Food and Nutrition Board, USA, 2001). According to current W.H.O.
statistics more than 3 billion people in the world live nowadays in I-deficient countries. In the
analysis of “National Health and Nutrition Examination Surveys” data of moderate to severe iodine
deficiency is present now in a significant proportion (11.7%) of the U.S. population, with a clear
increasing trend over the past 20 years, caused by reduced iodized table salt usage (Hollowell et al.
1998).
In conclusion, we suggest that iodide acts as a primitive antioxidant and apoptosis-inductor with a
presumed anti-tumoral and anti-atherosclerotic activity. Studies of molecular evolution of primitive
antioxidants might provide the basis for further research into “new” active substances against these
pathologies.
----------0000-----------REFERENCES
Abnet CC, Qiao YL, Kamangar F, Dong ZW, Taylor P, Mark S, Fraumeni J Jr, Dawsey S (2006) Selfreported goiter is associated with a significantly increased risk of gastric adenocarcinomain a large
population-based Chinese cohort. Int J Cancer 119:1508-10
Aceves C, Anguiano B, Delgado G (2005) Is Iodine A Gatekeeper of the Integrity of the Mammary
Gland? J of Mammary Gland Biol and Neopl 10 :189-196
Allen VG, Pond KR, Saker KE et al.(2001) Tasco-Forage: III. Influence of a seaweed extract on
performance, monocyte immune cell response, and carcass characteristics in feedlot-finished steers. J
Anim Sci 79:1032-40
18
Banerjee RK, Bose AK, Chakraborty TK et al. (1985) Peroxidase-catalysed iodotyrosine formation in
dispersed cells of mouse extrathyroidal tissues. J Endocrinol 106:159-65
.
Benzie IF (2000) Evolution of antioxidant defence mechanisms. Eur J Nutr 39:53–61
Benzie IF (2003) Evolution of dietary antioxidants. Comp Biochem Physiol A Mol Integr Physiol.
136:113-26
Berking S, Czech N, Gerharz M et al. (2005) A newly discovered oxidant defence system and its
involvement in the development of Aurelia aurita (Scyphozoa, Cnidaria): reactive oxygen species and
elemental iodine control medusa formation. Int J Dev Biol 49:969-76
Bjelakovic G, Nikolova D, Simonetti RG, Gluud C (2004) Antioxidant supplements for prevention of
gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2:1219-28
Bray W, Caulkins A (1921) A periodic reaction in homogeneous solution and its relation to catalysis.
J Am Chem Soc 43:1262-7
Broadhurst CL, Wang Y, Crawford MA, Cunnane SC et al. (2002) Brain-specific lipids from marine,
lacustrine, or terrestrial food resources: potential impact on early African Homo sapiens. Comp Biochem
Physiol B Biochem Mol Biol 131:653-73
Brown-Grant K (1961) Extrathyroidal iodide concentrating mechanisms. Physiol Rev 41:189-213
Burbridge E, Nawoor Z, Smith DF et al. (2005) Expression of iodide transporters in human placental
tissue. Endocrine Abstracts. 9 P.49
Cabello G, Vilaxa A, Spotorno AE et al. (2003) Evolutionary adaptation of a mammalian species to an
environment severely depleted of iodide. Pflugers Arch 446:42-5
Canfield DE (2005) The early History of Atmospheric Oxigen: Homage to Robert M. Garrels. Annu
Rev. Earth Planet Sci 33:1–36
Cann SA, van Netten JP, van Netten C (2000) Hypothesis: iodine, selenium and the development of
breast cancer. Cancer Causes Control 11:121-7
Cann SA (2006) Hypothesis: dietary iodine intake in the etiology of cardiovascular disease. J Am Coll
Nutr 25:1-11
Carpenter LJ, Sturges WT , Liss PS, Penkett SA, Alicke B, Hebestreit K, Platt U (1999) Short-lived
alkyl iodides and bromides at Mace Head: links to macroalgal emission and halogen oxide formation. J
Geophys Res 104: 1679–1689
Carpenter LJ, Malin G, Kuepper FC, Liss PS (2000) Novel biogenic iodine-containing trihalomethanes
and other shortlived halocarbons in the coastal East Atlantic.Global Biogeochem. Cycles 14: 1191–1204
Chino Y, Saito M, Yamasu K, Suyemitsu T, Ishihara K (1994) Formation of the adult rudiment of seaurchins is influenced by thyroidhormones. Dev Biol 161:1–11
Cocchi M, Venturi S (2000) Iodide, antioxidant function and omega-6 and omega-3 fatty acids: a new
hypothesis of a biochemical cooperation? Progress in Nutrition. 2 :15-19
Coic Y, Coppenet M (1990) Les oligoéléments en agiculture et élevage. INRA Publications route de St
Cyr, 78000 Versailles.
19
Colin C, Leblanc C, Wagner E et al. (2003) The brown algal kelp Laminaria digitata features distinct
bromoperoxidase and iodoperoxidase activities. J Biol Chem. 278:23545-52
Cordain L, Eaton SB, Sebastian A, Mann N, Lindeberg S, Watkins BA, O'Keefe JH, Brand-Miller J
(2005) Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin
Nutr 81:341-54
Cunnane SC (2005) Survival of the Fattest: The Key to Human Brain Evolution. World Scientific
Publishing Company (Hardcover)
Dai G, Levy O, Carrasco N (1996) Cloning and characterization of the thyroid iodide transporter.
Nature. 379:458-60
Dembitsky VM, Tolstikov GA (2003) Natural Halogenated Organic Compounds. Nauka Press,
Novosibirsk
Dobson JE (1998) The iodine factor in health and evolution. The Geographical Review 88:1-28
Dugrillon A (1996) Iodolactones and iodoaldehydes mediators of iodine in thyroid autoregulation. Exp
Clin Endocrinol Diabetes 104 Suppl 4:41-5
Dunn JT, Delange F (2001) Damaged reproduction: the most important consequence of iodine
deficiency. J Clin Endocrinol Metab 8:2360-3
Eales JG (1997) Iodine metabolism and thyroid-related functions in organisms lacking thyroid follicles:
are thyroid hormones also vitamins? Proc Soc Exp Biol Med 214:302–317
Elderfield H, Truesdale V W (1980) On the biophilic nature of iodine in seawater. Earth and Planetary
Science Letters. 50:105-114
Eskin BA (1970) Iodine metabolism and breast cancer. Trans N Y Acad Sci. 32(8): 911-947
Eskin BA (1977) Iodine and mammary cancer. Adv Exp Med Biol. 91:293-304
Evans ES, Schooley RA, Evans AB, Jenkins CA, Taurog A (1966) Biological evidence for
extrathyroidal thyroxine formation. Endocrinology 78:983-1001
Farrell AP, Davie P, Sparksman R (1992) The absence of coronary arterial lesions in five species of
elasmobranchs, Raja nasuta, Squalus acanthias L., Isurus oxyrinchus Rafinesque, Prionace glauca (L.)
and Lamna nasus (Bonnaterre). J Fish Disease 15:537-540
Favier A (1991) Les oligoelements en nutrition humaine. In: Les Oligoelements en Medicine et Biologie.
Ed Chappuis P. Publ Lavoisier, Paris
Fike JH, Allen VG, Schmidt RE, Zhang X, Fontenot JP, Bagley CP, Ivy RL, Evans RR, Coelho RW,
Wester DB (2001) Tasco-Forage: I. Influence of a seaweed extract on antioxidant activity in tall fescue
and in ruminants. J Anim Sci 79:1011-21
Flohe L, BrigeliusFlohe R, Saliou C, Traber MG, Packer L (1997) Redox regulation of NF-kappa B
activation. Free Radical Biol Med 22 :1115-1126
Food and Nutrition Board (2001) Institute of Medicine. Dietary Reference Intakes for Vitamin A,
Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon,
Vanadium, and Zinc. National Academy Press, Washington DC
20
Funahashi H, Imai T, Tanaka Y et al. (1996) Suppressive e.ect of iodine on DMBA-induced breast tumor
growth in the rat. J Surg Oncol 61: 209-213
Funahashi H, Imai T, Mase T, Sekiya M, Yokoi K, Hayashi H, Shibata A, Hayashi T, Nishikawa M,
Suda N, Hibi Y, Mizuno Y, Tsukamura K, Hayakawa A, Tanuma S (2001) Seaweed prevents breast
cancer? Jpn J Cancer Res 92 :483-7
Gall EA, Küpper FC, Kloareg B (2004) A survey of iodine content in Laminaria digitata. Botanica
Marina 47: 30–37
Goethe S, Wang Z, Ng L, Kindblom JM, Barros AC, Ohlsson C, Vennstrom B, Forrest D (1999) Mice
devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid
axis, growth, and bone maturation. Genes Dev 13:1329-41
Gottardi W (1991) Iodine and Iodine Compounds In: Block SS (ed) Disinfection, Sterilization,
and Preservation. Lippincott Williams & Wilkins, Philadelphia, pp.152-66
Gribble GW (1996) Naturally Occurring Organohalogen Compounds : A Comprehensive Survey;
Progress in the Chemistry of Organic Natural Products 68:1-528
Hardie LJ, Fletcher TC, Secombes CJ (1991) The effect of dietary vitamin C on the immune response
of the Atlantic salmon (Salmo salar). Aquaculture 95:201–214
Heyland A (2004) Thyroid Hormone-Like Function in Echinoids: A Modular Signaling System Coopted
for Larval Development and Critical for Life History Evolution. University of Florida, Gainesville, FL
Heyland A, Hodin J, Reitzel AM (2005) Hormone signaling in evolution and development: a non-model
system approach. Bioessays 27:64-75
Heyland A, Moroz LL (2005) Cross-kingdom hormonal signaling: an insight from thyroid hormone
functions in marine larvae. J Exp Biol 208 (Pt 23):4355-61.
Heyland A, Price DA, Bodnarova-Buganova M, Moroz LL (2006) Thyroid hormone metabolism
and peroxidase function in two non-chordate animals. J Exp Zoolog B Mol Dev Evol. May 31; [Epub
ahead of print]
Hollowell JG, Staehling NW, Hannon WH, et al. (1998) Iodine nutrition in the United States. Trends and
public health implications: iodine excretion data from National Health and Nutrition Examination
Surveys I and III (1971-1974 and 1988-1994). J Clin Endocrinol Metab 83: 3401-3408
Hung HC, Joshipura KJ, Jiang R, Hu FB, Hunter D, Smith-Warner SA, Colditz GA, Rosner B,
Spiegelman D, Willett WC (2004) Fruit and vegetable intake and risk of major chronic disease. J Natl
Cancer Inst 3:1577-84.
Ikuzawa M, Kobayashi K, Yasumasu S, Iuchi I (2005) Expression of CCAAT/enhancer binding protein
delta is closely associated with degeneration of surface mucous cells of larval stomach during the
metamorphosis of Xenopus laevis. Comp Biochem Physiol Biochem Mol Biol 140:505-11.
Ishizuya-Oka A, Shimizu K, Sakakibara S, Okano H, Ueda S (2003) Thyroid hormone-upregulated
expression of Musashi-1 is specific for progenitor cells of the adult epithelium during amphibian
gastrointestinal remodeling. J Cell Sci 116(Pt 15):3157-64
Katamine S, Hoshino N, Totsuka K, Suzuki M. 1985. Effects of the long-term feeding of high-iodine
eggs on lipid metabolism and thyroid function in rats. J Nutr Sci Vitaminol 31:339-5
21
Kessler JH (2004) The effect of supraphysiologic levels of iodine on patients with cyclic mastalgia.
Breast J 10:328-36
Kocher T (1883) Uber Kropfexstirpation und ihre Folgen. Arch Klin Chir 29:254-337
Küpper FC, Feiters MC, Meyer-Klaucke W, Kroneck PMH, Butler A (2002) Iodine Accumulation in
Laminaria (Phaeophyceae): an Inorganic Antioxidant in a Living System? Proceedings of the 13th
Congress of the Federation of European Societies of Plant Physiology, Heraklion, Greece, September 26, p. 571
Küpper 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. Planta 207:163-171
Lamand M (1991) Les oligoéléments dans la Biosphère. In: Les Oligoéléments en Medicine et Biologie.
Ed. Chappuis P. Publ. Lavoisier, Paris
Lane N (2002) Oxygen: The Molecule that made the World. Oxford Univ Press, Oxford, UK.
Li Z, Meng ZH, Chandrasekaran R, Kuo WL, Collins CC, Gray JW, Dairkee SH (2002) Biallelic
inactivation of the thyroid hormone receptor beta1 gene in early stage breast cancer. Cancer Res
62:1939-43
Lin J, Zhang SM, Cook NR, Rexrode KM, Liu S, Manson JE, Lee IM, Buring JE (2005) Dietary intakes
of fruit, vegetables, and fiber, and risk of colorectal cancer in a prospective cohort of women (United
States). Cancer Causes Control 16:225-233
Liu Y (2000a) Study on antioxidative unbalance and structural damage in iodine deficient rats. 12th
International Thyroid Congress Kioto, 22-27 October 2000: P-559
Liu Y (2000b.) The damage role of free radical in iodine deficient children. 12th International Thyroid
Congress, Kioto, 22-27 October 2000 :P-560/D
Manzon RG, Youson JH (1997) The effects of exogenous thyroxine (T4) or triiodothyronine (T3), in the
presence and absence of potassium perchlorate, on the incidence of metamorphosis and on serum T4 and
T3 concentrations in larval sea lampreys (Petromyzon marinus L.). Gen Comp Endocrinol 106:211-20.
Montgomery JL, Allen VG, Pond KR, Miller MF, Wester DB, Brown CP, Evans R, Bagley CP, Ivy RL,
Fontenot JP (2001) Tasco-Forage: IV. Influence of a seaweed extract applied to tall fescue pastures on
sensory characteristics, shelf-life, and vitamin E status in feedlot-finished steers. J Anim Sci (4):884-94
Morris CD, Carson S (2003) Routine vitamin supplementation to prevent cardiovascular disease: a
summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 139:56-70
Obinger C, Regelsberger C, Strasser C, Burner U, Peschek CA (1997) Purification and characterization
of a homodimeric catalase-peroxidase from the cyanobacterium Anacystis nidulans. Biochem Biophys
Res Commun 235:545-552
Obinger C, Regelsberger C, Strasser C, Peschek CA (1997) Scavenging of activated oxygen species in
cyanobacteria. 9th International Symposium on Phototrophic Prokaryotes.Vienna, Austria p.142
Oziol L, Faure P, Vergely C, Rochette L, Artur Y, Chomard P, Chomard P (2001) In vitro free radical
scavenging capacity of thyroid hormones and structural analogues. J Endocrinol 170 :197-206
Pedersén M, Collén J, Abrahamson J, Ekdahl A (1996) Production of halocarbons from seaweeds: an
oxidative stress reaction? Sci Mar 60 (Suppl. 1):257-263
22
Pisarev MA, Chazenbalk GD, Valsecchi RM, Burton G, Krawiec L, Monteagudo E, Juvenal GJ, Boado
RJ, Chester HA (1988) Thyroid autoregulation. Inhibition of goiter growth and of cyclic AMP formation
in rat thyroid by iodinated derivatives of arachidonic acid. J Endocrinol Invest 11:669-74
Purves WK, Sadava D, Orians GH, Heller HC (1998) Life.The Science of Biology. Part 4: The
Evolution of Diversity. Chapter 30
Roche J (1952) Biochimie comparée des scléroprotéines iodées des Anthozoaires et des Spongiaires.
Experientia 8:45-56
Roche J, Yagi Y (1952) Sur la fixation de l’iode radioactif par les algues et sur les constitues iodes des
laminaires. C.R Soc Biol. Paris, 146:642-645
Rodriguez AM, Perron B, Lacroix L, Caillou B, Leblanc G, Schlumberger M, Bidart JM, Pourcher T
(2002) Identification and characterization of a putative human iodide transporter located at the apical
membrane of thyrocytes. J Clin Endocrinol Metab 87:3500-3
Saker KE, Allen VG, Fontenot JP, Bagley CP, Ivy RL, Evans RR, Wester DB (2001) Tasco-Forage: II.
Monocyte immune cell response and performance of beef steers grazing tall fescue treated with a
seaweed extract. J Anim Sci 79:1022-31
Saker KE, Fike JH, Veit H, Ward DL (2004) Brown seaweed-(Tasco) treated conserved forage enhances
antioxidant status and immune function in heat-stressed wether lambs. J Anim Physiol Anim Nutr
(Berl). 88:122-30.
Sato Y, Tsubono Y, Nakaya N et al. (2005) Fruit and vegetable consumption and risk of colorectal
cancer in Japan: The Miyagi Cohort Study. Public Health Nutr 8:309-14
Sies H (1997) Antioxidants in disease mechanisms and therapy. Advances in Pharmacology ed.
Academic Press. San Diego
Smanik PA, Liu Q, Furminger TL, Ryu K, Xing S, Mazzaferri EL, Jhiang SM (1996) Cloning of the
human sodium iodide symporter. Biochem Biophys Res Commun 13:339-45
Smyth PP (2003a) Role of iodine in antioxidant defence in thyroid and breast disease. Biofactors
19:121-30
Smyth PP (2003b) The thyroid, iodine and breast cancer. Breast Cancer Res 5:235-8
Spangenberg DB (1971) Thyroxine induced metamorphosis in Aurelia. J Exp Zool 178:183-94
Stone OJ (1988) The role of the primitive sea in the natural selection of iodides as a regulating factor in
inflammation. Med Hypotheses 25:125-129
Stone OJ (1988) The role of the primitive sea in the natural selection of iodides as a regulating factor in
inflammation. Med Hypotheses. 25:125-129
Suzuki YJ, Forman HJ, Sevanian A (1997) Oxidants as stimulators of signal transduction. Free Radical
Biology & Medicine 22:269-285
Szybinski Z, Rachtan J, Huszno B, Hubalewska A, Buziak-Bereza M, Trofimiuk M (2004) Is iodineProphylaxis a protective factor against gastric cancer in iodine-deficient ares? 30th Annual Meeting of
European Thyroid Association. Istanbul, Turkey, 18-22 September. P.111 (Abstract No: 257)
Taurog A (1999) Molecular evolution of thyroid peroxidase. Biochimie 81:557-562
23
Teas J, Pino S, Critchley A, Braverman LE (2004) Variability of iodine content in common
commercially available edible seaweeds. Thyroid 14:836-41
Truesdale VW, Luther GW III, Canosa-Mas C (1995) Molecular iodine reduction in seawater: an
improved rate equation considering organic compounds. Mar Chem 48:143-150
Tseng YL, Latham KR (1984) Iodothyronines: oxidative deiodination by hemoglobin and inhibition of
lipid peroxidation. Lipids 19:96-102
Tsubono Y, Otani T, Kobayashi M, Yamamoto S, Sobue T, Tsugane S; JPHC Study Group (2005)
No association between fruit or vegetable consumption and the risk of colorectal cancer in Japan. Br J
Cancer 9; 92 :1782-4.
Turner KB (1933) Studies on the prevention of cholesterol atherosclerosis in rabbits. The effects of
whole thyroid and of potassium iodide. J Exp Med 58 :115-125
Turner KB, Khayat GB (1933) Studies on the prevention of cholesterol atherosclerosisin rabbits. The
influence of thyroidectomy upon the protective action of potassium iodide. J Exp Med 58:127-132
Upadhyay G, Singh R, Sharma R, Balapure AK, Godbole MM (2002) Differential action of iodine on
mitochondria from human tumoral- and extra-tumoral tissue in inducing the release of apoptogenic
proteins. Mitochondrion 2:199-210
Venturi S (1985) Preliminari ad uno studio sui rapporti tra cancro gastrico e carenza alimentare iodica:
prospettive specifiche di prevenzione. Editor USL n.1, Regione Marche, Novafeltria (PU)
Venturi S (2001) Is there a role for iodine in breast diseases? The Breast 10:379-382
Venturi S, Venturi M (1999) Iodide, thyroid and stomach carcinogenesis: Evolutionary story of a
primitive antioxidant? Eur J Endocrinol 140:371-372
Venturi S, Venturi A, Cimini D, Arduini C, Venturi M, Guidi A (1993) A new hypothesis: iodine and
gastric cancer. Eur J Cancer Prevent 2:17-23
Venturi S, Donati FM, Venturi A, Venturi M (2000a) Environmental iodine deficiency: A challenge to
the evolution of terrestrial life? Thyroid 10:727-9
Venturi S, Marani L, Magni MA(1987) Syndrome thyro-gastric: study on the relation between
alimentary iodine deficiency and gastric. In: Ghironzi G, Jackson CE, Schuman BM. Epidemiology,
Prevention and Early Detection of Gastric Cancer. CIC Edit. Rome, pp. 272-81
Venturi S, Donati FM, Venturi A, Venturi M, Grossi L, Guidi A (2000b) Role of iodine in evolution and
carcinogenesis of thyroid, breast and stomach. Adv Clin Path 4:11-7
Venturi S, Grossi L, Marra GA, Venturi A, Venturi M (2003) Iodine, Helicobacter Pylori, Stomach
Cancer and Evolution. European EPI-Marker 7:1-7
Venturi S, Venturi M (2004) Iodine and Evolution. Dimi Marche News. Dipartimento Interaziendale di
Medicina Interna della Regione Marche. Published on-line http://web.tiscali.it/iodio/
Venturi S, Venturi M (2006) Iodio ed Evoluzione. In: Guida alla Epidemiologia e Prevenzione
del Gozzo Endemico. Meringolo D. Bianchi D, Bellanova B. Malagoli Ed. Bologna, pp.11-25
Vilter H (1994) Extraction of proteins from sources containing tannins and anionic mucilages. Meth
Enzymol 228:665–672
24
Vilter H (1995) Vanadium-dependent haloperoxidases. In: Vanadium and its role in life. (H. Sigel and A
Sigel eds) MetalIons Biol Syst 31:325–362
Vilter H. Glombitza K-W and Grawe A (1983.) Peroxidases from Phaeophyceae. I. Extraction and
detection of the peroxidases. Bot Mar 26:331–340
Wang CS, Lin KH, Hsu YC (2002) Alterations of thyroid hormone receptor alpha gene: frequency and
association with Nm23 protein expression and metastasis in gastric cancer. Cancer Lett 175:121-7
Wiedenheft B, Mosolf J, Willits D, Yeager M, Dryden KA, Young M, Douglas T (2005) An archaeal
antioxidant: characterization of a Dps-like protein from Sulfolobus solfataricus. Proc Natl Acad Sci
USA 102:10551-6
Winkler R, Griebenow S, Wonisch W (2000) Effect of iodide on total antioxidant status of human
serum. Cell Biochem Funct 18:143-6
Wolff J (1964) Transport of iodide and other anions in the thyroid gland. Physiol Rev 44:45-90
Wolff J, Chaikoff IL, Goldberg RC, Meier JR (1949) The temporary nature of the inhibitory action of
excess iodide on organic iodine synthesis in the normal thyroid. Endocrinology 45:504-513
Youson JH (1997) Is lamprey metamorphosis regulated by thyroid hormones? Amer Zool 37:441–460
Youson JH, Sower SA (2001) Theory on the evolutionary history of lamprey metamorphosis: role of
reproductive and thyroid axes. Comp Biochem Physiol B Biochem Mol Biol 129:337-45
Yu BP (1994) Cellular defenses against damage from reactive oxygen species. Physiological Reviews
74:139-162
Yun AJ, Lee PY, Bazar KA, Daniel SM, Doux JD (2005) The incorporation of iodine in thyroid
hormone may stem from its role as a prehistoric signal of ecologic opportunity:an evolutionary
perspective and implications for modern diseases. Med Hypotheses 65:804-10
---------ooo---------
25