PHYSIOLOGY UPDATE 2008

DIETARY GOITROGENS AND THYROID

PHYSIOLOGY

DR. DISHARI GHOSH (LAHARI)

Address to Correspondence:
Dr. Dishari Ghosh (Lahari)
Scientist ‘B’
Defence Institute of Physiology and Allied Sciences
Defence Research and Development Organization
Lucknow Road, Timarpur
Delhi 110054
e-mail: dishari_l@yahoo.co.in
 ABSTRACT

A large number of agents in the environment both naturally occurring and man made are
known to interfere with thyroid gland morphology and function, posing the danger of thyroid
disease. Apart from the degrees of severity of the iodine deficiency, the frequencies and
symptomatologies of the utilization of iodine in the body are influenced by certain substances
present in foods and water which are recognized as the second major etiological factor for
iodine deficiency disorders (IDD). These factors are called goitrogens. The major dietary
goitrogens present in Indian cyanogenic plants are cyanogenic glucosides, glucosinolates and
thiocyanate play a contributing role in alteration of thyroid physiology.

INTRODUCTION

The discoveries of natural and synthetic substances that impair the synthesis of
thyroid hormone are landmarks in the history of pharmacology (Chesney et al 1928).
Although iodide deficiency is, without doubt, the major cause of endemic goiter and
cretinism throughout the world, dietary goitrogens may play a contributing role in some
endemics, and may possibly be the dominant factor in certain areas. Goitrogens are foods that
suppress thyroid function. In normal , goitrogens can induce hypothyroidism and goiter. In
hypos, goitrogens can further depress thyroidal function and stimulate the growth of the
thyroid (goiter).The dietary goitrogens fall into several categories, more than one of which
may occur in the same food.

Goitrogens viz. cyanogenic glucosides (Delange et al 1982; Delange1989),

glucosinolates (Ermans and Bourdoux 1989; Schone et al 1994), thiocyanate (Rao 1995),
flavonoids (Gaitan et al 1989; Lindsay et al 1989; Sartelet 1996) and disulfides (Gaitan 1990)
play a contributing role in the alteration of thyroid physiology and magnify the severity of
goitre endemia depending upon the state of iodine intake. Certain foods contain cyanogenic
glucosides (Ermans et al 1972) compounds that, upon hydrolysis by glucosidase, release free
cyanide. These foods include almond seeds and such important dietary items as cassava,
sorghum, maize, and millet.

Other important classes of antithyroid compounds arise from hydrolysis of the

thioglucosides (Langer 1966; Langer and Greer 1968; Ermans et al 1972) These compounds
are metabolized in the body to goitrin or thiocyanates and isothiocyanates, and ultimately to
other sulfur containing compounds, or are excreted as such. They are important in the
goitrogenic activity of seeds of plants of the genus Brassica and the cruciferae, compositae,
and unbelliferae. Among the plants containing these compounds are cabbage, kale, brussel
sprouts, cauliflower, kohlrabi, turnip, rutabaga, mustard, and horseradish.

The dietary goitrogens found in cyanogenic plants of Indian origin are cyanogenic
glucosides, glucosinolates and thiocyanate.

CYANOGENIC GLUCOSIDES

Cyanogenic glycosides are phytoanticipins which occur in at least 2500 plant species
of which a number of species are used as food in many areas of the world (Nartey 1980;
Vetter 2000; Zagrobelny et al 2004). They are considered to have an important role in plant
defense against herbivores due to bitter taste and release of toxic hydrogen cyanide upon
tissue disruption (Zagrobelny et al 2004).

Structure and Occurance

The cyanogenic glucosides, a secondary metabolite to the natural products of plants

are composed of an alphahyroxynitrile type aglycone and of a sugar moiety (mostly D-
glucose). They are optically active because of chirality of the hydroxylated C-atom 2, which
either occurs in the S- or R- configuration (Conn 1980; Seigler 1991; Nahrstedt 1989). More
than 60 cyanogenic glucosides are known which are widely distributed among the members
of plant family - Compositae, Euphorbiaceae, Linaceae, Fabaceae, Myrtaceae, Rosacea etc.
(Vetter 2000).

Fig 1. Structure of cyanogenic glucosides

Synthesis

Cyanogenic glucosides are derived from the five hydrophobic L-amino acids viz.
valine, leucine, isoleucine, phenylalanine and tyrosine (Poulton 1990) and biosynthesis seem
to be catalysed by a multi-enzyme complex (Conn 1980). In the first step, a L-amino acid N-
monooxygenase hydroxylates the amino group of L-amino acids. Upon oxidative
decarboxylation the N- hydroxy- L- amino acids are converted into an aldoxime. The nitrile
is then hydroxylated at the C2-position by a nitrile monooxygenase to yield the key
intermediate 2-hydroxynitrile or cyanohydrin. The final step in cyanogenic glucoside
synthesis is the glycosylation of the alpha-hydroxy moiety catalysed by a glucosyltransferase
(Conn 1981; White et al 1998; Anderson et al 2000; Vetter 2000).

Localisation

Cyanogenic glucosides are formed in the cytoplasm but stored in the central vacuoles
while the degradating enzymes are attached to the outside of the cell wall (Dziewanowska
1983). The tissue level compartmentation of cyanogenic glucosides and their hydrolysing
enzymes prevents large-scale hydrolysis in intact plant tissue (Vetter 2000). In case of
emergency the cellular compartmentation breaks down and cyanogenic glucosides come into
contact with an active β -glucosidase and hydroxynitrilelyase, which were demonstrated in
the adjacent mesophyll cells, safely away from the cyanogenic glucosides.

Fig 2. Biosynthetic pathway of cyanogenic glucosides

 Catabolism of cyanogenic glucosides

The generation of hydrogen cyanide (HCN) from cyanogenic glucosides is a two-step

process involving a deglycosilation and a cleavage of the molecule. β glucosidase
hydrolyzes them to yield 2-hydroxynitrile (cyanohydrin), 2-hydroxynitrile is further
cleaved into the corresponding aldehyde or ketone and HCN by a hydroxynitrilelyase
(Vetter 2000). HCN is highly toxic for animals or microorganisms due to its inhibition on
enzymes and binding to some enzymes containing heavy metals. The production of HCN
depends on both the biosynthesis of cyanogenic glucosides and on the existence (or
absence) of its degradating enzymes (Vetter 2000).

Fig 3. Degradation of cyanogenic glucosides

GLUCOSINOLATES

Glucosinolates (formerly called thioglucosides) commonly referred to as goitrogen, are a

group of more than 120 chemical compounds synthesized by thousands of plant species. They
are important in plant defence against insect herbivores, pathogens, nematodes and other
competing plants. Glucosinolates were first observed in the 1800’s when mustard flavour was
investigated (Fahey et al 2001).
Structure and Occurrence

Glucosinolates are amino acid derived natural plant products containing sulfur and
nitrogen (Mikkelsen et al 2002). Glucosinolates are thioethers. They generally consist of a
sugar entity, b-D-thioglucose; with an ester bond to an organic aglycone that is an alkyl group
yielding isothiocyanate, nitrile, thiocyanate or a similar compound upon hydrolysis. More
specifically they are named β-thioglucoside N-hydroxysulfates (or (z) (or cis) - N
hydroxyiminosulfate esters or S-glucopyranosyl thiohydroxyimates) (Fahey et al. 2001).
There are three parts to the glucosinolate molecule, the β-thioglucose moiety (or β-D-
glucopyranose moiety), the sulphonated oxime moiety and the side chain derived from an
amino acid that can be varied to compose different glucosinolates. The variation in side
chain is responsible for much of the variation in glucosinolates. Over 100 different side chain
structures are described, only seven of which come directly from a protein amino acid. The
majority of side chain variation is due to elongation and other modification (Mithen
2001). The glucosinolates side chains include aliphatic, aromatic or heteroaromatic grouping.
Differences in the chemical nature of the side chain –R lead to the differences between
glucosinolates and also in the ultimate hydrolysis end products. On the basis of the structure
of side chain glucosinolates are classified into alkenyl- glucosinolates having an open chain –
R group and indolyl- glucosinolates having a heterocyclic –R group (Henkel and Mosenthin
1989).

Glucosinolates are uniform class of naturally occurring compounds found exclusively in

the plant kingdom throughout the Capparales order (Bennett and Wallsgrove 1994;
Mikkelsen et al 2002) and only in limited number of dicotyledonous families mostly in the
Brassicaceae, Capparaceae, and the Caricaceae (Larsen 1981; Fahey et al 2001).

Fig 4. Structure of glucosinolates

Synthesis

Glucosinolates appeared to be derived from amino acids through a common

biosynthetic pathway (Underhill et al 1973). About 100 glucosinolates have been so far
identified (Fenwick and Heany 1983). Both protein and non-protein amino acids serve as
precursors for the biosynthesis of glucosinolates. Glucosinolates resemble cyanogens in
many respects, but contain sulfur as additional atom. The biosynthesis of glucosinolates
takes place in three stages. The first step is the amino acid chain elongation. Then the
glucone is formed from N-hydroxylation of an amino acid and subsequent
decarboxylation to form an aldoxime. Different enzymes carry out this process for
different amino acids (Fahey et al 2001; Mithen 2001). The first step in glucosinolate
biosynthesis is similar to that of cyanogenic glycoside biosynthesis (Fahey et al 2001).
The oxime is then converted to thiohydroximate in steps. The thiohydroximate is S-
glucosylated by UDP-glucose : thiohydroxyimate glucosyl transferase to produce
desulphoglucosinolate. This product is sulfated with a soluble 3’-phoshoadenosine 5’-
phoshosulphate by desulphoglucosinolate sulphotransferase. The side chains are then
extensively modified to produce a wide variety of glucosinolates. These can be complex
such as O- (α-L-rhamnopylransoyloxy)-benzyl).

Once produced glucosinolates are store in the vacuole until the cells are damaged. When
released, they come into contact with the thiogluoside glucohydrolases, ‘myrosinase’ .
Myrosinase hydrolyzes the glucosinolates to form an aglycone D-glucose. This aglycone,
depending on its environment can rearrange to form several products. These include
isothiocyanates, nitriles and thiocyanates, for all of which there are many important forms
(Fehey et al 2001; Dey and Harborne 1997; Mithren 2001).

Glucosinolates have been classified based on their structural similarity. Four main groups
dominate. They are the aliphatic, ε -methylthioalkyl, aromatic, and heterocyclic
glucosinolates. The side chains widely vary but the most numerous have branched or
straight chains. The largest group contains a sulfur group in different states of oxidation
(Fahey et al 2001). Graser et al (2001) reported on the side chain modification and
elongation involved in the biosythesis of benzoic acid glucosinolate esters. Three steps
were discovered - the first is the extension of methionine by the addition of one, two or
more methylene residues, the second step involves the conversion of the elongated amino
acid into glucosinolates with methythioalkly side chains. In the final step the side chains
are changed to hydroxyalkyl chains and condensed with an activated benzoic acid (Graser
et al 2001).

Fig 5. Biosynthesis of glucosinolates

Localisation

Glucosinolates are polar molecules, which are formed in the cytoplasm and stored in
vacuoles. Glucosinolates as such are considered to be non-toxic. It is, rather, their
hydrolytic products, which are associated with diverse anti-nutritional effects (Fahey et al
2001).
Catabolism of glucosinolates

All plants which sequester glucosinolates also possess thioglucoside glucohydrolases

(myrosinases) as mixture of iso enzymes; molecular weight 125000-150000 which hydrolyse
glucosinolates to D-glucose and an aglycone spontaneously rearranging to isothiocyanates or
nitriles. The isothiocyanate is unstable and cyclizes to give oxazolidin-2-thione (Greer 1962;
Larsen 1981).

There are distinct myrosin cells containing large quantities of a number of myrosinase
isoenzymes, are present in the leaves of Brassica vegetables while a variations in the cytology
of these cells and enzyme pattern and activity are also reported (Pocock et al 1987). On
myrosinase hydrolysis most glucosinolates form stable isothiocyanates or nitriles as well as
glucose and HSO4 ion (Tookey et al 1980).

The hydrolases are stored away from the vacuole (Maheshwari et al 1981) that
contains glucosinolates in the cell wall, endoplasmic reticulum, Golgi vesicles and
mitochondria. Upon cell and tissue disintrigation (wounding) or increase of membrane
permeability, the enzyme and its substrate come together liberating the pungent repellent and
antibiotic isothiocyanate. The thiocyanate ion is found in at least small amounts in all
glucosinolates containing plants after myrosinase hydrolysis under conditions favourable for
isothiocyanate formation (Cole 1980). Glucobrassicin and other indolylmethyl glucosinolates
form unstable isothiocyanate that decompose quantitatively to give inorganic thiocyanate
along with other products including indole-3-carbinol (Gmelin and Virtanen 1961).

Fig 6. Degradation of glucosinolates

THIOCYANATE

Thiocyanate ion was first observed to act as a goitrogen by Barker (1936).

Thiocyanate belongs to goitrogenic compounds and its main sources are plants of
Brassica family. Astwood (1943) found that thiocyanate ion acted as a goitrogen only
when the iodine content of the diet was low. Vanderlaan and Vanderlaan (1947) showed
that thiocyanate ion inhibited uptake of iodine by the thyroid. The thiocyanate ion
involves a linear SCN group in which the double bind character of the S-C reflects the
existence of two tautomeric structures –S-C≡ N and –N=C=S. This tautomerism explains
the existence of two series of covalent derivatives, the thiocyanate and isothiocyanate
(Delange 1989).

Thiocyanate is monovalent anions with a molecular size corresponding to that of

iodine. Thiocyanate has an inhibitory effect mainly on the uptake of iodine in the thyroid
gland but also on the iodination of thyroglobulin (Greer et al 1966).Thiocyanate is a
normal constituent of the blood of mammals and occurs at widely varying levels. The
small quantities of thiocyanate usually found in the human system arise from cyanide
produced by protein metabolism or introduced by tobacco smoke. Thiocyanate is a
complex anion, which is a potent inhibitor of iodide transport. It is the detoxification
product of cyanide and can easily be measured in body fluids. Consumption of naturally
occurring goitrogens, certain environmental toxins and cigarette smoke can significantly
increase SCN- concentrations to levels potentially capable of affecting the thyroid gland
(Erdogan 2003).

Thiocyanate and isothiocyanates have been demonstrated as goitrogenic principles in

plants of the Cruciferae family. The potent antithyroid/goitrogenic compound goitrin was
isolated from yellow turnip and from Brassica seeds (Astwood 1949). Cyanogenic
glucosides (thiocyanate precursors) have also been found in several staple foods like
cassava, maize, bamboo shoot etc. Many vegetables containing cyanogenic constituents
are often consumed but the information on the systemic quantification of different
goitrogenic/ antithyroid components of these vegetables of Indian origin is scanty. The
goitrogenic/ antithyroid potential of a plant not only depends on the relative concentration
of goitrogenic constituents present in fresh plant but also on its processing as food like
boiling, cooking etc (Oke 1982).
Systemic quantification of different goitrogenic / anti-thyroid components of the commonly
consumed Indian cyanogenic plants are very rare. The goitrogenic or anti-thyroid potential of
a plant not only depends on the relative concentrations of these constituents found in fresh
plants but also on the processing as foods.

EFFECT OF GOITROGENS ON THYROID PHYSIOLOGY

During recent past, it was found that Indian cyanogenic plants containing natural
goitrogens of cyanogenic origin had developed relative state of morphological as well as
biochemical hypothyroidism of various proportions after prolonged / chronic consumption
even in presence of iodine because cyanogenic glucosides, glucosinolates and thiocyanate
found in the edible part were metabolized producing anti-thyroid substances that not only
interfered the iodine concentrating mechanism in the thyroid gland but also inhibited the
thyroid peroxidase activity resulting in decreased synthesis of thyroid hormones as reflected
by total circulating thyroxine (T4) and triiodothyronine (T3) levels. Different degrees of
inhibition on thyroid peroxidase activity were found with different plant extracts ; the
inhibition was for the presence of goitrogenic constituents viz. cyanogenic glucosides,
glucosinolates and thiocyanate in the studied plants( Chandra et al 2004, 2005).

MECHANISM OF ACTION

Cyanogenic glucosides and glucosinolates present in the plants are readily converted
to active goitrogenic substances like thiocyanate by the enzyme glucosidases, sulphur
transferase and myrosinase present in the plant itself (Montgomery 1969; Van Etten 1969).
High concentration of thiocyanate is responsible for the inhibition of TPO catalised oxidation
(Virion 1980). Thiocyanate at high concentration also inhibits the incorporation of iodide into
thyroglobulin acting at thyroid peroxidase levels (Ermans and Bourdoux 1989) and forming
insoluble iodinated thyroglobulin in the thyroid gland (Van Middlesworth 1985).
Glucosinolates present in the plant also undergo rearrangement to form isothiocyanate
derivatives (Van Etten 1969). Isothiocyanate not only use the thiocyanate metabolic pathway
but also reacts spontaneously with thiourea like antithyroid effects that interfere in thyroid
peroxidase activity (Gaitan et al 1983; Ermans and Bourdoux 1989). Moreover glucosinolates
are iodine antagonist and they also interfere in the action of thyroid peroxidase enzyme
(Schone et al 2001).

Effect on thyroid morphological and histological status

The morphological/ histological status of thyroid glands have been studied in

experimental rats after prolonged feeding of different cyanogenic plants. Increased thyroid
gland weight followed by marked alteration in thyroid gland histological structure was the
characteristic feature of all the studied plants fed groups of rats. The changes were more or
less similar in nature in all the groups of rats fed different plant foods but of various
proportions. The number of thyroid follicles were increased but reduced in size containing
less colloid stained deeply with eosin in the experimental rats fed the studied plants.
Individual follicles were surrounded by thick layer of cuiboidal or columner epithelial cells
resembling hypertrophy and hyperplasia of follicular epithelium(Chandra et al 2005). This
observation is similar to goitrogen induced TSH stimulated diffuse goiter as shown by Kanno
et al (1990). Deeply stained eosinophilic colloid in the follicles in cyanogenic plant fed rats
indicated the development of a state of iodine deficiency in the thyroid .Sharpless 1939;
Gaitan et al 1993 reported that colloid of iodine deficient thyroid stained deeply with eosin
than control or iodine sufficient thyroid. These studies further reveals that in spite of adequate
iodine intake as evidenced by urinary iodine level thyroid follicles fail to concentrate
adequate iodine probably for the interference of thiocyanate or thiocyanate like compounds
arises from the goitrogenic precursors present in the plant foods .

Effect on thyroid functional status

Thiocyanate arises from the degradation of cyanogenic constituents present in plant

foods interferes with thyroid peroxidase enzyme acting mainly at the level of incorporation of
iodine into thyroglobulin and iodide oxidation (Maloof and Soodak 1959; Knudsen et al
2002; Virion et al 1980). Schone et al (2001) also found that glucosinolates present in the
plants are iodine antagonist so they interfere with the thyroid peroxidase activity.
Isothiocyanates arise from glucosinolates degradation also interfere with organification of
iodine thereby affecting thyroid peroxidase activity (Gaitan 1989) Inhibition of TPO activity
was probably for the interference of thiocyanate, isothiocyanate etc like metabolites of
cyanogenic goitrogens and partially for the direct action of glucosinolates present in the
studied plants.
 As mentioned the enzyme thyroid peroxidase regulates the synthesis of thyroid
hormones and thus inhibition in thyroid peroxidase activity is associated with decrease
synthesis of thyroid hormones (Coval and Taurog 1967; Taurog 1970; Pommier et al 1972).
Greer et al (1966) suggested that at high concentration thiocyanate effects organic binding of
iodine with thyroglobulin thereby affecting thyroid hormone synthesis. Therefore, decreased
circulating total T4 and T3 levels were probably for the reduced synthesis of those hormones.
Low concentration of iodine in thyroid gland and the inhibited thyroid peroxidase activity
under the influence of those plant foods as compared to control were the possible
consequences for the reduced thyroid hormone synthesis. Prolonged consumption of the
plants had shown more deleterious effects (Chandra et al 2004).

.Further investigations and detailed analysis are needed on the isolation, purification
and characterisation of the goitrogenic / anti-thyroid principles present in the Indian
cyanogenic plant foods and their in vitro and in vivo effects on thyroid hormone synthesis at
cellular level and specially on the measures for counteracting their adverse effect.
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