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Goitrogen in Food
Abstract
Goitrogens are naturally occurring substances that interfere with the function of the thyroid gland. Goitrogens get their name from the term “goiter” which means the enlargement of the thyroid gland. If the thyroid gland has difficulty synthesizing thyroid hormone, it may enlarge to compensate for this inadequate hormone production. Goitrogens cause difficulty for the thyroid in making its hormone. The role of iodine deficiency as an environmental factor in the development of goiter is established. Goiter is usually the most obvious sign of iodine deficiency; however, brain damage, mental retardation, reproductive failure, and childhood mortality are more serious consequences. Iodine deficiency also affects the socioeconomic development of a community. However, there are observations that indicate the existence of factors other than iodine deficiency. Iodine deficiency does not always cause endemic goiter, and iodine supplementation does not always result in complete eradication of goiter. Moreover, there is epidemiological and experimental evidence that concomitant exposure to other naturally occurring antithyroid agents magnifies the severity of endemic goiter. The foods that have been associated with disrupted thyroid hormone production in humans are broadly classified into two categories: cyanogenic plant foods, and flavonoids containing plant foods. Observations reveal that a number of plant foods usually consumed by the people of several regions contain goitrogenic/antithyroidal substances that interfere with thyroid hormone synthesis, acting at different levels in the thyroid gland and causing goiter and associated iodine deficiency disorders.
... Hypothyroidism is a state generated by an underactive thyroid gland which generally implies that all the metabolic processes of the individual are carried out more slowly; thus, symptoms like cold intolerance, constipation, fatigue, weight gain, dry skin, goiter, and even depression can also occur [1][2][3]. The t h y r o i d g l a n d s y n t h e s i z e s t h y r o i d h o r m o n e s , tetraiodothyronine or thyroxine (T4) and triiodothyronine (T3), from the amino acid tyrosine and the iodine ingested [3]. ...
... Hypothyroidism is a state generated by an underactive thyroid gland which generally implies that all the metabolic processes of the individual are carried out more slowly; thus, symptoms like cold intolerance, constipation, fatigue, weight gain, dry skin, goiter, and even depression can also occur [1][2][3]. The t h y r o i d g l a n d s y n t h e s i z e s t h y r o i d h o r m o n e s , tetraiodothyronine or thyroxine (T4) and triiodothyronine (T3), from the amino acid tyrosine and the iodine ingested [3]. Hypothyroidism is usually treated only with drugs such as L-thyroxine (sodium levothyroxine) that externally provide the amount of iodine required for each patient. ...
... Hypothyroidism is usually treated only with drugs such as L-thyroxine (sodium levothyroxine) that externally provide the amount of iodine required for each patient. But, the natural sources of iodine for human beings are foods [3]. Patients are rarely told that they could improve or regulate their levels of iodine with dietary recommendations together with their medical treatment. ...
Currently, hypothyroidism is usually treated only with drugs; patients are never told that they could regulate their levels of iodine with dietary recommendations in a complementary way. The objective of this work was to explore the effect of a constant iodine intake through the diet in a postmenopausal woman with subclinical grade II hypothyroidism, who also had mild hypercholesterolemia and obesity. Baseline anthropometric nutritional, pharmacological, and habit data were obtained, then the woman was scheduled for 1 month a diet in which she was provided food naturally containing iodine, so that the recommended requirements (iodine 150 μg/day) were met. All the information about which foods contain this mineral was supplied and explained to the patient. This diet was also designed to help her to gradually lose weight, and was more balanced and closer to the nutritional recommendations. The results obtained in this work were satisfactory, having achieved improved blood levels of thyroid-stimulating hormone (1.78 μIU/mL) and reduced total cholesterol levels (198 mg/dL). Statement of hypercholesterolemia was demoted. In addition, a significant improvement in relation to weight and body volume was reached (body mass index fell from 30.13 to 28.5 kg/m2), an important fact since it has impacted the overall well-being of the patient. In conclusion, it was demonstrated that a constant iodine intake through the diet for this patient with grade II hypothyroidism was very effective, and therefore, this aspect should be also considered during hypothyroidism treatment.
... Dietary goitrogens are substances that can interfere directly on iodine metabolism in thyroid. Goitrogens are classified as thiocyanate, isothiocyanate, cyanogenic glycosides, glucosinolates, thiourea, thionamides, flavonoids, etc. [46][47][48][49][50]. MUSCN is an excellent marker to study consumption of dietary goitrogens. ...
... It inhibits thyroidal accumulation of iodide. At higher dose, it competes with iodine during protein binding [46][47][48][49][50]. It serves as a substrate for thyroid peroxidase (TPO) to inhibit iodination of tyrosyl residues of thyroglobulin molecule [51]. ...
To evaluate the state of iodine nutrition in post-iodation scenario, 3500 children were examined clinically for endemic goitre. Iodine and thiocyanate were measured in 240 urine samples; iodine content in 210 salt samples was measured. Total goitre prevalence was 6.1%. Median urinary iodine level was 21.80 µg/dl, and mean (±SD) urinary thiocyanate was 0.89 ± 0.49 mg/dl. Iodine content of only 11.9% salt samples was below recommended level of 15 ppm, 25.2% was between 15 and 30 ppm and 62.9% was >30 ppm. Iodine deficiency disorders are thus clinically mild public health problem of the studied population; however, they have no biochemical iodine deficiency. Studied population found exposed to thiocyanate load that might be the possible cause for persistence of endemic goitre. People of Kolkata should be advised to eat commonly consumed goitrogenic foods after boiling and decanting the water. Periodical monitoring and evaluation of iodine status should be mandatory.
... This particular group of compounds inhibit the transport iodine which indices the proliferation of thyroid cells and also increases the secretion of TSH. Therefore, this compound is mainly found responsible for thyroid carcinomas (Chandra, 2010). The particular situation can't be cured by increasing the levels of iodine in regular diet as thiocyanate ions behaves competitively with iodine. ...
Brassica sprouts have emerged as a healthy alternative as they are rich sources of calcium, and folic acid. The phenolic profile and antioxidants enhanced during sprouting including anthocyanins, terpenes, flavonoids, coumarins etc.. Sprouting process not only improves the nutritional quality but also inhibits the antinutritional factors like oxalic and phytic acid, which improves the bioavailability of calcium. Desirable changes in the sprouts can be obtained by varying the process conditions, for instance soaking sprouts in the dark eliminates antinutritional factors. The important group of phytochemicals found in Brassica sprouts as well as vegetables are glucosinolates which is a large class of bioactive components containing sulphur that also imparts positive effects concerning human health. These compounds possess the ability of neutralizing the free radicals or reactive oxygen species and act as antioxidants.. Biofortification of sprouts is the most recent approach to enhance the nutritional profile and functionality of Brassica sprouts. Consumption of Brassica sprouts reduces risk of cancer (e.g. ovarian cancer, lung cancer, breast cancer, etc.), lowers cholesterol level, boosting bone density, and helps in eliminating inflammatory disorders. Sprouting in Brassica species enhances the bioavailability of sulphoraphanes and isothiocyanates, hence, proven as the best processing method to enhance the nutritional value of crop as compared raw. Therefore, consumption of sprouts from Brassica group must be included in regular diet.
... Goitrin (l-5-vinyl-2-thiooxazolidone) is a water-soluble component in plants. Progoitrin is a precursor of goitrin and is produced by the enzyme thioglucosidase from cysteine and methionine (Chandra, 2010). Sufficient genetic variability in the pearl millet germplasm for goitrogens renders the identification and manipulation of genes related to C-C-glycosylfalvones (C-GFs) there by reducing goitrogens accumulation in grains. ...
The consumption of healthy food, in order to strengthen the immune system, is now a major focus of people worldwide and is essential to tackle the emerging pandemic concerns. Moreover, research in this area paves the way for diversification of human diets by incorporating underutilized crops which are highly nutritious and climate-resilient in nature. However, although the consumption of healthy foods increases nutritional uptake, the bioavailability of nutrients and their absorption from foods also play an essential role in curbing malnutrition in developing countries. This has led to a focus on anti-nutrients that interfere with the digestion and absorption of nutrients and proteins from foods. Anti-nutritional factors in crops, such as phytic acid, gossypol, goitrogens, glucosinolates, lectins, oxalic acid, saponins, raffinose, tannins, enzyme inhibitors, alkaloids, β-N-oxalyl amino alanine (BOAA), and hydrogen cyanide (HCN), are synthesized in crop metabolic pathways and are interconnected with other essential growth regulation factors. Hence, breeding with the aim of completely eliminating anti-nutrition factors tends to compromise desirable features such as yield and seed size. However, advanced techniques, such as integrated multi-omics, RNAi, gene editing, and genomics-assisted breeding, aim to breed crops in which negative traits are minimized and to provide new strategies to handle these traits in crop improvement programs. There is also a need to emphasize individual crop-based approaches in upcoming research programs to achieve smart foods with minimum constraints in future. This review focuses on progress in molecular breeding and prospects for additional approaches to improve nutrient bioavailability in major crops.
... Thus, the removal of maximum GLS without coextraction of proteins in oil-extracted meal was required in animal feed [203]. Furthermore, thiocyanate ions and axazolidin-2-thiones formed from GLS are goitrogenic and cause thyroid cancer [204]. It was proven that Brassica vegetable intake was linked to thyroid cancer in a study on 293 women [205]. ...
Traditionally, Brassica species are widely used in traditional medicine, human food, and animal feed. Recently, special attention has been dedicated to Brassica seeds as source of health-promoting phytochemicals. This review provides a summary of recent research on the Brassica seed phytochemistry, bioactivity, dietary importance, and toxicity by screening the major online scientific database sources and papers published in recent decades by Elsevier, Springer, and John Wiley. The search was conducted covering the period from January 1964 to July 2022. Phytochemically, polyphenols, glucosinolates, and their degradation products were the predominant secondary metabolites in seeds. Different extracts and their purified constituents from seeds of Brassica species have been found to possess a wide range of biological properties including antioxidant, anticancer, antimicrobial, anti-inflammatory, antidiabetic, and neuroprotective activities. These valuable functional properties of Brassica seeds are related to their richness in active compounds responsible for the prevention and treatment of various chronic diseases such as obesity, diabetes, cancer, and COVID-19. Currently, the potential properties of Brassica seeds and their components are the main focus of research, but their toxicity and health risks must also be accounted for.
Systematic toxicity tests are often waived for the synthetic flavors as they are added in a very small amount in foods. However, their safety for some endpoints such as endocrine disruption should be concerned as they are likely to be active in low levels. In this case, structure-activity-relationship (SAR) models are good alternatives. In this study, therefore, binary, ternary, and quaternary prediction models were designed using simple or complex machine-learning methods. Overall, hard-voting classifiers outperformed other methods. The test scores for the best binary, ternary, and quaternary models were 0.6635, 0.5083, and 0.5217, respectively. Along with model development, some substructures including primary aromatic amine, (enol)ether, phenol, heterocyclic sulfur, and heterocyclic nitrogen, dominantly occurred in the most highly active compounds. The best predicting models were applied to synthetic flavors, and 22 agents appeared to have a strong inhibitory potential towards TPO activities.
Supplementary information:
The online version contains supplementary material available at 10.1007/s10068-022-01041-y.
It is well-known that ClO- and SCN- can cause adverse effects on the environment and organisms; therefore, development of new strategies for detecting ClO- and SCN-, especially in water, are highly desirable. Here, we present a luminous Eu (III) complex-functionalized Fe3O4 nanoparticles encapsulated into the zeolitic imidazolate framework materials (nano-ZIF-8) and successfully employ this nano-MOF as a fluorescence probe for selective and sensitive detection of ClO- and SCN-. The introduction of ClO- into nano-ZIF-8 solution induced a significant decrease in the characteristic fluorescence emission of Eu3+ at 613 nm. However, strong fluorescence emission was observed again when SCN- was successively injected into the prepared nano-ZIF-8-ClO-. Thus, such novel fluorescence system for simultaneous detection of free ClO- and SCN- was established. On the basis of the superior adsorption performance of nano-MOF materials, free residual ClO- and SCN- in water was rapidly, sensitively and selectively detected with a detection limit of 0.133 nM and 0.204 nM, respectively. Moreover, nano-ZIF-8 was successfully used for monitoring the concentration levels of ClO- and SCN- in the specimens of tap water and Yellow River water. Furthermore, the reversibility and regeneration of nano-ZIF-8 for sensing ClO- and SCN- provided many advantages to apply nano-ZIF-8 for solid-state sensing and anti-counterfeiting technique. As far as we know, this is the first time that nano-MOFs has been used as a selective fluorescence probe for ClO-/SCN- detection and anti-counterfeiting.
Context
Common environmental contaminants can disrupt normal thyroid function, which plays essential but varying roles at different ages.
Objective
To evaluate the relationship of perchlorate, thiocyanate, and nitrate, three sodium-iodide symporter (NIS) inhibitors, and thyroid function in different age-sex-stratified populations.
Design, Setting, Participants, and Intervention: This was a cross-sectional analysis of data from the 2009-2012 National Health and Nutrition Examination Surveys (NHANES) evaluating the exposure to perchlorate, thiocyanate, and nitrate in 3,151 participants aged 12-80.
Main Outcome Measure
Blood serum free thyroxine (FT4) as both a continuous and categorical variable. We also assessed blood serum thyroid stimulating hormone (TSH).
Results
Controlling for serum cotinine, BMI, total daily energy consumption, race/ethnicity, and poverty-to-income ratio, for each log unit increase in perchlorate, FT4 decreased by 0.03 ng/dL in both the general population (p=0.004) and in all women (p=0.005), and by 0.06 ng/dL in adolescent girls (p=0.029), corresponding to 4% and 8% decreases relative to median FT4, respectively. For each log unit increase thiocyanate, FT4 decreased by 0.07 ng/dL in adolescent boys (p=0.003), corresponding to a 9% decrease relative to median FT4, respectively.
Conclusions
Our results indicate that adolescent boys and girls represent vulnerable subpopulations to the thyroid-blocking effects of NIS symporter inhibitors. These results suggest a valuable screening and intervention opportunity.
Digitaria exilis (fonio) is a tiny variety of millet commonly eaten by inhabitants of semiarid regions. A sample of fonio collected right in the middle of a severely iodine-depleted goitrous endemic was submitted to phytochemical investigations in order to assess the potential contributory roles played by vegetable molecules to the goitrogenic processes. The total content of flavonoids amounts to 500 mg/kg of the edible whole cereal grains. Their extraction and identification fail to detect the C-glycosylflavones described in other millet varieties but point out the presence of apigenin (A = 150 mg/kg) and of luteolin (L1 = 350 mg/kg). Ten percent of A and 80% of L1 are present in free form, whereas the remaining 90% of A and 20% of L1 are bound as O-glycosylflavones. Both A and L1 aglycones manifest strong anti-thyroid peroxidase (TPO) activities, resulting in a significant reduction of the hormonogenic capacity of this enzyme. In addition, L1 significantly depresses the cyclic AMP phosphodiesterase, implying a concomitant overproduction of the thyrotropin-dependent nucleotide. These last unreported data are regarded as counteracting to some extent the TPO-mediated goitrogenic properties of L1. Since fonio is devoid of other molecules likely to interfere with the thyroid function, our results are directly and casually attributed to A and L1 found in the customary diet.
In 4 to 8 weeks, a diet containing 75% raw soy flour induces in the thyroid of young rats an enlargement of 3 to 5 times normal. The enlargement is accompanied by hyperplasia and loss of colloid. Although the diet contains more iodine than would be expected, additional iodine will completely prevent the enlargement.
The labelled compounds were injected into mice and sections of the whole animals were studied by an autoradiographic technique. The two compounds studied gave an almost identical autoradiographic distribution pattern. This was attributed to the fact that the activity after injection of KC14N was present mainly as thiocyanate. A very high activity was present in the stomach as early as 5 min after injection and it remained higher there than in any other organ during the 24-hours observation period. High activities were also found in the submaxillary salivary gland, the thyroid gland, the walls of the large vessels and the blood.
The soybean has been implicated in diet-induced goiter by many studies. The extensive consumption of soy products in infant formulas and in vegetarian diets makes it essential to define the goitrogenic potential. In this report, it was observed that an acidic methanolic extract of soybeans contains compounds that inhibit thyroid peroxidase- (TPO) catalyzed reactions essential to thyroid hormone synthesis. Analysis of the soybean extract using HPLC, UV-VIS spectrophotometry, and LC-MS led to identification of the isoflavones genistein and daidzein as major components by direct comparison with authentic standard reference isoflavones. HPLC fractionation and enzymatic assay of the soybean extract showed that the components responsible for inhibition of TPO-catalyzed reactions coeluted with daidzein and genistein. In the presence of iodide ion, genistein and daidzein blocked TPO-catalyzed tyrosine iodination by acting as alternate substrates, yielding mono-, di-, and triiodoisoflavones. Genistein also inhibited thyroxine synthesis using iodinated casein or human goiter thyroglobulin as substrates for the coupling reaction. Incubation of either isoflavone with TPO in the presence of H2O2 caused irreversible inactivation of the enzyme; however, the presence of iodide ion in the incubations completely abolished the inactivation. The ic50 values for inhibition of TPO-catalyzed reactions by genistein and daidzein were ca. 1–10 μM, concentrations that approach the total isoflavone levels (ca. 1 μM) previously measured in plasma from humans consuming soy products. Because inhibition of thyroid hormone synthesis can induce goiter and thyroid neoplasia in rodents, delineation of anti-thyroid mechanisms for soy isoflavones may be important for extrapolating goitrogenic hazards identified in chronic rodent bioassays to humans consuming soy products.
The seeds of Conringia orientalis, which contain a bitter principle, were crushed, freed from fat, and steeped in water. The chloroform extract of the aqueous liquor yielded a crystalline substance which was identified as 2-mercapto-5,5-dimethyl-oxazoline (I). It tastes bitter to some persons but is tasteless to others. The suggestion is made that the seeds contain β-methyl allyl isothiocyanate in the form of a glycoside, and that this substance is converted to (I) during the treatment described above.
The natural antithyroid factor l-5-vinyl-2-thioöxazolidone has been synthesized from buta-diene-1,2-oxide through 1-amino-3-buten-2-ol.
Lignans and flavonoids are naturally-occurring diphenolic compounds found in high concentrations in whole grains, legumes, fruits and vegetables. Seven lignans and six flavonoids were evaluated for their abilities to inhibit aromatase enzyme activity in a human preadipose cell culture system. The lignan, enterolactone (Enl) and its theoretical precursors, 3′-demethoxy-3O-demethylmatairesinol (DMDM) and didemethoxymatairesinol (DDMM) decreased aromatase enzyme activity, with Ki values of 14.4, 5.0 and 7.3 μM, respectively. The flavonoids, coumestrol, luteolin and kaempferol also decreased aromatase enzyme activity, with Ki values of 1.3, 4.8 and 27.2 μM, respectively. Amino-glutethimide, a pharmaceutical aromatase inhibitor, showed a Ki value of 0.5 μM. Kinetic studies showed the inhibition by all compounds to be competitive. Smaller decreases in aromatase activity were observed with the lignan, enterodiol (End) and its theoretical precursors, O-demethylsecoisolariciresinol (ODSI), demethoxysecoisolariciresinol (DMSI) and didemethylsecoisolariciresinol (DDSI). The flavonoids, O-demethylangolensin (O-Dma), fisetin and morin showed no inhibitory effects. The inhibition of human preadipocyte aromatase activity by lignans and flavonoids suggests a mechanism by which consumption of lignan- and flavonoid-rich plant foods may contribute to reduction of estrogen-dependent disease, such as breast cancer.
IN AN EARLIER STUDY 106 compounds were tested in rats for their capacity to interferewith the endocrine function of the thyroid gland. Each substance was administered to young rats bymixing it withthe food or drinking water in various concentrations. At the end of ten days the thyroid glands were examined grossly and microscopically for evidence of hypertrophy and hyperplasia,and the relative activities of the compounds were then roughly compared on the basis of the minimal dose required to produce a noticeable effect (Astwood, 1943). Although this assay method was sufficiently reliable to detect wide differences in activity and to form the basis for the selection of compounds such as thiouracil for clinical trial, it suffered the handicap of subjective criteria and no quantitative dosage-response relationship could be established.
A more accurate and reproducible method based upon the weight and iodine concentration of the thyroid gland (Astwood & Bissell,1944) has been used in the present investigation.
Cassava (Manihot esculenta Crantz), a widely used common vegetable of Indian origin contains dietary goitrogens. Goitrogenic content, in vitro anti-thyroidal activity and in vivo antithyroid potential of fresh and cooked cassava of Indian origin in albino rats with and without iodine supplementation were evaluated in this study. In vitro inhibition of thyroid peroxidase (TPO )activity was found with fresh and cooked cassava extract but the presence of extra iodide in the incubation media had shown reduction in such inhibition to an extent. Inhibition constant (IC50) and PTU equivalence of fresh cassava were 42.5 ± 1.35μg and 2.21 respectively.After consumption, cyanogenic constituents in cassava are metabolized to thiocyanate and iodine-retaining capacity seems to be dependent on thiocyanate exposure. In cassava fed rats, the urinary iodine concentration resembled the state of adequate iodine nutriture but thyroid gland fails to utilize available iodine. Increased thyroid weight (P < 0.001), inhibited thyroid peroxidase (TPO) activity and reduced thyroid hormone profiles (P < 0.001) were noted in fresh and cooked cassava fed rats, resembling a relative state of morphological as well as biochemical hypothyroidism even in presence of adequate iodine.
The content of the potentially anticarcinogenic flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin of 28 vegetables and 9 fruits was determined by RP-HPLC with UV detection. Fresh foods were purchased in a supermarket, agrocery, and a street market and combined to composites. Processed foods were purchased additionally. Sampling was carried out in spring, summer, winter, and spring of the following year. Quercetin levels in the edible parts of most vegetables were generally below 10 mg/kg except for onions (284-486 mg/kg), kale (110 mg/kg), broccoli (30 mg/kg), French beans (32-45 mg/kg), and slicing beans (28-30 mg/kg). Kaempferol could only be detected in kale (211 mg/kg), endive (15-91 mg/kg), leek (11-56 mg/kg), and turnip tops (31-64 mg/kg). In most fruits the quercetin content averaged 15 mg/kg, except for different apple varieties in which 21-72 mg/kg was found. The content of myricetin, luteolin, and apigenin was below the limit of detection (
Mammalian lignans such as enterolactone and enterodiol, which are produced in the colon from precursors in foods, have been suggested as playing a role in the cancer-protective effect of vegetarian diets. Despite this, very little is known regarding the amount that is produced from different food products. Therefore, the objective of this study was to determine the production of mammalian lignans from 68 common plant foods by using the technique of in vitro fermentation with human fecal microbiota, which simulates colonic fermentation. Results showed a wide range (21-67,541 microgram(s)/100 g sample) in the amount of lignans produced. On the average as a group, the oilseeds produced the highest amounts (20,461 +/- 12,685), followed by the dried seaweeds (900 +/- 247), whole legumes (562 +/- 211), cereal brans (486 +/- 90), legume hulls (371 +/- 52), whole grain cereals (359 +/- 81), vegetables (144 +/- 23), and fruits (84 +/- 22). The vegetables produced the second highest concentration of lignans (1,546 +/- 280) when the data were expressed on a moisture-free basis. Flaxseed flour and its defatted meal were the highest producers of lignans (mean 60,110 +/- 7,431). Lignan production with the in vitro method related well to the urinary lignan excretion observed in rats and humans. The data should be useful in the estimation of lignan production from a given diet and in the formulation of high-lignan-producing diet for the purpose of reducing the cancer risk.
Epidemiologic and experimental evidence reviewed in this article emphasizes the complex and multifactorial etiology of endemic goiter. The important role of iodine deficiency as an etiologic factor in endemic goiter is firmly established, but there is evidence that other environmental factors can play an equally important role in the pathogenesis of this condition. Chemical categories, sources, and sites of action of the various classes of naturally occurring goitrogens and antithyroid agents are reviewed in this article. Evidence of the presence of these compounds in foodstuffs and drinking water is discussed. Bacterial contamination of water supplies also appears to be important in the development of goiter. Microorganisms appear to intervene in the biosynthesis and degradation of organic goitrogenic pollutants or may induce thyroid growth-promoting activity in the host, or both. Malnutrition and poor socioeconomic conditions, as for iodine deficiency, enhance the action of environmental goitrogens. Thus, a coordinated multidisciplinary approach is essential to solving this public health problem.
Pearl millet [Pennisetum millet (L.) leeke] is the main source of food energy for the rural poor in many areas of the semiarid tropics. Epidemiological evidence suggests that millet may play a role in the genesis of endemic goiter in these areas, and sparse experimental data in rats support this suspicion. This study was undertaken to determine in vivo in rats and in vitro using porcine thyroid slices and a thyroid peroxidase (TPO) assay the goitrogenic and antithyroid effects of millet diets, extracts of millet, and certain pure compounds contained therein. For use in these studies, whole grain millet was progressively dehulled to yield successively four bran and four flour fractions in which direct analyses revealed progressively lower concentrations of C-glycosylflavones. In vivo feeding of bran fraction 1, that richest in C-glycosylflavones, led to a significant increase in thyroid weight and antithyroid effects. Feeding of bran fraction 2, the next richest in C-glycosylflavones, produced similar, but less marked, changes. In vitro studies of 125I metabolism using porcine thyroid slices indicated that extracts of bran fractions 1 and 2 were most potent, producing changes similar to those produced by methimazole (MMI). At a concentration of 60 mumol/L, glucosylvitexin, the major C-glycosylflavone present in millet, had effects comparable to those of 1 mumol/L MMI. Similarly, in studies of porcine TPO, extracts of bran fraction 1 caused pronounced (85%) inhibition of enzyme activity, and progressively less inhibition was induced by extracts of bran fractions 2, 3, and 4. Overall, the TPO-inhibiting activities of the various millet fractions closely correlated with their C-glycosylflavone concentrations. Three C-glycosylflavones present concentrations. Three C-glycosylflavones present in millet, glucosylvitexin, glycosylorientin, and vitexin, also inhibited TPO activity. Thus, in vivo and in vitro studies revealed that millet diets rich in C-glycosylflavones produce goitrogenic and antithyroid effects similar to those of certain other antithyroid agents and small doses of MMI. We conclude that in areas of iodine deficiency in which millet is a major component of the diet, its ingestion may contribute to the genesis of endemic goiter.
Effects of KSCN on thyroidal iodine metabolism were studied in weanling mice fed a low iodide diet (LID) labeled continuously with 125I as iodide. The addition of KSCN (0.3 and 0.6 mg/g diet) resulted in the accumulation of an unusual iodinated protein within the follicles of the mouse thyroids. After 60 days, total thyroidal iodine was 4 times greater than in controls without thiocyanate. The iodinated protein was essentially insoluble at pH 8.0 and was very slowly released from the thyroids; it contained more MIT than DIT and little thyroid hormone. By use of three isotopes (125I, 127I, and 131I) and auto-radiographs, there were shown different iodinated proteins synthesized during high and low iodine intakes and coexistent but segregated in the colloid. Low doses of perchlorate or iodide inhibited or prevented accumulation of the essentially insoluble iodinated protein. It is suggested that when mouse thyroids are iodine depleted, thiocyanate increases the formation of an essentially insoluble iodinated thyroglobulin within the thyroid. Only a small fraction of the iodination may have occurred by this route, but the rate of formation exceeded the rate of release, so the product continuously accumulated.
This chapter primarily discusses the results obtained in the preparations of purified thyroid peroxidase. Two different preparations of thyroid peroxidase were used for the studies described in the chapter. The first preparation, referred to in this chapter as Prep. I, was isolated by a procedure. The second one is more highly purified preparation, isolated by a modified procedure described and is referred to as Prep. II. In a study described in the chapter, the specific activity of Prep. II was about five times greater than that of Prep. I. The molecular weight of thyroid peroxidase was determined by filtration through a calibrated column of Biogel P-100. The proteins of known molecular weight used to calibrate the column were myoglobulin (17,800), ovalbumin (45,000), and bovine serum albumin (67,000). Each of these proteins was separately applied to the column and eluted; the elution volume was determined on the basis of measurement of absorbance at 280 mμ. The elution volume of thyroid peroxidase was then determined, based on its iodide peroxidase activity. A plot of effluent volume against log molecular weight for the marker proteins yielded a straight line, and the molecular weight of thyroid peroxidase determined from this standard curve was 62,000. This is in very close agreement with the value of 64,000 reported in another study for a different preparation of the enzyme. The molecular weight of a sample of purified horseradish peroxidase (Calbiochem) determined on the same column was 42,000, in close agreement with the reported value of 40,000.
Endemic goiter prevalence has been systematically measured in 85% of the population of Idjwi Island. The average prevalence of goiter on the island as a whole is 32.3%. There are very marked geographical variations. Three regions are distinguishable: a hyperendemic region in the north, where the average prevalence of goiter is 52.8%, a region with very low endemicity (7.7%) in the southwest, and a region of intermediate severity (26.0%) in the southeast. There is a distinct relationship between goiter prevalence and age and sex. The familial tendency to goiter on Idjwi is only slight and may be explained either by a form of multigenic heredity or by the intervention of etiological factors of the microenvironment.
Relationships between regional goiter prevalence and parameters of thyroid function were studied in 693 subjects from 30 villages scattered throughout the island. No relationship was observed between goiter prevalence and the degree of iodine deficiency: this deficiency is homogeneous and severe throughout the island. The rise in the level of goiter prevalence is accompanied by a significant increase of ¹³¹I thyroidal uptake at the 6th hr and by a significant decrease in the PB ¹²⁷I level in the plasma.
In goitrous adults, thyroidal uptake is higher and PBI lower than in nongoitrous adults. However, the modifications of thyroid metabolism are influenced far less by the presence or absence of goiter in a particular subject than by regional variations in the prevalence of goiter.
Iodine deficiency constitutes the main etiological factor of endemic goiter on Idjwi Island. However, the pattern of goiter prevalence and the extent to which thyroid metabolism varies cannot be explained by the degree of iodine deficiency; we show that they are determined essentially by a geographical factor. This factor is closely related to the nature of the soil. Furthermore, when compared with nongoitrous subjects, goitrous individuals appear to be less efficient in their adaptation to environmental conditions in the Idjwi endemic goiter area.
A review has been presented of the biochemistry and pharmacology of a class of natural products, the flavonoids. These substances which are widely distributed in the plant kingdom and present in considerable quantities in common food products, spices and beverages have in a concentrated form (Propolis) been used since ancient times by physicians and laymen to treat a great variety of human diseases but they have yet to pass the tests of modern, controlled, clinical experimentation. An attempt has been made to present the fundamental evidence from the basic biological sciences which is required to stimulate the interest of the clinicians in this new field. The few existing reports on the careful pharmacodynamic, pharmacokinetic and clinical studies which have been made have been summarized to provide a basis for a full-scale investigation of the therapeutic potential of flavonoids.
The effect of a pseudohalide, SCN ⁻ , an anion with the same molecular size as iodide, was studied on two reactions: thyroglobulin iodination and thyroid hormone synthesis (coupling reaction) catalyzed by peroxidases. The coupling reaction was studied separately from the iodination reaction by using labelled thyroglobulin samples previously iodinated but containing little or no hormones.
SCN ⁻ inhibits iodide oxidation (I ⁻ → I 2 ) whatever the enzyme, thyroid, lactoperoxidase or horseradish peroxidase. The amount of SCN ⁻ required to completely inhibit this reaction varies depending on the enzyme. Similarly tyrosine iodination is inhibited by SCN ⁻ with large variations, depending on the peroxidase, in the concentration of this anion required for inhibition.
In contrast SCN ⁻ stimulates the coupling reaction: (a) this effect is seen with the thyroid and lactoperoxidases but not with horseradish peroxidase; (b) the concentration of SCN ⁻ required for half‐maximal stimulation of the coupling reaction is much lower (0.5–1 μM) than that required for the inhibition of iodide oxidation (60–80 μM); (c) CIO ⁻ 4 , an anion with the same molecular size as SCN ⁻ and I ⁻ , has no effect on the coupling reaction; (d) this stimulatory effect of SCN ⁻ does not depend on a modification of the thyroglobulin molecule since it is not seen with horseradish peroxidase or in purely chemical coupling conditions.
The stimulatory effect of SCN ⁻ is therefore seen as resulting from the binding of this anion to a limited number of high‐affinity sites present at the surface of both thyroid and lactoperoxidases. The inhibitory effect depends, in contrast, on the binding of SCN ⁻ to the substrate site with lower affinities. Since iodide also behaves both as a substrate for the iodination reaction and as a stimulatory ligand for the coupling reaction, these data provide further support in favour of the existence of an enzyme‐iodide (or SCN ⁻ ) complex with catalytic properties different from those of the native peroxidase.
Millet diets rich in C-glycosylflavones (C-GF) are goitrogenic, and its three most abundant C-GF inhibit in vitro thyroid peroxidase, suggesting that these compounds are the goitrogens in millet. However, proof of a cause and effect relationship between C-GF and goitrogenesis requires a demonstration of in vivo antithyroid activity by the purified isolated compounds. Vitexin, one of the three major C-GF in millet, was used to test this hypothesis. Twenty-four female Wistar rats, divided into groups of six rats each and fed Purina iodine-rich diet (12 micrograms I-/day.rat), were administered acutely by gastrointestinal tube goitrogen-free water (controls), methimazole (0.5 mumol), and vitexin (20 and 80 mumol). 125I (1 microCi) was injected ip 1 h later, and the rats were killed 2 h after the injection. The thyroid glands were removed and analyzed for their content of total 125I and 125I-labeled compounds. Rats given vitexin, in contrast to those receiving methimazole, did not show suppressed thyroid 125I uptake. However, significant inhibition of the coupling mechanism (high 125I-labeled monoiodotyrosine plus diiodotyrosine/125T3 plus T4 ratio and low 125T3 and T4 concentrations) did occur with the highest dose of vitexin. These results provide direct evidence in vivo of C-GF antithyroid activity, strongly supporting the concept that C-GF are the goitrogens in millet.
Tea polyphenols (flavan-3-ol derivatives) suppressed the oxidative modification of low density lipoprotein (LDL) which is assumed to be an important step in the pathogenesis of atherosclerosis lesions. Inhibitory experiments on the oxidative impairment of porcine serum LDL by flavan-3-ols were carried out by incubating them at 37 degrees C in the presence of 5 microM Cu2+. The oxidation of LDL was monitored either by an absorption increase at 234 nm due to the conjugated diene formation, or the formation of hydroperoxides and thiobarbituric acid reactive substances (TBARS). It was found that the oxidation was strongly inhibited by various flavan-3-ols, and a lag time over 100 min appeared, depending on the types of flavan-3-ols used. The activities based on the prolongation of the lag time were in the order of (-)-epigallocatechin (EGC) < (+)-catechin (C) < (-)-epicatechin (EC) < (-)-epicatechingallate (ECG) < (-)-epigallocatechingallate (EGCG). IC50 of flavan-3-ols on Cu2+ mediated hydroperoxides and TBARS formation of LDL were 0.90, 0.95 microM for ECG and 2.38, 2.74 microM for EGC, respectively. It was found that the Cu2+ mediated cholesterol ester degradation in LDL was almost completely inhibited by 5.0 microM C or EGCG. Cu2+ mediated apolipoprotein B-100 fragmentation was also inhibited (up to 60%) in the presence of C or EGCG.
High-performance liquid chromatographic (HPLC) and mass spectrometric (MS) procedures were developed to determine lignans in flaxseed (Linum usitatissimum) and chaparral (Larrea tridentata). Flaxseed contains high levels of phytoestrogens. Chaparral has been associated with acute nonviral toxic hepatitis and contains lignans that are structurally similar to known estrogenic compounds. Both flaxseed and chaparral products have been marketed as dietary supplements. A mild enzyme hydrolysis procedure to prevent the formation of artifacts in the isolation step was used in the determination of secoisolariciresinol in flaxseed products. HPLC with ultraviolet spectral (UV) or MS detection was used as the determinative steps. HPLC procedures with UV detection and mass spectrometry were developed to characterize the phenolic components, including lignans and flavonoids, of chaparral and to direct fractionation studies for the bioassays.
Due to growing evidence suggesting that phytoestrogens might protect against various cancers, particularly against breast and prostate cancer, it is important to measure the exposure of populations to these compounds by determining levels in food and in human tissue or body fluids to assess the possible cancer protective properties of these agents. Therefore, we developed a simple and fast procedure to extract and simultaneously hydrolyze phytoestrogens and their conjugates from food items, and present a fast and selective high-performance liquid chromatography (HPLC) method for precise determinations of the most common dietary phytoestrogens genistein, biochanin-A, daidzein, formononetin, and coumestrol using flavone as internal standard. For the first time HPLC was applied to measure these phytoestrogens and their most abundant metabolites equol and O-desmethyl-angolensin from human urine. The proposed methodology has been evaluated for losses due to thermal degradation during extraction and hydrolysis and due to sample handling during the entire work-up including solid phase extraction, and values are given for inter- and intra-assay variability. We present isoflavonoid levels of most common peas and beans used in "western" and "eastern" diets and compare isoflavonoid and coumestrol levels of raw, canned, and cooked foods which can be used in future epidemiological studies. We also determined human urinary levels with our methodology comparing values before and after soybean intake.
As the intakes of soy foods rise in the American diet, the weak estrogenic activity of plant phytoestrogens may reach biologically effective levels. We determined the content of phytoestrogens (plant compounds with weak estrogenic activity in human beings) in tofu, a commercially produced soy drink, and three soy-based formulas.
A modified isotope dilution gas chromatography-mass spectrometry method was used to analyze samples obtained from supermarkets or manufacturers.
Two or three lots of duplicate samples of four brands of tofu, one commercially produced soy drink, and three soy-based specialty formulas were analyzed. Means and standard deviations were calculated for the isoflavones daidzein, Biochanin A, genistein, coumestrol, and formononetin.
Tofu soy products were highest in isoflavone content; means of brands ranged from 73.0 to 97.5 micrograms/g daidzein per g wet weight and 187.4 to 215.9 micrograms genistein per g wet weight. The commercial soy drink followed with 7.0 micrograms daidzein per g wet weight and 21.0 micrograms genistein per g wet weight; the soy-based formulas were nearly devoid of these two isoflavones. Mean levels of Biochanin A, formononetin, and coumestrol were very low or nil (eg, 0 to 1.0 microgram/g) in all products.
Tofu contained the highest amounts of isoflavones among the products tested, and there was some variability from brand to brand. The soy drink contained lesser amounts, and soy-based formulas were devoid of isoflavones.
Gaitan E, Cooksey RC, Legan J, Lindsay RH, Ingbar SH, Medeiros-Neto G. Antithyroid effects in vivo and in vitro of babassu and mandioca: a staple food in goiter areas of Brazil. Eur J Endocrinol 1994;131:138–44. ISSN 0804–4643
Babassu ( Orbignya phalerata ), a palm-tree coconut fruit, mixed with mandioca ( Manihot utilissima ) is the staple food of people living in the endemic goiter area of Maranhao in Brazil, where goiter prevalence among schoolchildren was still 38% in 1986 despite an adequate iodine intake in most of the population. Therefore, the question arose as to whether or not the ingestion of babassu alone or mixed with mandioca contributed to the persistence of endemic goiter in this area of Brazil. In this investigation we examined the potential antithyroid effects of babassu and mandioca by means of in vivo studies in Sprague-Dawley rats, in vitro studies in porcine thyroid slices and using a purified porcine thyroid peroxidase (TPO) system. Samples of various edible parts of babassu and mandioca flour were homogenized and extracted in goitrogen-free water (GFW) for in vivo experiments, and in methanol (100 g/l), GFW or 0.06 mol/l phosphate buffer (pH 7.0) for in vitro experiments. The edible parts of babassu produced significant in vivo antithyroid effects (p < 0.05–< 0.001) in rats on a high iodine intake (14 μg I ⁻ day ⁻¹ · rat ⁻¹ ), as well as distinct and reproducible antithyroid and anti-TPO activities in both in vitro systems, their action being similar to that of the thionamide-like antithyroid drugs propylthiouracil and methimazole. The antithyroid action of aqueous extracts of mandioca flour in vivo and in thyroid slices in vitro was also evident by significant (p < 0.01–< 0.001) and pronounced inhibition of the iodide organification process; however, in contrast to babassu, methanol and aqueous extracts of mandioca flour caused little inhibition in vitro in the TPO system. Little or no effect was produced by babassu or mandioca on thyroid iodide transport by thyroid slices or in vivo in the rat, indicating that neither thiocyanate nor perchlorate-like compounds are responsible for their antithyroid effects. Results of this study provide direct experimental evidence, both in vivo and in vitro, of antithyroid effects of babassu and mandioca, supporting the hypothesis that this staple food is responsible, at least in part, for the persistence of goiter in the iodine-supplemented endemic region of Maranhao in Brazil.
Eduardo Gaitan, Endocrinology Section (151), VA Medical Center, 1500 E. Woodrow Wilson Drive, Jackson, MS 39216, USA
Pharmacologists have realized that tyrosine kinase inhibitors (TKI) have potential as anti-cancer agents, both in prevention and therapy protocols. Nonetheless, concern about the risk of toxicity caused by synthetic TKIs restricted their development as chemoprevention agents. However, a naturally occurring TKI (the isoflavone genistein) in soy was discovered in 1987. The concentration of genistein in most soy food materials ranges from 1-2 mg/g. Oriental populations, who have low rates of breast and prostate cancer, consume 20-80 mg of genistein/day, almost entirely derived from soy, whereas the dietary intake of genistein in the US is only 1-3 mg/day. Chronic use of genistein as a chemopreventive agent has an advantage over synthetic TKIs because it is naturally found in soy foods. It could be delivered either in a purified state as a pill (to high-risk, motivated patient groups), or in the form of soy foods or soy-containing foods. Delivery of genistein in soy foods is more economically viable (5/day) and would require no prior approval by the FDA. Accordingly, investigators at several different sites have begun or are planning chemoprevention trials using a soy beverage product based on SUPRO, an isolated soy protein manufactured by Protein Technologies International of St. Louis, MO. These investigators are examining the effect of the soy beverage on surrogate intermediate endpoint biomarkers (SIEBs) in patients at risk for breast and colon cancer, defining potential SIEBs in patients at risk for prostate cancer, and determining whether the soy beverage reduces the incidence of cancer recurrence.(ABSTRACT TRUNCATED AT 250 WORDS)
Metabolic experiments in rats were undertaken to relate excretory pattern of iodine and thiocyanate, with thyroid weight and the circulating levels of thyroxine, in response to moderate and high intake of iodine and under conditions of goitrogen induced altered thyroid status. On a moderate intake of iodine (by depriving diet of KI) 25 mg of thiocyanate or substitution of 1/3rd proportion of casein based diet with dry cabbage, could significantly reduce plasma thyroxine level by 60 days. Neither body weight nor the weights of liver, kidney, heart or spleen were affected due to exposure to goitrogens. A significant increase in thyroid weight as well as higher excretion of iodine and thiocyanate were evident in goitrogen-fed rats. Presence of high amounts of KI, to a certain extent, offered protection from adverse effects of the goitrogens. Semi quantitative assessment of thyroid, indicated hypofunctioning of thyroid with follicular hyperplasia in thiocyanate fed rats. These alterations were of moderate degree in response to cabbage feeding. These results emphasize that, moderate intake of iodine, adequate to meet iodine requirement, may not ensure normal functioning of thyroid in the presence of goitrogens.
Flavonols and flavones are subgroups of flavonoids and are found in tea, vegetables, fruits, and red wine. Because they have antioxidant properties, we investigated whether intake of these dietary compounds is associated with a lower risk for fatal and nonfatal coronary heart disease.
Prospective cohort study.
United States.
34,789 male health professionals, 40 to 75 years of age, who responded to a questionnaire in 1986.
In 1986 and 1990, detailed, 131-item questionnaires were used to assess dietary intake of flavonols and flavones.
Between 1986 and 1992, 496 patients received a new diagnosis of nonfatal myocardial infarction. The relative risk for nonfatal myocardial infarction was 1.08 (95% Cl, 0.81 to 1.43) for the highest (median, 40.0 mg/d) compared with the lowest (median, 7.1 mg/d) quintiles for intake of flavonols and flavones after adjustment for age, obesity, smoking, intake of vitamin E, intake of alcohol, diabetes, hypertension, hypercholesterolemia, and family history of coronary heart disease. Among the 4814 men who reported that they had previously had coronary heart disease, we found a modest but nonsignificant inverse association between intake of flavonols and flavones and subsequent coronary mortality rates (relative risk, 0.63 [Cl, 0.33 to 1.20] for the highest compared with the lowest quintile for intake of flavonoids).
The data do not support a strong inverse association between intake of flavonoids and total coronary heart disease, but they do not exclude the possibility that flavonoids have a protective effect in men with established coronary heart disease.