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Review |
Faculdade de Ciências da Saúde, Universidade de Brasília, Brasília, BRAZIL
Address reprint requests to: Jose G. Dorea, PhD, FACN, C.P. 04322, Universidade de Brasilia, 70919-970 Brasilia, DF, BRAZIL
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ABSTRACT |
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Key words: thiocyanate, cyanide, milk, cassava, smoking
Key teaching points:
• Cyanogenic glucosides are naturally present in plant foods but safely metabolized.
• CN as a by-product of cigarette smoking is metabolized differently from plant-food CN.
• Maternal serum-SCN are used as markers to study adverse effects of cigarette smoking during pregnancy.
• SCN is an activator of the lactoperoxidase-defense system of nursing infants.
• Only during inadequate protein nutrition can food-SCN aggravate endemic iodine-deficient disorders.
Environmental substances that can alter thyroid function include pollutants and naturally occurring constituents of plant foods. Xenobiotics present in the environment are of concern because they reach the food chain and can interfere with thyroid function through a variety of pathways: inhibition of iodine trapping, blockage of iodine binding to tyrosine, coupling of iodothyronines to thyroxin, inhibition of thyroid hormone action and production of thyroid antibodies. These substances include organochlorine compounds, polychlorinated biphenyls, dioxins, and discussion of them is found elsewhere [1]. Some naturally occurring substances in plants can also interfere with the hypothalamic-pituitary-thyroid axis, if excessive amounts are consumed. A review of experimental animal-data on food-goitrogens showed evidence that thiocyanate (SCN) decreases cow’s milk-I, somehow implying that SCN in human diet could have similar effects [2]. Because of the goitrogenic differences in plants that serve as food for animals and man, and also intrinsic features of breast-feeding associated with thyroid function, extrapolation of animal-data to humans requires special considerations.
Besides iodine, normal thyroid function depends on sufficient supply of key nutrients and adequate processing of our daily food to neutralize potentially thyroactive substances. The deiodination reactions regulating synthesis and storage of thyroid hormone are dependent on seleno-enzymes and other nutrients and are discussed elsewhere [3]. Knudsen et al. [4] discussed goiter prevention in relation to demographic and lifestyle-associated factors. However, central to the goitrogenic effects of naturally-occurring substances in plant foods is the intake of cyanogenic glucosides from cassava in certain geographic areas of Africa with endemic iodine deficiency disorders-IDD [5].
There are several classes of naturally-occurring substances capable of altering thyroid function in animals. While some (such as isoflavones) are experimentally goitrogenic [6], other chemical classes have shown thyroid effects in farm animals (isothiocyanate, isoSCN) and man (SCN). The goitrogenic activity of cassava plants are caused by SCN formed after ingestion of cyanogenic glucosides or residual cyanide (CN) from incomplete detoxified products. SCN inhibits the uptake of iodine by the thyroid gland, but this is easily overcome by sufficient dietary iodine. Cyanogenic glucosides are present in more than 2500 plant species [7]. As part of its defense-mechanism, the plant liberates CN after spontaneous hydrolysis or linamarinase-controlled reactions. Goitrogens such as SCN and isoSCN are metabolites of cyanogenic glucosides (CG) or glucosinolates abundantly found in the plant kingdom especially in the Brasicasseae and Euphorbiaceae families that serve as food for animals and man. The Brasicasseae or Cruciferous plants (such as cabbage, turnips, radishes, mustard, broccoli, Brussels sprouts, cauliflower, cabbage, kale) contain glucosinolates that after the action of B-glucosidases form isoSCN (5-vinyl-2-thiooxazolidine). These substances inhibit thyroid peroxidase, preventing formation of thyroxine (T-4), and can be a problem to the animal-feeding industry and possibly humans [8].
Cassava plants (also known as manioc and yucca) are among the most important starchy foods eaten by man. As summarized by Wilson et al. [9], cassava (Manihot esculenta Crantz) is cultivated without mechanization in 92 tropical and subtropical countries, usually by small-scale farmers. This resistant crop does not require fertilizer or pesticides. It is the main staple food for millions of people in equatorial regions where it is grown, and among Amerindians it composes up to 80% of their diet [10]. Because of its taste, some varieties known as "bitter" contain higher glucoside concentrations (320 to 1120 µgCN/g) than the "sweet" (non-bitter; 27 to 77 µgCN/g) varieties [11]. The sweet varieties are eaten simply boiled or baked, while the bitter varieties require elaborate processing before being consumed [8]. Dufour [12] described how the traditional processing is effective in destroying cyanogen glucosides (mainly linamarin) before its consumption. The roots are soaked in the river for approximately three days, followed by grating or peeling. After peeling the soft water-soaked roots are squeezed in cloth or left to dewater in basketry sleeves. The chemical action of linamarinase present in the plant, as well as hydrolysis during manipulation, forms cyanohydrin. Depending on the final product, the cassava dough is dried, fermented, or pan baked. Residual linamarin-metabolites are neutralized by the S-amino acids from abundant animal-protein (game and fish) in the diet of native Amazonians. CN is metabolized by the formation of SCN which is catalyzed by rhodanese. This enzyme forms SCN by transferring S from various S-compounds, mainly cysteine and S-containing amino-acids [13]. Indeed, residual CN in traditionally processed cassava in Amazonia is low (0–50 ppm) and consumed in large quantities without thyroid disorders. Dietary intake of residual CN is over 20 mg/d (w.w.) with serum-SCN measuring 180µmol/L [14].
SCN is found ubiquitously in tissues and secretions of mammals mainly as a detoxification product of CN in food or recreation habit (cigarette smoking). Non-smoking adults consuming sweet varieties of cassava (1–4 kg) showed that after two days, urinary SCN increased from 12 to 22µmol/L, while linamarin increased from 2 to 68µmol/L [15]. The estimated linamarin half-life in blood is short (<8 hours) [16] and equivalent to the 7.3h for CN [17], but that of smoking-SCN is estimated at 2 weeks [18]. The exposure to linamarin and its metabolites via ingested food is attenuated by proper metabolism via the intestines (which slow down toxicity), portal system and liver. However, when absorbed by lungs in cigarette smoking, CN metabolism can be altered. The CN (from cigarette smoking) absorbed by the lungs gains the systemic circulation spreading out in the entire organism bypassing the portal circulation. Indeed, studies by Ngogang et al. [19] suggested altered SCN metabolism in smokers.
SCN-adverse effects during pregnancy and lactation in industrialized societies are mainly derived from non-food sources, i.e., cigarette smoking. CN in tobacco smoking is associated with low birth weight [20]. Serum-SCN of smoking mothers is significantly higher than non-smoking controls [18,20] and is used as a marker of the adverse effects of smoking on birth weight. Maternal serum-SCN levels were positively correlated with cigarette smoking, umbilical-cord serum-SCN levels, and inversely correlated with infant’s birth weight [20]. Nafstad et al. [21] observed that serum-SCN in smoking mothers (69µmol/L) was significantly higher than SCN in cord blood (47µmol/L). Infants of smoking mothers had significantly decreased weight and length at birth compared to infants of non-smokers [20], but children seem to catch up any losses in birth weight due to maternal smoking [22]. However, some studies showed that smoking has a negative influence on breast-milk volume [23] and growth in breastfed children [24], contrary to the early findings of Little et al. [25]. The risk of thyroid problems caused by cassava-SCN is secondary to iodine deficiency. In Africa, poverty and food scarcity due to drought and war force consumption of incomplete detoxified-cassava [26]. SCN overload originating from consumption of poorly detoxified cassava is considered a contributing factor in increased rate of goiter [5]. However, the work of Jackson [27] suggests that CN clearance is also modulated by immunological mechanisms in these susceptible African populations.
Serum SCN of pregnant, lactating mothers and breast-fed infants was significantly higher in the cassava-eating population of Zaire (showing altered thyroid function) than in Belgian controls [28]. Mean milk-SCN concentrations were 22% (2.6 mg/L) less in Belgians (non-cassava eaters) than in cassava eaters (3.3 mg/L) from Zaire [29]. The milk-SCN concentrations in goiter-endemic populations varied from 3.3 mg/L in Zaire [30] to 9.75 mg/L in Nigeria [31]. Meberg et al. [19] reported that in Norway the mean breast-milk-SCN of smokers (10–20 cigarettes/d) was not significantly different from non-smokers (9.0 and 10.5 mg/L respectively). Comparatively, in the USA the breast-milk-SCN concentrations of smokers (4.2 mg/L) was fourfold higher (0.92 mg/L) than of non-smokers [32]. Babies breast-feeding on smoking mothers increased fifteenfold the urinary-SCN after three days compared to nursing babies of non-smoking mothers [33]. Finnstrom et al. [33] determined urine-SCN and estimated that urine-SCN of breast-fed babies (on a body weight basis) were close to urine-SCN of adult smokers.
The mammary gland barrier reduces the SCN passage from maternal serum to milk, apparently protecting the breast-fed infant. In areas of endemic hypothyroidism and high intakes of cassava the milk:plasma SCN-ratio varied from 0.42 in Zaire [30] to 0.82 in (non-smoking) Nigerian mothers [31]. Signs of hypothyroidism in Zairian children appeared much later after weaning when infants were on an adult-style diet [30]. Indeed, a subsequent study showed that low serum-SCN in breast-fed infants did increase after weaning [34]. Milk:serum SCN-ratios for non-smokers in Norway [19] and the USA [35] were respectively 0.41 and 0.69, comparable to African cassava-eaters. SCN metabolism in smokers, however, may be slower than in non-smokers [18], thus maintaining higher plasma levels and altering milk:plasma SCN-ratios. In spite of high plasma-SCN concentrations, the milk:plasma SCN-ratio of smokers varied from 0.16 [19] to 0.37 [35]. Although SCN concentrations are higher in colostrum (5.0 ppm) than in mature milk (2.9 ppm) of non-cassava-eating mothers [36], there are no reported adverse thyroid-effects on breast-fed babies. Indeed, no significant correlation existed between maternal serum-SCN and milk-SCN concentrations of cassava-eating mothers [31].
Cigarette smoking can be related to thyroid disorders [37], but so far no studies of smoking mothers addressed breast-milk-I and thyroid status of breast-fed infants. Animal studies showed interaction between SCN and cow’s milk-I; however, the extrapolation that "thiocyanate may impair iodine nutrition in the breast fed baby" [2] has to consider intrinsic aspects of breast-feeding and thyroid function. The protective effect of breast-feeding on thyroid metabolism is well documented. Long lasting effects of breast-feeding on thyroid function was observed after three years [38]. Phillips et al. [39] speculated that a "biochemical imprinting" in iodine metabolism operates in breast-fed infants. Thyroid function in later life of women (aged 60–71 years) that were breast fed beyond one year showed that free T-4 concentrations were increased, whereas in women who were bottle fed, serum TSH (thyroid stimulating hormone) rose and free T-4 fell with increasing birth weight. Phillips et al. [39] hypothesized that a "set point of thyroid function in the adult is determined by fetal growth and infant feeding." Breast feeding was beneficial in most cases of neonatal hypothyroidism [40–42] in spite of studies showing that it may [43] or may not [44] affect infant’s thyroid function. Compared to formula-fed (with and without iodine supplementation) exclusive (or partial) breast-fed infants showed the greatest reduction in spontaneous thyroid-volume-development during the first three months of life [45]. Infant’s serum T-4 and T-3 (triiodothyronine) were significantly higher in breast-fed compared to formula-fed infants [46]. It is interesting to notice that breast-fed infants of mothers with thyroid conditions (goiter, Graves and Hashimoto diseases) showed serum thyroid-hormones comparable to formula-fed infants [47]. Even in circumstances of low breast-milk iodine, thyroid status was better in breast-feeding than feeding cow’s milk-based-formulas [48]. A comprehensive review of iodine and breast feeding is presented elsewhere [49].
Van Middlesworth [32] and others [50] suggested that SCN has a physiological role of its own. Indeed, SCN is required to activate the antimicrobial properties of the milk-lactoperoxidase (LP) system [36]. We know very little relating breast-milk-LP activity and maternal SCN. Gothefors and Marklund [51] observed that SCN and LP activity was high in newborn saliva but low in colostrum, whereas it was the opposite in calves and cow’s milk. Data from farm animals showed no correlation between lactoperoxidase activity and SCN content in either cow’s or goat’s milk [52]. Nevertheless, the antimicrobial activity of the LP system has been explored by addition of SCN. Added to commercial-milk as an antibacterial-agent, SCN appears to impair thyroid function in Indian women [53], but when supplemented with iodine (SCN, 19 mg/L; 0.1mgI/L) it does not have a negative effect on the thyroid function [54]. Furthermore, iso-SCN is currently studied because of anticancer properties [55].
In conclusion: only under conditions of insufficient protein nutrition of populations living in endemic iodine-deficiency areas can poorly-detoxified cassava aggravate IDD.
Received July 2, 2003. Accepted September 23, 2003.
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