Administration of ptu would produce the following effects on the synthesis of thyroid hormone?

9.2.1.1.2.1 Goiter

The thiocyanate generated during detoxification of cyanide in the body is believed to interfere with iodine uptake because of its structural similarity. It increases the iodine requirement in iodine-deficient populations. The thiocyanate thus acts as an additional factor for the development of goiter in such populations.

9.2.1.1.2.2 Konzo

It is a neurologic condition associated with the intake of improperly processed (i.e., without peeling, slicing, and cooking) cassava fruit (Nzwalo and Cliff, 2011). The cyanogenic glycosides of the plant, namely linamarin and lotaustralin, are released by the plant to defend it against animals. These cyanide compounds produce konzo that is characterized by a sudden onset of spastic parapresis. Konzo has been reported in the African continent.

9.2.1.1.2.3 Tropical ataxic neuropathy

Tropical ataxic neuropathy is another condition that is associated with chronic consumption of products derived from cassava and consequent exposure to cyanide. It manifests in the form of neurologic symptoms that mainly affect vision and hearing abilities. This condition has been reported in Kerala, India.

Exogenous Compounds

Goitrogenic substances such as thiocyanate and perchlorate compete with iodide uptake. Iodide oxidation and coupling of iodotyrosines are inhibited by drugs such as sulfonamides, phenylbutazone, phenothiazines, thiouracils, thiopental, and methimazole. One study found no suppressive effect of trimethoprim-sulfadiazine on equine thyroid function.439 Soybean meal, linseed meal, and plants of the Brassica family (i.e., rapeseed) contain goitrogenic substances.339,356 Phenylbutazone administration decreases TH concentrations in horses,405,440 and this effect can last up to 10 days after discontinuation of phenylbutazone.440 The TSH stimulation test may be normal or exacerbated in horses receiving phenylbutazone.405 High levels of nitrates in the water may induce thyroid gland hypertrophy in people,441 as nitrates reduce the iodine transport into the thyroid gland.

Propylthiouracil (PTU), in addition to affecting iodine metabolism, inhibits the peripheral conversion of T4 to T3. Substances that compete for TH binding sites on transporting proteins could potentially lead to a hypermetabolic state by increasing their free fractions (fT4, fT3).395 Human athletes receiving anabolic steroids had decreased TSH, T4, T3, and TBG concentrations441a; however, anabolic steroid administration to horses did not affect thyroid function tests.442

Exogenous compounds containing iodine or iodides are of particular interest. Both iodine excess and deficiency can induce thyroid dysfunction and interfere with thyroid tests.443 Horses are exposed to iodine or iodide compounds in the form of feedstuffs, expectorants, leg paints, shampoos, injectable counterirritants, radiographic contrast media, and antiprotozoal drugs (iodochlorhydroxyquin). Animals can respond to excessive amounts of iodine by either suppressing or accelerating hormone production.

Iodine excess reduces thyroidal iodine uptake and organification (incorporation into inactive MIT and DIT) and decreases TH concentrations and the response to the TSH and TRH stimulation tests. The end result could be hypothyroidism, which is known as the “Wolff-Chaikoff effect.” Iodine-containing drugs such as amiodarone have been shown to cause this effect in people and dogs444 but not in horses. The second way animals and people can respond to excessive iodine exposure is by elevating TH production. This is referred to as “Jod-Basedow phenomenon” that in general is seen in individuals with iodine deficiency.357

Newborn foals of mares grazing Neotyphodium coenophialum–infected fescue had lower T3 concentrations than controls, with no differences in T4 and rT3 concentrations.445 Endophyte alkaloids are D2 dopamine receptor agonists, and dopamine is an inhibitor of TSH secretion. It remains unclear whether the low TH concentrations in these foals are a direct consequence of the alkaloids on the fetal HPTA or an indirect effect through placental and fetal development. Endophyte alkaloids do not appear to alter thyroid function in adult horses.446

Lactoperoxidase

Lactoperoxidase, with hydrogen peroxide and thiocyanate, constitutes what is known as the lactoperoxidase system (LPS), a natural antibacterial system in milk. The required amounts of lactoperoxidase, H2O2 and thiocyanate for effective inhibition of bacterial growth are 0.5–1.0 ppm, 100 U ml−1 and 0.25 mmol l−1, respectively; the levels in cows' milk are about 30 ppm, 1–2 U ml−1 and 0.02–0.25 mmol l−1, respectively. Additional hydrogen peroxide can be supplied by:

direct addition of hydrogen peroxide

addition of an enzyme system which generates hydrogen peroxide (such as glucose/glucose oxidase) or

inoculation with microorganisms, such as lactic acid bacteria, that generate hydrogen peroxide. This is the most feasible method for large-scale dairy applications.

The LPS is latent in normal milk. The thiocyanate ion levels are too low, for optimum activity and hydrogen peroxide breaks down after leaving the udder. Activation of the LPS by adding 10–12 ppm thiocyanate ion and 8–10 ppm of hydrogen peroxide is necessary to achieve successful shelf-life in milk.

The LPS is capable of destroying Gram-negative bacteria such as coliforms, Pseudomonas, Salmonella and Shigella, while Gram-positive organisms, including streptococci and lactobacilli, are only temporarily inhibited. The LPS is also capable of inactivating viruses.

It is most useful for preservation of raw milk in countries with limited refrigeration facilities. However, it is also suitable for preservation of milk following pasteurization because lactoperoxidase is only partly inactivated under HTST pasteurization conditions. In this way, the shelf-life of pasteurized milk can be extended, although this is not practised commercially (see ENZYMES INDIGENOUS TO MILK | Lactoperoxidase).

Formation of an oxathiolone derivative

When rutin is mixed with nitrite and thiocyanate under acidic conditions (pH 2), a stable oxathiolone derivative of rutin (5,7-dihydroxy-2-(7-hydroxy-2-oxobenzo[d][1,3]oxathiol-4-yl)-4H-chromen-4-one 3-O-β-rutinoside) is produced (Figure 13.5) (Takahama et al., 2009). This component is also produced by the addition of both nitrite and thiocyanate to an acidic suspension of buckwheat flour and by the acidification of masticated buckwheat dough, suggesting that its formation is possible in the stomach after the ingestion of foods containing buckwheat flour or rutin.

The oxathiolone derivative of rutin can be produced as shown in Figure 13.6. Rutin may be transformed to the quinone form via a rutin radical to react with thiocyanate producing 2-thiocyanaterutin, which can be transformed to the oxathiolone derivative by hydrolysis. Thiocyanic acid might contribute to the formation of 2-thiocyanaterutin. The contribution of thiocyanic acid (pKa = 0.8) could be deduced from the observation that the oxathiolone derivative of caffeic acid was detected at pH 2.0 but not pH 3.3, although caffeic acid was oxidized by nitrite at both pH values (unpublished observation).

Chlorogenic acid, which is a common phenolic compound contained in foods and beverages, is also oxidized to its quinone form by nitrite under the acidic conditions. This quinone can be transformed to its oxathiolone derivative in the presence of thiocyanic acid as shown in Figure 13.6 (Takahama et al., 2007). A component with an oxathiolone moiety (6-hydroxy-1,3-benzoxathiol-2-one) is used for the treatment of acne, and its derivatives can inhibit the activity of carbonic anhydrase and inhibitory κB kinase-β. Oxathiolone derivatives of chalcones can inhibit the growth of Micrococcus luteus and Staphylococcus aureus. Our results showed that the oxathiolone derivative of rutin inhibited the growth of M. luteus, but not that of E. coli, under aerobic conditions. Further studies are required to elucidate the function of oxathiolone derivatives of phenolic compounds, which may be produced in the stomach.

10.3.6.6 Glucosinolates

Major glucosinolates are goitrin, isothiocyanates, and thiocyanates (Fig. 10.2) that naturally exist in cruciferous plants such as cabbage, kale, broccoli, and green leafy vegetables. Glucosinolates are also found in oilseed crops such as rapeseed and soybean meal. They are water soluble and derived from glucose and amino acids that contain a sulfur group. Glucosinolates can contain different side groups that play important roles in their biological activities. The hydrolysis products of glucosinolates are antithyroid and reduce the level of the thyroid hormones triiodothyronine (T3) and thyroxine (T4) in animals. The threshold of glucosinolates in fish diets depends on the species, but 1.4 μmol/g of diet is considered a safe for most species (NRC, 2011).

Analysis of intact glucosinolates in various plant ingredients is done by their extraction at high temperatures with methanol–water mixture. This method can disable myrosinase activity that can be purified in an ion-exchange column. Finally, detection is done with an HPLC with a photodiode array or ultraviolet device (Grosser and van Dam, 2017).

Solutions

Buffer D (denaturing buffer):

Guanidium thiocyanate (4 M)

Sodium citrate (25 mM), pH 7

Sarkosyl lauryl sulfate (0.5%)

Mercaptoethanol (0.1 M)

Mix guanidium, sodium citrate, and sarkosyl, and store in 50-ml Falcon tubes.

Before use, add 360 μl of 2-mercaptoethanol/50 ml.

Sodium acetate (2 M), pH 4

Chloroform-isoamyl alcohol, 49:1

Water-saturated phenol

2-Propanol

Glyoxal solution

ComponentStockFor 300 μlFor 600 μlNaHPO4 (100 mM), pH 7100 mM30 μl60 μlDeionized glyoxal70 μl140 μlDimethyl sulfoxide200 μl400 μl

Hybridization solution

ComponentStockFor 20 mlFor 40 mlDeionized formamide (50%)100%10 ml20 mlNaHPO4 buffer (50 mM), pH 71 M1 ml2 mlSSC (3×)20×6 ml12 mlSDS (0.5%)10%1 ml2 mlNa2EDTA (5 mM)0.5 M200 μl400 μlssDNA (250 μg/ml)10 mg/ml500 μl1 mlDenhardt's solution (5×)50×2 ml4 ml

What is the effect of the drug PTU on the secretion of thyroid hormone?

How does propylthiouracil PTU inhibit thyroid synthesis?

What was the effect of PTU injections?

Does PTU decrease TSH?