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PubMed1999

Resolution of fetal goiter after discontinuation of propylthiouracil in a pregnant woman with Graves' hyperthyroidism.

We report a case of Graves' hyperthyroidism in a 34-year-old pregnant woman treated with propylthiouracil (PTU) complicated by the development of a fetal goiter. Because of the fetal goiter and normal maternal thyroid function tests, the PTU was discontinued. Over the next 10 weeks, there was a progressive decrease in the fetal thyroid volume as documented by ultrasonography. The fetal neck returned to a normal flexed position, fetal growth and amniotic fluid remained normal, and the patient remained asymptomatic. A normal infant was delivered at term. This is the first report to demonstrate that noninvasive management may be appropriate for fetuses with goiter caused by antithyroid drug therapy.

Adult↗

PubMed1999

Methimazole and propylthiouracil increase cellular thyroid peroxidase activity and thyroid peroxidase mRNA in cultured porcine thyroid follicles.

Methimazole (MMI) and propylthiouracil (PTU) are common antithyroid drugs for treating hyperthyroidism because the 2 drugs inhibit thyroid peroxidase (TPO)-catalyzed thyroid hormone formation. We studied whether the 2 drugs actually inhibit cellular TPO activity in cultured porcine follicles. Porcine follicles were cultured in the presence of 1 mU/mL thyrotropin (TSH) for 7 days. Then follicles were exposed to MMI or PTU in the presence of 0.1 microM Kl for 2 days. TPO activity was measured in the 100,000 x g-pellet of the thyroid sonicate by the guaiacol oxidation method. Exposure to MMI (1 microM and 10 microM) or PTU (10 microM and 100 microM) for 2 days caused a significant increase in cellular TPO activity; 100 microM MMI inhibited cellular TPO activity. The presence of cyclic adenosine monophosphate (cAMP)-generating system (forskolin) in TSH-free medium increased MMI-mediated TPO activity. Cyclohexamide inhibited MMI-mediated TPO activation, indicating that new protein synthesis is required for increased TPO activity. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed an increase in TPO mRNA by PTU or MMI. In conclusion, MMI and PTU at therapeutic concentrations can increase TPO mRNA and cellular TPO activity, although the 2 drugs inhibit the TPO-H2O2-mediated catalytic reaction.

Animals↗

PubMed2000

Treatment with propylthiouracil is associated with appearance of antineutrophil cytoplasmic antibodies in some patients with Graves' disease.

The use of propylthiouracil (PTU) for the treatment of Graves' disease is associated with few adverse effects such as skin eruptions, liver dysfunction, and agranulocytosis. Furthermore, recent studies described the development of antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis and vasculitis in patients treated with PTU. Here we investigated whether PTU therapy per se is associated with the appearance of ANCA in patients with Graves' disease. We analyzed 119 serum samples from 117 patients with Graves' disease treated with either PTU (n = 56), or methimazole (MMI) (n = 21), as well as untreated patients (n = 42). Myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA were tested by enzyme-linked immunosorbent assay (ELISA) kits. MPO-ANCA was negative in all patients treated with MMI therapy and untreated patients. However, MPO-ANCA was detected in 21 (37.5%) of 56 patients treated with PTU therapy. Furthermore, two patients who were negative for MPO-ANCA became positive after PTU therapy. The proportion of patients positive for MPO-ANCA increased with the prolongation of PTU therapy, but did not correlate with age, gender, and positive antithyroperoxidase (TPO) antibody. Among 21 MPO-ANCA positive patients, 12 had no symptoms, but 9 patients complained of myalgia, arthralgia, or common cold like symptoms after the appearance of MPO-ANCA. Three patients developed agranulocytosis or granulocytopenia, but none showed abnormal urinary findings. Our results suggest that PTU per se is associated with the production of MPO-ANCA in patients with Graves' disease.

Adult↗

PubMed2004

Successful treatment of hyperthyroidism with amiodarone in a patient with propylthiouracil-induced acute hepatic failure.

Acute hepatic failure is a rare and potentially lethal complication of propylthiouracil (PTU) use for hyperthyroidism. We present a 20-year-old woman with Basedow-Graves' disease who developed PTU-induced fulminant hepatitis, which progressed to acute hepatic failure with grade III hepatic encephalopathy. Laboratory evaluation ruled out the most common causes of fulminant hepatitis. We treated her hyperthyroidism with amiodarone (average daily dose, 200 mg) for 3 weeks, achieving rapid and persistent euthyroidism, (triiodothyronine [T(3)] levels ranged between 64 and 109 ng/dL) without side effects. Amiodarone treatment did not abolish the thyroid radioactive iodine uptake (RAIU), allowing for subsequent treatment with radioactive iodine. The clinical course was favorable and the patient achieved full hepatic recovery 3 months after the hepatic failure was detected. After an extensive review of the literature, we believe that this is the first communication of the successful use of amiodarone to control hyperthyroidism in a patient with PTU-induced fulminant hepatitis.

Adult↗

PubMed1991

Children's food preferences and genetic sensitivity to the bitter taste of 6-n-propylthiouracil (PROP).

Genetic sensitivity to bitter taste may be associated with preference or rejection of some foods by children. Thirty-four children aged 5-7 y participated in the following assessments: a threshold test for 6-n-propylthiouracil (PROP), a scaling test to determine PROP sensitivity above threshold concentrations, a taste test of 11 foods and beverages with two methods of assessing preference (order of food selection and hedonic rating), and a verbally administered food-preference questionnaire. The 30 children who completed these tests successfully were classified as nontasters or tasters based on their PROP thresholds as well as their suprathreshold PROP functions. Analysis of variance showed significant differences in acceptance of cheese and milk for the two taste groups on one of the three preference tasks, selection of foods in order of preference. Tasters selected cheese later than did nontasters, suggesting that they like it less. Tasters selected milk earlier than did nontasters, suggesting that they like it more.

Animals↗

PubMed1997

Taste responses to naringin, a flavonoid, and the acceptance of grapefruit juice are related to genetic sensitivity to 6-n-propylthiouracil.

Increased consumption of vegetables and fruit has long been the focus of dietary strategies for disease prevention. Some vegetables and fruit have bitter tastes, which can be aversive to consumers, particularly children. The present study tested the hypothesis that acceptance of grapefruit juice is influenced, in part, by sensitivity to the bitter taste of 6-n-propylthiouracil (Prop), a heritable trait. A sample of 123 women, mean age 28 y, was divided into nontasters (n = 39), tasters (n = 49), and supertasters (n = 35) of Prop by using procedures validated previously based on Prop detection thresholds and on intensity scaling of five suprathreshold solutions of Prop and sodium chloride. The subjects tasted and rated five solutions of the bioflavonoid naringin in 4% sucrose. Naringin, the principal bitter ingredient of grapefruit juice, has been implicated in the regulation of cytochrome P-450 enzymes. Increased taste acuity for both Prop and naringin was associated with greater dislike for each bitter compound. Prop supertasters disliked bitter naringin solutions significantly more than did either tasters or nontasters. Prop sensitivity was also associated with reduced acceptability of grapefruit juice. Acceptability of orange juice, which does not contain naringin, was unrelated to Prop taster status. Is the acceptability of other bitter vegetables and fruit also limited by inherited taste factors? If so, then genetic taste markers might limit dietary exposure to valuable dietary constituents and pose a barrier to current strategies for dietary change.

Adult↗

PubMed1984

Effect of propylthiouracil on the thyroid tumorigenesis induced by N-bis(2-hydroxypropyl)nitrosamine in rats.

The effect of 0.15% propylthiouracil (PTU) on thyroid tumorigenesis was studied in male Wistar rats given a single i.p. injection of 280 mg of N-bis(-2-hydroxypropyl)nitrosamine (DHPN) per 100 g body weight. The mean weights of the thyroid of rats treated with DHPN followed by PTU and with PTU alone were significantly higher than those of rats treated with DHPN only and control rats. The incidences of follicular adenoma at the end of week 20 of the experiment were 100% (21/21) in rats treated with DHPN followed by PTU, and 19% (4/21) in rats given DHPN alone. Papillary adenoma was observed in one rat treated with DHPN followed by PTU. The incidence of follicular carcinomas with invasive growth into the capsule, adipose tissues or blood vessels was 52% (11/21) in rats given DHPN and then PTU. No papillary carcinomas or solid tumors were found in any rats. Rats given PTU alone and untreated rats had no thyroid tumors. The serum concentration of T4 in rats treated with PTU alone was significantly lower than that in the control group. The serum concentration of T4 in rats treated with DHPN followed by PTU was slightly, but not significantly, lower than that in control rats. The serum concentrations of T3 in rats treated with DHPN followed by PTU, DHPN alone and PTU alone were also slightly, but not significantly, lower than that in controls.

Adenoma↗

PubMed1995

Propylthiouracil tasting: determination of underlying threshold distributions using maximum likelihood.

The ability to taste low concentrations of propylthiouracil (PROP) and related bitter compounds is heritable. The current analysis determines whether the distribution of PROP taste thresholds is consistent with an additive or a dominant mode of Mendelian transmission. To that end, the lowest concentration of PROP detectable was determined for 1015 subjects and models of bi- or tri-modal distributions of PROP taste thresholds were tested. The model with the greatest likelihood had three distributions and followed an additive model of PROP taste sensitivity if the variances associated with the distributions were assumed to be equal. However, if the taste thresholds were transformed to remove skewness, or if the variances were unequal, then three- or two-distribution models were equally likely. Resolution of the mode of inheritance for bitter taste perception awaits additional family studies and the characterization of the molecular basis of taste perception for these bitter compounds.

Adolescent↗

PubMed1997

Genetic sensitivity to 6-n-propylthiouracil (PROP) and hedonic responses to bitter and sweet tastes.

Genetically mediated sensitivity to the bitter taste of 6-n-propylthiouracil (PROP) has been associated with greater acuity for bitter and for some sweet tastes. Thus far, few studies have explored the relationship between PROP taste sensitivity and hedonic responses to bitter and sweet. In this study, 87 normal-weight young women were divided into PROP non-tasters (n = 18), regular tasters (n = 49), and supertasters (n = 20), based on their PROP detection thresholds and the scaling of five suprathreshold solutions of PROP and NaCl. Non-tasters had thresholds > 1.8 x 10(-4) mol/l PROP. Supertasters had thresholds < 3.2 x 10(-5) mol/l PROP and PROP/NaCl ratios > 1.70. As expected, dislike of the bitter taste of PROP was determined by its perceived intensity, which was greater among supertasters than among regular tasters or non-tasters. Significant correlations were observed between PROP taste thresholds and the sum of intensity ratings (r = -0.61) and between summed intensity and summed hedonic ratings (r = -0.80). PROP taste sensitivity was weakly linked to enhanced perception of sweet taste, but did not predict hedonic responses to sucrose or to saccharin solutions. Given that the dislike of PROP solutions is determined by their perceived intensity, hedonic responses to PROP solutions may provide a rapid way of screening for PROP taster status.

Factor Analysis, Statistical↗

PubMed2001

PROP (6-n-Propylthiouracil) tasting and sensory responses to caffeine,sucrose, neohesperidin dihydrochalcone and chocolate.

The genetically determined ability to taste 6-n-propylthiouracil (PROP) has been linked with lowered acceptance of some bitter foods. Fifty-four women, aged 18-30 years, tasted and rated PROP-impregnated filter paper and seven solutions of PROP. Summed bitterness intensity ratings for PROP solutions determined PROP taster status. Respondents also tasted five sucrose and seven caffeine solutions, as well as seven solutions each of caffeine and PROP that had been sweetened with 0.3 mmol/l neohesperidin dihydrochalcone (NHDC). Respondents also rated three kinds of chocolate using 9-point category scales. PROP tasters rated caffeine solutions as more bitter than did non-tasters and liked them less. PROP tasters did not rate either sucrose or NHDC as more sweet. The addition of NHDC to PROP and caffeine solutions suppressed bitterness intensity more effectively for tasters than for non-tasters and improved hedonic ratings among both groups. PROP tasters and non-tasters showed the same hedonic response to sweetened caffeine solutions and did not differ in their sensory responses to chocolate. Genetic taste markers may have only a minor impact on the consumption of such foods as sweetened coffee or chocolate.

Adolescent↗

PubMed2001

Genetic taste responses to 6-n-propylthiouracil among adults: a screening tool for epidemiological studies.

Genetically mediated taste responsiveness to 6-n-propylthiouracil (PROP) has been linked to reduced acceptance of some bitter foods. In this community-based study male (n = 364) and female (n = 378) adults enrolled in a self-help dietary intervention trial were screened for PROP taster status. Respondents, aged 18--70 years, were mailed filter papers impregnated with PROP or with aspartame solutions. They received instructions to rate taste intensity and hedonic preference using nine point category scales. Women rated PROP as more bitter than did men. Both sweetness and bitterness ratings were lower for older adults. Taste responsiveness to PROP was unrelated to body mass index in women or men. Higher bitterness ratings for PROP were weakly associated with higher sweetness ratings for aspartame, but were unrelated to sweet taste preferences. Successful administration of PROP filter papers by mail suggests new avenues for the screening of taste phenotypes in epidemiological studies.

Adolescent↗

PubMed1996

Relative and combined effects of propylthiouracil, ethanol and protein deficiency on muscle.

A hypermetabolic state with increased oxygen consumption has been described in alcoholic hepatitis, playing a major role in ethanol-induced liver damage. Based on its ability to decrease oxygen consumption, propylthiouracil (PTU) has been proposed as a therapeutic agent in this context. On the other hand, several muscle changes have been described in hypothyroidism, including both atrophy and hypertrophy of muscle fibres. The aim of this experimental study was to analyse the effects of PTU on the alcohol-induced changes in muscle fibre size and proportion, also taking into account the presence or absence of protein deficiency. The study was performed on 64 male Wistar rats divided into eight groups, fed with: (1) Lieber-DeCarli control diet: (2) an isocaloric 36% ethanol-containing diet: (3) an isocaloric 2% protein-containing diet: (4) an isocaloric 36% ethanol 2% protein-containing diet, without and with PTU, respectively. Right gastrocnemius muscle was removed 2 months later and histochemical and morphometric studies were performed. Type IIb fibre atrophy was observed both in the alcoholic and protein-deficient animals, but not in the PTU-treated animals. The combination of protein deficiency and ethanol led to a more marked type IIb atrophy, with PTU reversing this effect. Malnutrition led to a decrease in type I fibre diameter: ethanol and PTU caused an increase in its size and PTU reversed the effect of protein deficiency. Proportion of type IIb fibres decreased in the three experimental groups without PTU with respect to the control, especially in the alcoholic protein-deficient animals. PTU-treated animals, especially those fed a low-protein diet, showed a more marked reduction in type IIb fibre proportion than that presented by the groups without PTU. However, an increase in type I fibre proportion was observed in the PTU-treated animals, especially marked in those fed a low-protein diet. Thus, PTU seems to ameliorate ethanol-induced changes on type IIb muscle fibres.

Animals↗

PubMed1996

Relative and combined effects of propylthiouracil, ethanol and protein deficiency on liver histology and hepatic iron, zinc, manganese and copper contents.

The present study was performed in order to discern the effects of propylthiouracil (PTU) on ethanol and/or protein deficiency-mediated liver histological changes and liver Fe, Zn, Cu and Mn alterations in male adult Wistar rats. The study was performed on 64 animals divided into eight groups, fed with the Leiber-DeCarli control, 36% ethanol-2% protein- and 36% ethanol-2% protein-containing diets, without and with PTU, respectively. PTU was administered at a concentration of 0.05%, an amount which rendered the animals hypothyroid. Two further groups of 5 animals each, with and without PTU respectively, were allowed to consume the control diet ad libitum. Animals treated with PTU showed significantly less fibrosis, but more fat, than animals without PTU. Liver fibrosis was inversely correlated with liver zinc, liver content of this element being higher in the PTU-treated and the ethanol or protein deficiency groups. PTU also reversed ethanol-mediated hepatocyte ballooning and also led to a reduction in nuclear areas.

Animals↗

PubMed1997

Transient hypothyroidism reinitiates egg laying in turkey breeder hens: termination of photorefractoriness by propylthiouracil.

A study was conducted to determine the effects of transient hypothyroidism induced by propylthiouracil (PTU) on termination of photorefractoriness and reinitiation of lay in turkey breeder hens. The PTU was given for 6- or 8-wk periods via the feed and at various doses to yearling hens that had been continuously exposed to long photoperiods [16 h light (L):8 h dark (D)] for at least 25 wk. There was a dose-dependent cessation of lay as well as deletion of thyroxine (T4) and triiodothyronine (T3) during the treatment period. Hens receiving 0.1% PTU or more had little or no circulating thyroid hormones after 2 wk of treatment. Furthermore, resumption of a normal rate and duration of egg laying occurred following withdrawal of the PTU, without any changes in photoperiod. However, this effect only occurred in those hens that had received PTU doses of 0.1% or more and only when the treatment had been given for greater than 6 wk. The resumption of normal levels of egg laying occurred in the absence of a typical preceding molt. Body weights, livability, and fertility and hatchability of eggs from these hens were similar to those of controls. Clearly, turkey hens can be effectively recycled by pharmacological manipulation of the thyroid gland and the results are supportive of thyroid hormone(s) involvement in maintaining photorefractoriness in turkey hens.

Animals↗

PubMed1999

Effects of phenobarbital, pregnenolone-16alpha-carbonitrile, and propylthiouracil on thyroid follicular cell proliferation.

Reduced thyroid hormone concentrations (T4 and/or T3) and increased thyroid-stimulating hormone (TSH) have been proposed to mediate the thyroid tumor promoting effects of hepatic microsomal enzyme inducers (MEI) and antithyroid drugs. TSH is known to stimulate thyroid gland function and growth, as well as neoplasia. Thyroid weight has been used as an indicator of thyroid gland growth in MEI studies, but little is known about the effects of these inducers on thyroid cell proliferation. Therefore, we determined the time-course of thyroid cell proliferation of rats treated with MEI, and with the antithyroid drug propylthiouracil (PTU). Male Sprague-Dawley rats were fed either a basal diet or a diet containing phenobarbitol (PB) (1200 ppm), PCN (500 ppm), or PTU (30 ppm) for 3, 7, 14, 21, 30, 45, 60, or 90 days. PB and PCN treatments did not affect T3, but PTU reduced T3 60%. PB and PCN treatments reduced T4 25%, whereas PTU treatment reduced T4 90%. PB and PCN treatments increased thyroid weight 80%, and PTU increased thyroid weight 500%. TSH was not appreciably altered in PB-treated rats, but was increased 75% and 830% in PCN- and PTU-treated rats, respectively. Thyroid cell proliferation was increased 260, 330, and 850% in rats treated with PB, PCN, or PTU, respectively, for 7 days, but returned to control levels by the 45th treatment day. In conclusion, treatment with MEI that produced mild increases in TSH resulted in dramatic increases in thyroid cell proliferation, which peaked after 7 days of treatment and then returned to control values. This result is similar to that of antithyroid drugs, which produce large increases in TSH. These findings may have important implications for the role thyroid follicular cell proliferation has in mediating the thyroid tumor promoting effects of MEI.

Animals↗

PubMed2005

Progress towards development of an amphibian-based thyroid screening assay using Xenopus laevis. Organismal and thyroidal responses to the model compounds 6-propylthiouracil, methimazole, and thyroxine.

In response to the initial Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) recommendations, research was conducted on the development of a Xenopus laevis based tail resorption assay for evaluating thyroid axis disruption. This research highlighted key limitations associated with relying on tail resorption as a measure of anti/thyroid activity. The most critical limitation being that tail tissues of tadpoles at metamorphic climax are insensitive to perturbation by thyroid axis agonists/antagonists. To improve upon the initial proposal, we have conducted experiments comparing the sensitivity of pre-metamorphic (stage 51) and pro-metamorphic (stage 54) larvae to the model thyroid axis disruptors methimazole (control, 6.25, 12.5, 25, 50, 100 mg/l), 6-propylthiouracil (PTU) (control, 1.25, 2.5, 5, 10, and 20 mg/l), and thyroxine (T4) (0.25, 0.5, 1, 2, 4 microg/l). Exposures were conducted using two different experimental designs. For experimental design 1, tadpoles were exposed to methimazole or PTU starting at either NF stage 51 or NF 54 for 14 days. For experimental design 2, tadpoles were exposed to PTU or T4 starting at NF stage 51 or NF 54 for 14 and 21 days, respectively. Methimazole and PTU, which are thyroid hormone synthesis inhibitors, both caused a concentration dependent delay in larval development. As determined from this endpoint, there were only minor differences in sensitivity observed among the two stages examined. Further, both compounds caused concentration dependent changes in thyroid gland morphology. These changes were characterized as reduced colloid, glandular hypertrophy, and cellular hyperplasia and hypertrophy. Treatment failed to negatively affect growth, even in tadpoles that experienced significant metamorphic inhibition. T4 treatment resulted in a concentration dependent increase in developmental rate, as would be expected. Similar to studies with methimazole, there were no differences in sensitivity among the two developmental stages examined. These results indicate that tadpoles in the early stages of metamorphosis are sensitive to thyroid axis disruption and that development of a short-term, diagnostic amphibian-based thyroid screening assay shows considerable promise.

Animals↗

PubMed1994

Developmental expression of testis messenger ribonucleic acids in the rat following propylthiouracil-induced neonatal hypothyroidism.

Propylthiouracil- (PTU) induced transient neonatal hypothyroidism increases adult rat testis weight 80-100%; this effect involves prolongation of Sertoli cell proliferation. To gain insight into developmental effects of PTU on the testis, we used Northern analysis to examine chronological expression of Sertoli cell mRNA in postnatal rat testes from rats that were untreated (controls) or were given PTU from birth to Day 25. Treated rats showed prolonged early expression of genes associated with dividing Sertoli cells such as MIS (Müllerian inhibiting substance) and c-erbA alpha (thyroid hormone receptor). Expression of several other Sertoli cell mRNAs (androgen-binding protein [ABP], clusterin, and inhibin-beta B) was delayed, as was that of hemiferrin, a spermatid-specific mRNA. Temporal expression patterns for other mRNAs (sulfated glycoprotein [SGP]-1, transferrin, and inhibin-alpha) were similar in control and treated animals. Additionally, thyroid hormone replacement in PTU-treated animals decreased MIS and c-erbA alpha mRNA expression to control levels. The altered developmental pattern of expression of a number of major Sertoli cell genes reflects a prolonged mitogenesis and delayed maturation of Sertoli cells in neonatally hypothyroid animals. Furthermore, our results suggest that thyroid hormone may directly potentiate molecular events associated with cessation of Sertoli cell proliferation and maturation during early testis development.

Animals↗

PubMed2002

Inhibition of testosterone production by propylthiouracil in rat Leydig cells.

Propylthiouracil (PTU) is a thioamide drug used clinically to inhibit thyroid hormone production. However, PTU is associated with some side effects in different organs. In the present study, the acute and direct effects of PTU on testosterone production in rat Leydig cells were investigated. Leydig cells were isolated from rat testes, and an investigation was performed on the effects of PTU on basal and evoked-testosterone release, the functions of steroidogenic enzymes, including protein expression of cytochrome P450 side-chain cleavage enzyme (P450(scc)) and mRNA expression of the steroidogenic acute regulatory protein (StAR). Rat Leydig cells were challenged with hCG, forskolin, and 8-bromo-cAMP to stimulate testosterone release. PTU inhibited both basal and evoked-testosterone release. To study the effects of PTU on steroidogenesis, steroidogenic precursor-stimulated testosterone release was examined. PTU inhibited pregnenolone production (i.e., it diminished the function of P450(scc) in Leydig cells). In addition to inhibiting hormone secretion, PTU also regulated steroidogenesis by diminishing mRNA expression of StAR. These results suggest that PTU acts directly on rat Leydig cells to diminish testosterone production by inhibiting P450(scc) function and StAR expression.

Animals↗