Paraoxonase and arylesterase levels in autoimmune thyroid diseases.

OBJECTIVE: The aim of this study was to evaluate serum paraoxonase-1 (PON1) activity and its association with oxidative stress in autoimmune thyroid disease (AITD). METHODS: A total of 50 patients with AITD, including 25 with Hashimoto's thyroiditis and 25 with Graves' disease were enrolled. The control group comprised 27 healthy subjects. Blood samples were obtained in the euthyroid period and 3 months after initiation of medical treatment. Serum samples from patients with AITD and the healthy control group were analyzed for basal PON1, salt-stimulated PON1, and arylesterase (ARE) activities, along with lipid hydroperoxide (LOOH) and total free sulfhydryl (-SH) levels. RESULTS: Serum PON1 activities and -SH levels were significantly lower (P < 0.001, for each), whereas LOOH levels were significantly higher (P < 0.001, for each) in patients with AITD, compared to the control group. We observed no significant differences in ARE levels between the patient and healthy control groups (P > 0.05). PON1 activity was positively correlated with -SH (r = 0.522, P < 0.001) and negatively correlated with LOOH (r = -0.487, P < 0.001). PON1 phenotype distribution of the subjects was not significantly different among the three groups (P = 0.961). CONCLUSIONS: Serum PON1 activity is decreased in patients with AITD, and correlated positively with -SH, a well-known antioxidant, and negatively with LOOH, an index of lipid oxidation.

Wortmannin, PI3K/Akt signaling pathway inhibitor, attenuates thyroid injury associated with severe acute pancreatitis in rats.

Increasing evidences suggest that PI3K/AKT pathway plays an important role in the pathogenesis of inflammatory diseases such as acute pancreatitis. However, the exact effect of PI3K/AKT on thyroid injury associated with acute pancreatitis has not been investigated. This study aimed to investigate the protective effects of wortmannin, PI3K/AKT inhibitor, on thyroid injury in a rat model of severe acute pancreatitis (SAP). Sixty male SD rats were randomly divided into four groups: sham operating group (SO), SAP group, wortmannin treatment (WOR) group and drug control (WOR-CON) group. Serum amylase (AMY), lipase (LIP) and thyroid hormone levels were evaluated. The morphological change of thyroid tissue was analyzed under the light and transmission electron microscopy. AKT, P38MAPK and NF-κB expression in the thyroid tissue was evaluated by immunohistochemical staining. Oxidative stress and inflammatory cytokines were detected. Results showed that wortmannin attenuated the following: (1) serum AMY, LIP and thyroid hormone (2) pancreatic and thyroid pathological injuries (3) thyroid MDA, (4) thyroid ultrastructural change, (5) serum TNF-α, IL-6 and IL-1ß (6) AKT, MAPKP38 and NF-κB expression in thyroid tissues. These results suggested that wortmannin attenuates thyroid injury in SAP rats, presumably because of its role on prevent ROS generation and inhibits the activation of P38MAPK, NF-κB pathway. Our findings provide new therapeutic targets for thyroid injury associated with SAP.

[Association of polymorph variants of CYP1A2 and CYP1A1 genes with reproductive and thyroid diseases in female workers of petrochemical industry].

The article presents results obtained in study of relationship between polymorph variants of CYP1A1 and CYP1A2 genes with reproductive and thyroid diseases risk in female workers of petrochemical industry, when compared with reference group females. Variants TD and DD of CYP1A2 gene appeared to be associated with nodes formation in uterus and breast in female workers and reference group females. Following liability markers are obtained: homozygous in rare allele genotype CC of CYP1A1 gene for reproductive and thyroid diseaes (fibrous cystic mastopathy and nodular goitre), heterozygous genotype AG of CYP1A1 gene in uterine myoma and fibrous cystic mastopathy, homozygous in deleted T genotype of CYP1A2 gene in autoimmune thyroiditis. Occupational hazards and long length of service at hazardous industries increase effects of rare alleles of the genes studied.

Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany.

OBJECTIVE: To investigate regional variations in the frequency of undiagnosed thyroid disorders among 25- to 88-year-old men and women in two communities in the northeast and the south of Germany. In addition, autoantibodies to thyroperoxidase (TPO-Abs) and urinary iodine excretion were determined. METHODS: Two population-based surveys of men and women using a common standardized protocol, the Study of Health in Pomerania (SHIP) in the northeast of Germany (2505 participants) and the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) in the south of Germany (2316 participants), were compared with regard to the frequency of undiagnosed thyroid disorders. RESULTS: Compared with the northeast of Germany, urinary iodine excretion and serum thyroid-stimulating hormone (TSH) levels were significantly higher in the south. The median urinary iodine concentration was 110 µg/l (64; 169 µg/l) in SHIP and 151 µg/l (97; 214 µg/l) in KORA, and the median TSH value was 0.81 mIU/l (0.56; 1.15 mIU/l) in SHIP and 1.22 mIU/l (0.84; 1.80 mIU/l) in KORA. The frequency of elevated TSH (TSH ≥ 2.12 mIU/l) was 4.3% in SHIP and 14.1% in KORA (P<0.001); the corresponding values for suppressed TSH (<0.25 mIU/l) were 3.5 and 1.7% (P<0.001). The proportion of ultrasonographic findings was 55.5% in SHIP and 68.0% in KORA. The frequency of serum TPO-Abs did not differ significantly between northeast and south Germany. CONCLUSIONS: There were considerable regional disparities in the frequency of thyroid disorders within Germany. These differences can be explained not only by different regional histories of natural iodine deficiency but also by current differences in the iodine supply under an identical nationwide iodine fortification program.

Further studies on delineating thyroid-stimulating hormone (TSH) reference range.

The aim of the study was to evaluate thyroid-stimulating hormone (TSH) concentration in a reference group and to compare it with the TSH in subjects with high probability of thyroid dysfunction. The study population consisted of 852 subjects. The reference group consisting of 316 subjects was obtained by the exclusion of the subjects having thyroid disease, taking thyroid influencing drugs, having increased thyroid peroxidase (TPO) antibodies, or having abnormal thyroid ultrasound. 42 high probability of thyroid dysfunction subjects were defined by the association of increased TPO antibody concentration, changed echogenicity, and changed echosonographic structure of thyroid parenchyma. In the reference group TSH reference range was 0.45 mU/l (95% CI 0.39-0.56 mU/l) to 3.43 mU/l (95% CI 3.10-4.22 mU/l). To distinguish reference and high probability of thyroid dysfunction group a TSH threshold was calculated. At a threshold value of 3.09 mU/l (95% CI 2.93-3.38 mU/l), specificity was 95% and sensitivity 38.1%. Using 2 different approaches to find upper limit of the TSH reference range we obtained similar results. Using reference group only a value of 3.43 mU/l was obtained. Using both reference group and subjects with the high probability of thyroid dysfunction we obtained 95% CI for the upper reference limit between 2.93 and 3.38 mU/l. Based on these premises, it could be argued that conservative estimate of the TSH upper reference range should be 3.4 mU/l for both sexes.

[B-, H- and L-cathepsin-like activity in blood plasma of patients with diseases of the thyroid, parathyroid and adrenal glands].

B-, H- and L-catepsine-like activity regarding Na-benzoyl-D,L-arginine-4-nitroanilide, L-leucine-4-nitroanilide and azocasein was studied in the blood plasma of patients with different diseases of thyroid, parathyroid and adrenal glands. It has been shown that the high H- catepsine-like activity confirming the activation of blood catepsin H secretion accompanied by the tissue growth under any pathology took place in the blood plasma of patients with all the above diseases. High B- catepsine-like activity in the blood plasma of patients with thyroid diseases was exceptionally fixed under the nodular forms of thyroid pathology, while the character of changes in L catepsine-like activity under these diseases was not so natural. In diaseses of the adrenal glands the changes in the B- and L-catepsine-like activity were only shown in the blood plasma of patients with cerebral layer tumors but not the gland cortex: B-catepsine-like activity increased in the blood plasma of patients with benign or malignant tumors, and L-catepsine-like activity decreased under benign tumor from chromaffin tissue. The established picture of changes in enzymatic activity in the blood plasma of patients does not allow to think that the determination of blood B- and L- catepsine-like activity can be recommended for obtaining additional information at diagnosis thyroid diseases.

Evaluation of FAK and Src expression in human benign and malignant thyroid lesions.

Focal Adhesion Kinase (FAK) and Src have been reported to regulate tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate by immunohistochemistry the clinical significance of FAK and Src expression in 108 patients with benign and malignant thyroid lesions. Total FAK expression provided a distinct discrimination between malignant and benign (p = 0.00001), as well as between papillary carcinoma and hyperplastic nodules thyroid lesions (p = 0.00005), being also associated with follicular cells' proliferative capacity (p = 0.0003). In malignant thyroid lesions, total FAK expression was associated with tumor size (p = 0.0455), and presence of capsular (p = 0.0102) and lymphatic (p = 0.0173) invasion. Total Src expression was borderline increased in cases of papillary carcinoma compared to hyperplastic nodules (p = 0.0993), being also correlated with tumor size (p = 0.0169). FAK and Src expression was ascribed to a significant extent to the phosphorylated forms of the enzymes, which provided a better discrimination between malignant and benign thyroid lesions. The current data revealed that FAK and to a lesser extent Src expression could be considered of clinical utility in thyroid neoplasia with potential use as therapeutic targets.

Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study.

An increased frequency of skewed X-chromosome inactivation (XCI) is found in clinically overt autoimmune thyroid disease (AITD) compared with controls. Whether skewed XCI is involved in the pathogenesis of autoantibodies to thyroid peroxidase (TPOAb) in euthyroid subjects is unknown. To examine the impact of XCI on the serum concentration of TPOAb, we studied whether within-cohort and within-twin-pair differences in XCI are associated with differences in serum concentrations of TPOAb. A total of 318 euthyroid female twin individuals distributed in 159 pairs were investigated. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. TPOAb concentrations were measured using a solid-phase time-resolved fluoroimmunometric assay. Overall (within cohort), there was a significant association between XCI and serum concentrations of TPOAb; regression coefficient (beta)=1.45 (95% confidence interval, 0.52-2.38), P=0.003. The association remained significant in the within-pair analysis; beta=1.74 (0.79-2.69), P<0.001. The relationship was nonsignificant within the 82 monozygotic pairs (beta=0.57 (-0.78-1.92), P=0.405), whereas the association was significant in the 77 dizygotic pairs (beta=2.17 (0.81-3.53), P=0.002). This preliminary finding of a significant association between TPOAb concentrations and XCI within cohort and within dizygotic but not within monozygotic twin pairs may indicate that XCI per se does not have a major role in the pathogenesis of TPOAb. More likely, XCI and TPOAb are influenced by shared genetic determinants.

Protective role of melatonin against the mercury induced oxidative stress in the rat thyroid.

Present study investigated the protective role of melatonin (MLT, 5mg/kg body wt., ip) against the long term effects of mercuric chloride (MC; 2 and 4 mg/kg body wt., po) in the thyroid gland of the rats through certain antioxidative indices like superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione (GSH), catalase (CAT) and lipid peroxidation (LPO), other biochemical parameters such as succinate dehydrogenase (SDH), adenosine triphosphatase (ATPase), acid phosphatase (ACPase) and alkaline phosphatase (ALPase) were also measured. Antioxidative enzymes and other parameters showed a significant reduction while LPO and mercury levels increased significantly in a dose dependent manner in MC treated animals as compared to control groups. Co-treatment with MLT revealed no significant effect on antioxidative and metabolic indices in the thyroid gland of rats. The results of present study thus strongly suggest that mercury affected antioxidant defense system and other metabolic enzymes of thyroid. Co-administration of melatonin exerted a protective effect against mercury induced endocrine toxicity.

Activation of dual oxidases Duox1 and Duox2: differential regulation mediated by camp-dependent protein kinase and protein kinase C-dependent phosphorylation.

Dual oxidases were initially identified as NADPH oxidases producing H(2)O(2) necessary for thyroid hormone biosynthesis. The crucial role of Duox2 has been demonstrated in patients suffering from partial iodide organification defect caused by bi-allelic mutations in the DUOX2 gene. However, the Duox1 function in thyroid remains elusive. We optimized a functional assay by co-expressing Duox1 or Duox2 with their respective maturation factors, DuoxA1 and DuoxA2, to compare their intrinsic enzymatic activities under stimulation of the major signaling pathways active in the thyroid in relation to their membrane expression. We showed that basal activity of both Duox isoenzymes depends on calcium and functional EF-hand motifs. However, the two oxidases are differentially regulated by activation of intracellular signaling cascades. Duox1 but not Duox2 activity is stimulated by forskolin (EC(50) = 0.1 microm) via protein kinase A-mediated Duox1 phosphorylation on serine 955. In contrast, phorbol esters induce Duox2 phosphorylation via protein kinase C activation associated with high H(2)O(2) generation (phorbol 12-myristate 13-acetate EC(50) = 0.8 nm). These results were confirmed in human thyroid cells, suggesting that Duox1 is also involved in thyroid hormonogenesis. Our data provide, for the first time, detailed insights into the mechanisms controlling the activation of Duox1-2 proteins and reveal additional phosphorylation-mediated regulation.

A novel mutation in the DNASE1 gene is related with protein instability and decreased enzyme activity in thyroid autoimmunity.

A deficiency in the DNase enzyme, and thereby, a failure to remove DNA from nuclear antigens promotes disease susceptibility to autoimmune disorders. This study examined in patients with autoimmune thyroid disease (AITD) whether a reduced DNase activity is associated with sequence variations in the DNASE1 gene. The study included 18 patients with AITD, their 10 relatives, and 111 unrelated healthy controls. Serum DNase activity was determined with a validated, standardized enzyme-linked-immunosorbent assay. The promoter and all nine exons of the DNASE1 gene were sequenced. Heat stability of DNase enzyme was tested. In patients with AITD, a novel mutation (1218G>A, exon 5) and multiple polymorphisms were identified in the DNASE1 gene. The allele frequency of the mutation was increased in patients vs controls (P=0.001). In contrast to controls, the novel mutation was present in all five members of a family with AITD showing decreased DNase activity. The mutation resulted in the replacement of highly conserved valine with methionine at amino acid position 89 of the DNase enzyme. It was related to lowered heat stability and lowered activity of the enzyme. The identified new mutation and numerous polymorphisms, noted for the first time in AITD patients, may alter transcription and translation of the DNASE1 gene, thereby decreasing the stability and activity of the corresponding enzyme.

[Mechanism of apoptosis in the thyroid cells in thyroid pathology].

The literature data and the results of own examinations concerning the changes in programmed cell death processes of goiter alterated thyroid tissue in patients with euthyroid or toxic goiter and also the extranodular tissue of the gland in the presence of pathological changes in it (the pronounced hyperplastic process, sclerotic and/or dystrophic changes, lymphoid infiltration, chronic or autoimmune thyroiditis) were analyzed. It has been shown that the significant changes in the processes ofmitochondria and postmitochondria regulation and apoptosis realization are occurred under thyroid pathology. The character and the degree of disorders in the apoptosis mitochondria mechanisms and the activity of destructive processes in the patient thyroid cells are dependent on many factors such as the type of pathology, the severity of its occurrence, the peculiarities of tissue follicular structure and the patient sex. Obtained resistance of the apoptosis mitochondria mechanisms can play an important role in the pathogenesis of thyroid nodular pathology or in the development of inflammatory and autoimmune processes.

Phosphodiesterase 8B gene variants are associated with serum TSH levels and thyroid function.

Thyroid-stimulating hormone (TSH) controls thyroid growth and hormone secretion through binding to its G protein-coupled receptor (TSHR) and production of cyclic AMP (cAMP). Serum TSH is a sensitive indicator of thyroid function, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over a life span. By genotyping 362,129 SNPs in 4,300 Sardinians, we identified a strong association (p = 1.3 x 10(-11)) between alleles of rs4704397 and circulating TSH levels; each additional copy of the minor A allele was associated with an increase of 0.13 muIU/ml in TSH. The single-nucleotide polymorphism (SNP) is located in intron 1 of PDE8B, encoding a high-affinity cAMP-specific phosphodiesterase. The association was replicated in 4,158 individuals, including additional Sardinians and two genetically distant cohorts from Tuscany and the Old Order Amish (overall p value = 1.9 x 10(-20)). In addition to association of TSH levels with SNPs in PDE8B, our genome scan provided evidence for association with PDE10A and several biologically interesting candidates in a focused analysis of 24 genes. In particular, we found evidence for association of TSH levels with SNPs in the THRB (rs1505287, p = 7.3 x 10(-5)), GNAQ (rs10512065, p = 2.0 x 10(-4)), TG (rs2252696, p = 2.2 x 10(-3)), POU1F1 (rs1976324, p = 3.9 x 10(-3)), PDE4D (rs27178, p = 8.3 x 10(-3)), and TSHR (rs4903957, p = 8.6 x 10(-3)) loci. Overall, the results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. PDE8B may thus provide a candidate target for the treatment of thyroid dysfunction.

[The complex hygienic characteristics preventive iodine deficiency in population of Siberia].

In the research we used hygienic, social-hygienic and statistical methods. The study showed that 58,3-88,1% of examined children in Siberia, in the north, south and in the center of Krasnoyarsk territory suffer from iodine deficiency. There was no difference iodine content medians between boys and girls. Preventive iodine deficiency which arise at absence or decrease in food and are the reason of many illness, is important and till now a unresolved problem of Krasnoyarsk areas.

PTPN22: its role in SLE and autoimmunity.

A functional variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22) has recently been shown to be associated with multiple autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, type 1 diabetes, and autoimmune thyroid disease. In this review, we discuss the structure and function of this gene and its disease-associated polymorphisms. In addition, we review the studies investigating the association between this gene and SLE, along with other autoimmune diseases.

Characterisation of DEHAL1 expression in thyroid pathologies.

UNLABELLED: Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide in the human thyroid. The aim of the present study was (I) to investigate whether DEHAL1 expression is different in differentially functioning thyroid pathologies and (II) to evaluate DEHAL1 as a possible marker of thyroid cell differentiation. DESIGN AND METHODS: Real-time PCR for DEHAL1 and its isoform DEHAL1B was performed in a series of 105 thyroid specimens, including toxic thyroid nodules (TTN), Graves' disease (GD) thyroids, benign cold thyroid nodules (CTN), normal thyroid tissues and thyroid cancers (follicular thyroid carcinomas (FTC), papillary thyroid carcinomas (PTC), partially differentiated thyroid cancers (PDTC) and anaplastic thyroid carcinomas (ATC)). In addition, DEHAL1 protein expression was studied by immunohistochemistry in 163 benign and malignant thyroid pathologies and normal thyroids. RESULTS: (I) The highest DEHAL1 mRNA levels were found in GD thyroids, while downregulation of DEHAL1 and DEHAL1B mRNA occurred in PTC and ATC (P<0.001 and <0.05 respectively); (II) DEHAL1 protein was overexpressed in TTNs and GD thyroids with predominant apical staining in all samples; (III) a weaker and patchy staining pattern was found in CTNs and normal thyroids; (IV) in differentiated thyroid cancers (FTC and PTC), a diffuse cytoplasmic DEHAL1 expression was found; and (V) in PDTC and ATC, DEHAL1 expression was faint or absent. CONCLUSION: Upregulation of DEHAL1 protein expression and sublocalisation of DEHAL1 at the apical cell pole in TTNs and GD thyroids is consistent with increased thyroid hormone turnover during thyrotoxicosis. Diffuse cytoplasmatic localisation or downregulation of DEHAL1 expression in thyroid cancers suggests alteration or loss of DEHAL1 function during thyroid cell dedifferentiation.

Thyroid peroxidase immunohistochemistry in differential diagnosis of thyroid tumors.

Thyroperoxidase (TPO) is a thyroid-specific enzyme expressed by differentiated thyroid cells. Initial immunohistochemical studies claimed that TPO expression, detected by the monoclonal antibody mAb 47, may be a potentially important diagnostic tool in differentiating malignant from benign lesions. However, some recent studies have failed to reproduce the earlier results, suggesting the limitations for TPO immunohistochemistry. To assess these observations we have evaluated the immunohistochemical expression of TPO in thyroid tissue from 215 patients. The studied material included 87 nonmalignant thyroid lesions and 128 thyroid carcinomas. TPO expression was investigated using newly available mAb 47 and staining of less than 80% of the follicular cells/specimen as the threshold indicating a malignant lesion. We found that TPO had a sensitivity of 89.9% for cancer and a specificity of 64.4% for nonmalignant lesions, showing that it does not give a sufficient degree of diagnostic certainty that the lesion is benign. In addition, the variability in the degree of TPO expression found within and between follicular carcinomas, and the significant number of benign adenomas having similar immunostaining patterns, assured us that TPO immunostaining is not sufficiently discriminatory in the differential diagnosis of thyroid cancer versus benign lesions.

Prevalence of abnormal thyroid stimulating hormone and thyroid peroxidase antibody-positive results in a population of pregnant women in the Samara region of the Russian Federation.

Undiagnosed thyroid disease is a common problem with significant public health implications. This is especially true during pregnancy, when the health of both the mother and the developing child can be adversely affected by abnormal maternal thyroid function. Measurement of serum thyroid stimulating hormone (TSH) and thyroid peroxidase antibodies (TPO-Ab) are two common ways to assess maternal thyroid status. The objective of our study was to determine the prevalence of abnormal TSH and TPO-Ab tests in a population of pregnant women in the Samara region of the Russian Federation. Serum samples were obtained from 1588 pregnant women as part of their routine antenatal care. TSH and TPO-Ab were measured, and trimester-specific reference values for TSH (2.5-97.5 percentiles) were calculated using TPO-Ab-negative women. TSH results outside these ranges were considered abnormal; TPO-Ab levels outside the manufacturer's reference range (>12 IU/mL) were considered abnormal. Overall, the prevalence of abnormal results was 6.3% for TSH and 10.7% for TPO-Ab. High TSH (>97.5 trimester-specific percentile) and TPO-Ab-positive results were most common in the first trimester (5.7% and 13.8%, respectively). TSH levels were associated with gestational age and TPO-Ab status, and with maternal age in TPO-Ab-negative women. TPO-Ab status was associated with both maternal and gestational age. Women with TSH >2.5 mIU/L had a significantly increased risk of being TPO-Ab-positive, and this risk increased with age. Based on our data, we conclude that abnormal TSH and TPO-Ab are common in pregnant women of the Samara region. Given the association of thyroid dysfunction to adverse pregnancy outcomes, screening of this population for abnormal thyroid function should be considered.

Human thyroid phenol sulfotransferase enzymes 1A1 and 1A3: activities in normal and diseased thyroid glands, and inhibition by thyroid hormones and phytoestrogens.

Sulfation by sulfotransferase enzymes (SULTs) is an important pathway for the metabolism of thyroid hormones and phytoestrogens. Intrathyroidal SULTs may contribute to the processing of thyroid hormones for the reutilization of iodide. SULT1A1 and SULT1A3 activities were identified in normal and diseased human thyroid glands. Biochemical properties that included apparent K(m) values, thermal stabilities, and responses to inhibitors were characterized in a normal human thyroid high speed supernatant pool. Apparent K(m) values for SULT1A1 and SULT1A3 activities with the model substrates p-nitrophenol and dopamine were 0.58 +/- 0.04 and 11.3 +/- 1.3 microm, respectively. Activities of SULT1A1 and SULT1A3 determined in individual normal thyroid (n = 35), nodular goiter (n = 26), and autoimmune thyroid disease (n = 25) glands were 0.34 +/- 0.06, 0.52 +/- 0.09, and 0.82 +/- 0.19 U/mg protein for SULT1A1, respectively, and 0.22 +/- 0.04, 0.21 +/- 0.04, and 0.48 +/- 0.11 U/mg protein for SULT1A3, respectively. Both SULT activities in autoimmune thyroid disease glands were significantly higher than those in normal thyroids. Only 3,3'-diiodothyronine (3,3'-T(2)) and the phytoestrogen daidzein served as substrates for the normal thyroid SULT activities, yet each thyroid hormone and phytoestrogen tested were found to inhibit thyroid SULT1A1 and SULT1A3 activities. The preference of thyroid gland SULT activities for 3,3'-T(2) suggests that sulfation may enhance degradation of intrathyroidal 3,3'-T(2) for iodide reutilization. Inhibition of these SULT activities by the exogenous phytoestrogens daidzein and genistein, with a potential decrease in iodide reutilization, presents another mechanism through which these compounds may adversely affect human thyroid function.

Activities of UDP-glucuronyltransferase, beta-glucuronidase and deiodinase types I and II in hyper- and hypothyroid rats.

We have investigated the hypothesis that uridine 5'-diphosphate (UDP)-glucuronyltransferases (UGTs) and beta-glucuronidase are jointly involved in a mechanism for the storage and mobilization of iodothyronine metabolites in liver, kidney, heart and brain. Specifically, we predicted UGT activities to decrease and increase respectively, and beta-glucuronidase activity to increase and decrease respectively in hypo- and hyperthyroidism. To this end we have studied the effects of thyroid status on the activities of different enzymes involved in thyroid hormone metabolism in liver, kidney, heart and brain from adult rats with experimentally induced hypo- and hyperthyroidism. We used whole organ homogenates to determine the specific enzyme activities of phenol- and androsteron-UGT, beta-glucuronidase, as well as iodothyronine deiodinase types I and II. Deiodinase type I activities in liver and kidney were decreased in hypothyroid animals and, in liver only, increased in hyperthyroidism. Deiodinase type II activity was increased in hyperthyroid rat kidney only. Interestingly, in the heart, deiodinase type I-specific activity was increased fourfold, although the increase was not statistically significant. Cardiac deiodinase type I activity was detectable but not sensitive to thyroid status. Hepatic phenol-UGT as well as androsteron-UGT activities were decreased in hypothyroid rats, with specific androsteron-UGT activities two to three orders of magnitude lower than phenol-UGT activities. Both UGT isozymes were well above detection limits in heart, but appeared to be insensitive to thyroid status. In contrast, cardiac beta-glucuronidase activity decreased in hypothyroid tissue, whereas the activity of this enzyme in the other organs investigated did not change significantly. In summary, cardiac beta-glucuronidase, albeit in low levels, and hepatic phenol-UGT activities were responsive only to experimental hypothyroidism. Although a high basal activity of the pleiotropic beta-glucuronidase masking subtle activity changes in response to thyroid status cannot be ruled out, we conclude that hepatic, renal and cardiac UGT and beta-glucuronidase activities are not regulated reciprocally with thyroid status.