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Biomedical subjects

R Docter

Publications and source records attributed to R Docter.

At least 73 records · Page 4Linked to original sources
PubMed1985

Further studies on thyroid growth-stimulating immunoglobulins in euthyroid nonendemic goiter.

Sixty-two consecutive patients with sporadic euthyroid goiter (57 women and 5 men) from noniodine-deficient areas, including 15 patients with diffuse goiter, 39 patients with multinodular goiter, and 8 patients with a single nodule, were studied for the presence of serum thyroid growth-stimulating immunoglobulins (TGI) by the ultrasensitive cytochemical bioassay based on DNA cytophotometry (Feulgen-cytochemical bioassay). Using strictly specified conditions, 43 patients (67%) were positive. Values tended to be high in diffuse goiter, nodular goiters reccuring after partial thyroidectomy, and those with recent growth. Thirty-seven individual immunoglobulin (Ig)-rich fractions obtained by ammonium-sulfate precipitation from 20 normal subjects, 13 atrophic thyroiditis patients, and 4 dyshormonogenetic goiter patients were tested similarly, and only 3 gave positive growth assays. These results lend further support to our concept that a majority of patients with sporadic nontoxic simple goiters have a variant of thyroid autoimmune diseases separate from lymphocytic thyroiditis. With regard to assays thought to reflect activities of TSH receptor antibodies, none of 20 tested Ig preparations stimulated thyroid cAMP production. The TSH binding inhibition assay gave weak positive activity, but failed to correlate with either TGI or TSH unresponsiveness to TRH. These findings suggest that sporadic goiter TGI is not directed to the TSH-binding site. Dose-response studies performed with Igs of patients with nontoxic goiters and with human TSH standard and goitrous hyperthyroid Graves Igs as controls all revealed bell-shaped responses. Similar maximal values were reached regardless of the growth stimulus applied. However, approximately 10 times more Ig was needed to reach maximal responsiveness in sporadic goiter than in goitrous Graves' disease (i.e. 125-500 micrograms vs. 15-125 micrograms Ig/ml culture fluid). The optimal dose of human TSH ranged from 0.01-1.0 microU/ml. The assays in the present series of the 62 consecutive patients with nontoxic diffuse or nodular goiter were all carried out with a fixed amount of 125 micrograms Ig/ml and considering a value above 5% of cells in the S-phase as a positive assay. Some Ig preparations negative for TGI at this concentration may contain TGI when tested using other doses, and these are a prerequisite to assess the potency of growth antibodies in individual patients.

Adolescent↗
PubMed1984

Inactivation and affinity-labeling of rat liver iodothyronine deiodinase with N-bromoacetyl-3,3',5-triiodothyronine.

The thyroid hormone derivative N-bromoacetyl-3,3',5-triiodothyronine (BrAcT3) acts as an active site-directed inhibitor of rat liver iodothyronine deiodinase. Lineweaver Burk analysis of enzyme kinetic measurements showed that BrAcT3 is a competitive inhibitor of the 5'-deiodination of 3,3',5'-triiodothyronine (rT3) with an apparent Ki value of 0.1 nM. Preincubations of enzyme with BrAcT3 indicated that inhibition by this compound is irreversible. The inactivation rate obeyed saturation kinetics with a limiting inactivation rate constant of 0.35 min-1. Substrates and substrate analogs protected against inactivation by BrAcT3. Covalent incorporation of 125I-labeled BrAcT3 into "substrate-protectable" sites was proportional to the loss of deiodinase activity. The results suggest that BrAcT3 is a very useful affinity label for rat liver iodothyronine deiodinase.

Affinity Labels↗
PubMed1984

Modification of rat liver iodothyronine 5'-deiodinase activity with diethylpyrocarbonate and rose bengal; evidence for an active site histidine residue.

Iodothyronine 5'-deiodinase activity of rat liver microsomes was rapidly and completely lost by treatment with diethylpyrocarbonate (DEP) and by photo-oxidation with Rose Bengal (RB). In both cases inactivation followed pseudo first order reaction kinetics. Inactivation by DEP was diminished in the presence of substrate or competitive inhibitors, and was reversed by hydroxylamine treatment. In addition to photo-oxidation, deiodinase activity was also inhibited by RB in the dark. This inhibition was reversible and competitive with substrate (Ki 60 nM). These results suggest the location of an essential histidine residue at or near the active site of rat liver iodothyronine deiodinase.

Animals↗
PubMed1984

Anti-tumor and endocrine effects of chronic LHRH agonist treatment (Buserelin) with or without tamoxifen in premenopausal metastatic breast cancer.

Seventeen premenopausal women with metastatic breast cancer were treated with the potent Luteinizing Hormone Releasing Hormone (LHRH) agonist Buserelin as a first-line agent. Twelve patients (group A) were treated with Buserelin alone and five patients (group B) with the combination of Buserelin and tamoxifen from the start of treatment. In nine patients of group A tamoxifen was added to Buserelin later on because of tumor progression or recurrent peaks of plasma estradiol (E2). Chronic intranasal therapy with Buserelin alone, preceeded by parenteral administration, caused an objective remission in four patients (2 X C.R., 2 X P.R.) and stable disease in four further patients without causing side effects. The longest duration of response until now is more than 29 months. After addition of tamoxifen a partial response occurred in two more patients of group A. Anovulation with suppressed progesterone secretion was reached in all patients treated with Buserelin alone, but transient peaks of E2 occurred in the majority (60%) of the patients. Addition of tamoxifen to Buserelin treatment caused disappearance of E2 peaks in 2 patients, but also reappearance of progesterone secretion with recurring E2 peaks in 3 other patients; in one case hyperstimulation of the ovaries was observed without progression of tumor growth. In group B only one woman showed a complete castration effect, while in four patients progesterone secretion was not (completely) suppressed. In two of these five patients an objective response occurred. In conclusion, Buserelin appears effective in the treatment of premenopausal women with metastatic breast carcinoma, but with the regimen used close control of endocrine parameters is necessary because of the variation in hormonal response with a risk of (hyper)stimulation of the ovaries, especially during combination therapy with tamoxifen.

Adult↗
PubMed1984

Treatment of metastatic breast cancer patients with different dosages of megestrol acetate; dose relations, metabolic and endocrine effects.

Megestrol acetate (MA) is of therapeutic value in breast cancer patients. This study was designed to evaluate the effects of different dosages of MA on endocrine events potentially influenced by the drug in relation to plasma level of MA and clinical effects in patients with advanced breast cancer. Eighteen postmenopausal patients were randomly distributed over six groups to receive daily 90, 180 or 270 mg of MA (niagestin) orally in a cross-over study consisting of 3 periods of 6 weeks. Complete remission was observed in 1 patient, partial remission in 9, no change in 4 and failure in 4 patients. During the 18 weeks of treatment plasma levels of MA gradually increased, irrespective of the dose administered. Significant rises of the basal and TRH-stimulated plasma PRL and basal insulin levels were observed, whereas LH and FSH, estradiol, SHBG and the pituitary-adrenal axis were suppressed. None of these metabolic effects showed a correlation with the clinical response. We concluded that treatment of metastatic breast cancer with 180 mg MA/day is effective and causes minimal adverse effects.

Administration, Oral↗
PubMed1984

Metabolism of 3,3'-diiodothyronine in rat hepatocytes: interaction of sulfation with deiodination.

Production of 3,3'-diiodothyronine (3,3'-T2) is an important step in the peripheral metabolism of thyroid hormone in man. The rapid clearance of 3,3'-T2 is accomplished to a large extent in the liver. We have studied in detail the mechanisms of this process using monolayers of freshly isolated rat hepatocytes. After incubation with 3,[3'-125I]T2, chromatographic analysis of the medium revealed two major metabolic routes: outer ring deiodination and sulfation. We recently demonstrated that sulfate conjugation precedes and in effect accelerates deiodination of 3,3'-T2. In media containing different serum concentrations the cellular clearance rate was determined by the nonprotein-bound fraction of 3,3'-T2. At substrate concentrations below 10(-8) M 125I- was the main product observed. At higher concentrations deiodination became saturated, and 3,3'-T2 sulfate (T2S) accumulated in the medium. Saturation of 3,3'-T2 clearance was found to occur only at very high (greater than 10(-6)M) substrate concentrations. The sulfating capacity of the cells exceeded that of deiodination by at least 20-fold. Deiodination was completely inhibited by 10(-4) M propylthiouracil or thiouracil, resulting in the accumulation of T2S while clearance of 3,3'-T2 was little affected. No effect was seen with methimazole. Hepatocytes from 72-h fasted rats showed a significant reduction of deiodination but unimpaired sulfation. Other iodothyronines interfered with 3,3'-T2 metabolism. Deiodination was strongly inhibited by 2 microM T4 and rT3 (80%) but little by T3 (15%), whereas the clearance of 3,3'-T2 was reduced by 27% (T4 and rT3) and 12% (T3). It is concluded that the rapid hepatic clearance of 3,3'-T2 is determined by the sulfate-transferring capacity of the liver cells. Subsequent outer ring deiodination of the intermediate T2S is inhibited by propylthiouracil and by fasting, essentially without an effect on overall 3,3'-T2 clearance.

Animals↗
PubMed1984

Sulfation facilitates hepatic deiodination of iodothyronines.

The metabolism of 3,3',5'-triiodothyronine (rT3), 3,3'-5-triiodothyronine (T3) and 3,3'-diiodothyronine (3,3'-T2) by isolated rat hepatocytes in primary culture was studied by radioimmunoassay and by Sephadex LH-20 chromatography. The first step in the metabolism of rT3 is outer ring deiodination which is inhibited by thiouracil. In incubations with outer ring-labeled 3,3'-T2 or T3 the main products observed are iodide in the absence of thiouracil and the sulfate conjugates in the presence of the inhibitor. Rates of sulfation and iodide formation were both determined by the phenol sulfotransferase activity of the cells. Inner ring deiodination of T3 sulfate and subsequent outer ring deiodination of 3,3'-T2 sulfate by rat liver microsomes are much faster than the corresponding reactions for the non-conjugated iodothyronines. The results strongly suggest that sulfation precedes and in effect accelerates hepatic deiodination of T3 and 3,3'-T2.

Animals↗
PubMed1982

Hyperthyroxinaemia due to decreased peripheral triiodothyronine production.

Two patients, a boy of 8 and a women of 60 years of age, had higher than normal levels of serum total thyroxine (T4), free T4, (FT4), FT4 index, and reverse triiodothyronine, but normal serum triiodothyronine (T3) levels. The pituitary-thyroid axis could be normally stimulated by thyrotropin-releasing hormone, suggesting euthyroidism at the pituitary level. High levels of serum T4-binding globulin decreased during T3 treatment in the boy. Studies show that in these patients a raised serum FT4 is necessary to produce in the peripheral tissues sufficient amounts of T3 for biological action. Two possible mechanisms for a basic defect underlying this newly recognised syndrome are proposed: inhibition of T4 transport into tissue cells and reduced intracellular 5'-deiodinase activity catalysing T4 to T3 conversion.

Child↗
PubMed1982

Evidence that the uptake of tri-iodo-L-thyronine by human erythrocytes is carrier-mediated but not energy-dependent.

We investigated 3,3',5-tri-iodo-l-thyronine transport by human erythrocytes and by ;ghosts' prepared from these cells. Uptake of tri-iodothyronine by erythrocytes at 37 degrees C was time-dependent with a maximum reached after 60min. Tracer analysis after incubation for 1min revealed only one saturable binding site, with K(m) 128+/-19nm (mean+/-s.e.m.; n=7) and V(max.) 4.6+/-0.7pmol of tri-iodothyronine/min per 6x10(7) cells. After 10min incubation K(m) 100+/-16nm (n=10) was found with V(max.) 7.7+/-1.2pmol of tri-iodothyronine/10min per 6x10(7) cells. At 0 degrees C the uptake system is still active, with K(m) 132+/-26nm and V(max.) 1.8+/-0.3pmol of tri-iodothyronine/10min per 6x10(7) cells. The V(max.) with intact cells is 5-fold greater than the V(max.) with membranes derived from the same amount of cells when uptake studies are performed in media with similar free tri-iodothyronine concentrations. This indicates that at least 80% of tri-iodothyronine taken up by the intact erythrocytes enters the cell. This saturable uptake system can be inhibited by X-ray-contrast agents in a dose-dependent fashion. (+/-)-Propranolol, but not atenolol, has the same effect, indicating that the membrane-stabilizing properties of (+/-)-propranolol are involved. Furthermore, there is no inhibition by ouabain or vanadate, which indicates that tri-iodothyronine uptake is not dependent on the activity of Na(+)+K(+)-dependent adenosine triphosphatase. We have prepared erythrocyte ;ghosts', resealed after 2.5min with 0mm-, 2mm- or 4mm-ATP inside. Inclusion of ATP and integrity of the membrane of the erythrocyte ;ghosts' were verified on the basis of an ATP-concentration-dependent functioning of the Ca(2+) pump. No difference was found in the uptake of tri-iodothyronine by erythrocyte ;ghosts' with or without ATP included, indicating that uptake of tri-iodothyronine is not ATP-dependent. The following conclusions are drawn. (1) Tri-iodothyronine enters human erythrocytes. (2) There is only one saturable uptake system present for tri-iodothyronine, which is neither energy (i.e. ATP)-dependent nor influenced by the absence of an Na(+) gradient across the plasma membrane. This mode of uptake of tri-iodothyronine by human erythrocytes is in sharp contrast with that of rat hepatocytes, which uptake system is energy-dependent and ouabain-sensitive [Krenning, Docter, Bernard, Visser & Hennemann (1978) FEBS Lett.91, 113-116; Krenning, Docter, Bernard, Visser & Hennemann (1980) FEBS Lett.119, 279-282]. (3) X-ray-contrast agents inhibit tri-iodothyronine uptake by erythrocytes in a similar fashion to that by which they inhibit the uptake of tri-iodothyronine by rat hepatocytes [Krenning, Docter, Bernard, Visser & Hennemann (1982) FEBS Lett.140, 229-233].

Adenosine Triphosphate↗
PubMed1981

Characteristics of active transport of thyroid hormone into rat hepatocytes.

Thyroid hormone uptake into primary cultured rat hepatocytes was studied using 1-min incubations with radio-iodine-labelled iodothyronines. (1) Uptake of thyroxine indicates two saturable sites with apparent Km values of 1.2 nM and 1.0 microM, and non-saturable uptake. Similar kinetics of triiodothyronine uptake have been observed. (2) The high-affinity systems of both hormones are energy-dependent (i.e., inhibited by KCN and oligomycin). It is postulated that these systems represent active transport of thyroid hormone into the cell. (3) Analysis of mutual inhibition by the substrates for the triiodothyronine and thyroxine transport systems indicates that triiodothyronine and thyroxine cross the cell membrane via separate transport systems. (4) Preincubation with ouabain resulted in a decrease in uptake of both triiodothyronine and thyroxine, suggesting that a sodium gradient is essential for this transport.

Animals↗
PubMed1981

Inherited thyroxine excess: a serum abnormality due to an increased affinity for modified albumin.

Further analysis of sera from euthyroid subjects with dominantly-inherited, elevated serum total thyroxine (T4) and free T4 index but with normal free T4 levels was performed as an extension of a previous study (Hennemann et al., 1979a). Scatchard analysis and isoelectric focusing of whole sera and purified serum fractions suggest that this T4 excess is due to increased T4 binding by modified serum albumin. Recognition of this syndrome and appreciation that the free T4 index does not reflect the free T4 levels is important to protect patients from the consequences of an incorrect diagnosis of thyrotoxicosis.

Humans↗