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PubMed1992

Characterization of cytoplasmic T3 binding sites by adsorption to hydroxyapatite: effects of drug inhibitors of T3 and relationship to glutathione-S-transferases.

To facilitate studies of thyroid hormone (T3) binding to cytoplasmic proteins, we prepared monkey (M. fascicularis) liver cytosol (100,000g supernatant) and examined T3 binding using hydroxyapatite (HAP) separation. HAP adsorbs cytoplasmic and nuclear binding sites but not serum T4 binding proteins. Cytosol was incubated with [125I]T3 for 30 min at 4 degrees C and separated by adding an equal volume of HAP (15 g/100 mL). After a further incubation of 10 min, the HAP pellet was washed three times in buffer containing Triton X-100, 0.5%. With this method, a single class of T3 binding site was observed with Kd 15.8 +/- 1.2 nM, concentration 0.62 +/- 0.17 pmol/mg protein (n = 3, mean +/- SD). We used this assay to assess potential drug inhibitors of cytoplasmic binding and to evaluate the proposal that glutathione-S-transferases (GST) and cytoplasmic T3 binding proteins are identical. Displacement of [125I]T3 by unlabeled iodothyronines relative to T3 (100) was T4 58, Triac 7, rT3 7, Tetrac less than or equal to 1. This hierarchy indicates that this binding site is distinct from nuclear or serum binding sites. T3 binding was displaceable by nonsteroidal anti-inflammatory drugs (NSAID) and nonbile acid cholephils (NBAC). Half-inhibitory concentrations (microM, mean +/- SD, n greater than or equal to 3) were diclofenac 4.9 +/- 1.3, mefenamic acid 13.6 +/- 0.6, bromosulphthalein 45 +/- 3, iopanoic acid approximately 200. Amiodarone and furosemide were inactive up to 100 microM. No displacement was observed with cortisol or the bile acid taurocholate, up to 100 microM. Dithiothreitol, 5 mM, did not change binding affinity or capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1983

Depletion of hepatic uridine diphosphoglucuronic acid decreases the biliary excretion of drugs.

Hepatic levels of uridine diphosphoglucuronic acid (UDPGA) in rats decreased substantially (greater than 80%) 40 min after galactosamine (GAL) (600 mg/kg i.p.) or after 1 hr of diethyl ether (DE) narcosis. Biliary excretion of several cholephils requiring glucuronidation before excretion was reduced by GAL 76, 62, 92, 90 and 97% for bilirubin, diethylstilbestrol, iopanoic acid, phenolphthalein and valproic acid, respectively. GAL treatment caused delayed plasma clearances of the parent compounds and reductions in plasma concentrations and biliary excretions of glucuronide conjugates. The degree of this reduction was related to the maximal excretion rate of the individual compounds. For phenolphthalein glucuronide and phenol-3,6-dibromphthalein disulfonate, which do not undergo conjugation, GAL had no effect on their biliary excretion. DE-induced UDPGA depletion had no effect on phenolphthalein glucuronide excretion but reduced that of phenol-3,6-dibromphthalein disulfonate 25%. DE did not affect the plasma elimination or biliary secretion of phenolphthalein. Of the other cholephils requiring conjugation, DE reduced the excretion of bilirubin, diethylstilbestrol, iopanoic acid and valproic acid by 41, 29, 76 and 28%, respectively. DE decreased the plasma elimination of the parent compounds and the appearance of the conjugates in both plasma and bile. Reduction of glucuronide excretion into bile was less pronounced at higher doses of the cholephilic anions. Neither treatment reduced in vitro hepatic UDP-glucuronosyltransferase activity toward these substrates or substantially altered extrahepatic UDPGA concentrations. Thus, both GAL and DE decreased UDPGA to similar concentrations, but the biliary excretion of compounds requiring glucuronidation before secretion was depressed to a greater extent by GAL.

Animals↗
PubMed1984

The effects of propylthiouracil, iodothyronines, and other agents on thyroid hormone metabolism in human placenta.

Human and rat placental homogenates contain inner ring deiodinase activity (PT4ase) towards T4 and T3. This activity may decrease the transfer of T4 and T3 across the placenta and influence thyroid hormone disposal in the fetal circulation. Data are now presented on human PT4ase in subcellular fractions, the Km of human PT4ase, and the effects of drugs and other compounds on human and rat PT4ase. The specific activity (nanograms of rT3 produced per min/mg protein) of each fraction of human placenta was as follows: nuclear, 0.07; mitochondrial, 0.15; lysosomal, 0.19; microsomal, 1.30; and cytosol, 0.01. The apparent Michaelis-Menton (Km) for PT4ase in human placental microsomes was 1.2 X 10(-7) M. T3, 3,3'-diiodothyronine, iopanoic acid, iodoacetic acid, diamide, and propranolol all exhibited dose-dependent inhibition of human and rat PT4ase when tested in the presence of 10 mM dithiothreitol (DTT). Propylthiouracil did not inhibit PT4ase at 10 mM DTT, but when the DTT concentration was lowered to 0.25 mM, up to 71% inhibition was noted. Many drugs, as noted in other organs with respect to outer and inner ring iodothyronine deiodinases, inhibited human PT4ase. These studies may be relevant to the practice of administering propylthiouracil, propranolol, and iopanoic acid to pregnant women.

Animals↗
PubMed1981

Tyropanoate cholecystography early in the course of acute pancreatitis.

Oral cholecystography (OCG) has traditionally been delayed until several weeks after hospitalization for pancreatitis because of the putative frequent poor visualization during the acute episode. Recently, OCG with iopanoic acid was reported successful in most patients with acute pancreatitis soon after resumption of a solid diet. We evaluated OCG with sodium tyropanoate, a pharmacokinetically different contrast material, in 30 hospitalized patients with pancreatitis before resumption of solid food. It accurately evaluated the gallbladder in 24 cases (80%). Abnormal liver function tests, including mild hyperbilirubinemia, did not interfere with the examination. Consequently, 1) tyropanoate OCG adequately opacifies the gallbladder in most patients with acute pancreatitis who are fasting or taking liquids only; 2) allows gallbladder evaluation earlier than with iopanoic acid OCG; 3) is less affected by hepatic dysfunction; and 4) provides an alternative to ultrasonography.

Acute Disease↗
PubMed1979

Physiological and pharmacological influences on thyroxine to 3,5,3'-triiodothyronine conversion and nuclear 3,5,3'-triiodothyronine binding in rat anterior pituitary.

Our recent in vivo studies have suggested that intrapituitary l-thyroxine (T(4)) to 3,5,3'-triiodo-l-thyronine (T(3)) conversion with subsequent nuclear binding of T(3) is an important pathway by which circulating T(4) can inhibit thyrotropin release. The present studies were performed to evaluate various physiological and pharmacological influences on these two processes in rat anterior pituitary tissue. Intact pituitary fragments were incubated in buffer-1% bovine serum albumin containing 0.14 ng/ml [(131)I]T(3) and 3.8 ng/ml [(125)I]T(4). Nuclei were isolated after 3 h of incubation and the bound iodothyronines identified by paper chromatography. There was 0.3-1% [(125)I]T(3) contaminating the medium [(125)I]T(4), and this did not change during incubation. Nuclear [(125)I]T(4) was not decreased by 650-fold excesses of medium T(3) or T(4), suggesting that it was nonspecifically bound. The ratio of nuclear to medium [(131)I]- and [(125)I]T(3) were expressed as nuclear counts per minute per milligram wet weight of tissue:counts per minute per microliter medium. Intrapituitary T(4) to T(3) conversion was evidenced by the fact that the nuclear:medium (N:M) ratio for [(131)I]T(3) was 0.45+/-0.21, whereas that for [(125)I]T(3) was 2.23+/-1.28 (mean+/-SD, n = 51). A ratio (R), the N:M [(125)I]T(3) divided by the N:M [(131)I]T(3), was used as an index of intrapituitary T(4) to T(3) conversion. Increasing medium T(3) concentrations up to 50 ng/ml caused a progressive decrease in the N:M ratio for both T(3) isotopes, but no change in the value for R, indicating that both competed for the same limited-capacity nuclear receptors. Increasing concentrations of medium T(4) caused no change in the N:M [(131)I]T(3) but did cause a significant decrease in R in three of four experiments. These results suggest saturation of T(4)-5'-monodeiodination occurred at lower T(4) concentrations than saturation of nuclear T(3) binding sites. In hypothyroid rats, the N:M ratios for both [(131)I]T(3) and [(125)I]T(3) were increased (P < 0.005), but R was three-fold higher than in controls (P < 0.005). Animals given 10 mug T(4)/100 g body wt per d for 5 d had significantly decreased N:M ratios for both [(131)I]T(3) and [(125)I]T(3), as well as a decreased value for R. In fasted rats, neither N:M ratio was depressed, although hepatic T(4) to T(3) conversion in the same animals was 50% of control (P < 0.005). Iopanoic acid (13 muM), but not 6-n-propylthiouracil (29 muM), decreased the N:M [(125)I]T(3) with a significant decrease in the value for R (P < 0.025 or less). Neither sodium iodide (6 muM) nor thyrotropin-releasing hormone (7-700 nM) affected the T(3) N:M ratios. These results indicate that intrapituitary T(4) to T(3) conversion is stimulated in hypothyroidism and depressed in T(4)-treated animals, whereas opposite changes occur in hepatic T(4)-5'-monodeiodination. Unlike liver, anterior pituitary T(4)-5'-monodeiodination is not affected by fasting or incubation with 6-n-propyl-2-thiouracil, but T(4) to T(3) conversion is inhibited in both by iopanoic acid. These results indicate that there are important differences between anterior pituitary and other tissues in the regulation of T(4)-5'-monodeiodination.

Animals↗
PubMed1979

Determinants of the rate of intestinal absorption of oral cholecystographic contrast agents in the dog jejunum.

Successful opacification of the gallbladder during oral cholecystography depends on adequate absorption of the contrast agent from the intestine. The present studies were undertaken to define the specific characteristics of the intestinal mucosa and the properties of the various contrast agents which determine their rates of intestinal absorption. The polarity of the compounds was established by determining the ratios of their distribution between bulk solvents (benzene and water). In addition, the maximum aqueous solubility of each compound was determined. Using in vivo cannulated segments of dog jejunum, apparent passive permeability coefficients were measured. From these data, the apparent maximal rate of intestinal absorption was calculated. The six cholecystopaques studied differed markedly in polarity as judged by their varying ratios of distribution between benzene and water. The permeability coefficients varied inversely with the polarity of the compounds. However, the incremental changes in the coefficients were considerably less than the corresponding changes observed in the partition ratios. The rates of absorption of the more polar contrast agents (tyropanoate, iopronic acid, and iocetamic acid) were greater than the less polar compounds (iopanoic acid, sodium ipodate, and calcium ipodate) under the conditions in which the resistance of the unstirred water layer is not rate limiting and where bile acid micelles are not present.

Animals↗
PubMed1978

The micellar sink: a quantitative assessment of the association of organic anions with mixed micelles and other macromolecular aggregates in rat bile.

Although the importance of mixed micelles in the solubilization and biliary excretion of lipids is established, little is known about a possible role of mixed micelles in the excretion of other biliary solutes. Ultrafiltration and ultracentrifugation techniques were used to investigate the interaction between substances that are excreted in bile and biliary mixed micelles. Substances (urea, erythritol, sucrose) excreted in bile at concentrations equal to, or less than, that in plasma did not show an association with mixed micelles, whereas substances (indocyanine green, iopanoic acid, rose bengal, unconjugated and conjugated sulfobromophthalein, and conjugated bilirubin) excreted in bile at high concentration relative to plasma did. The percentage of these latter substances in bile associated with micelles varied from 26 to 93% and was relatively independent of concentration. In addition to their association with mixed micelles, these test solutes formed self-aggregates that were stabilized primarily by ionic bonds, and only a small percentage (range = 0-5%) of these solutes were present in bile in the form of monomer or complexes small enough to pass a 5,000-mol wt membrane.These findings offer a possible explanation for the increase in sulfobromophthalein, bilirubin, and indocyanine green maximal biliary excretory rate produced by bile salt infusion, and suggest that the concentrative transport into bile of endogenous compounds and xenobiotics may result from their incorporation into mixed micelles and other macromolecular complexes.

Animals↗
PubMed2003

Thyroid hormones interact with glucocorticoids to affect somatotroph abundance in chicken embryonic pituitary cells in vitro.

Our laboratory has reported that somatotroph differentiation occurs between d 14 and d 16 of chicken embryonic development and that corticosterone (CORT) can induce somatotroph differentiation at an earlier age in vitro and in vivo. The objective of the present study was to test for thyroid hormone-CORT interactions on somatotroph differentiation in vitro. Pituitary cells from d 11 chicken embryos were treated with CORT and thyroid hormones, and GH-producing somatotrophs were detected by reverse hemolytic plaque assays and immunocytochemistry. We found that thyroid hormones can act synergistically with CORT to further augment the abundance of somatotrophs in vitro but have little to no effect on their own. Both T(4) and T(3) could act synergistically with CORT to increase somatotroph abundance, but the effects of T(3) were biphasic, inhibiting CORT actions at higher concentrations. The monodeiodination inhibitor iopanoic acid inhibited the synergistic effect of T(4) on CORT induction of GH cells in vitro but not the synergistic effect of CORT and T(3) or the effect of CORT alone. Furthermore, T(3) treatment overcame the iopanoic acid-induced reduction in the T(4)-CORT effect. Our findings indicate that thyroid hormones act synergistically with CORT to further augment the abundance of somatotrophs in vitro and that conversion of T(4) to T(3) within the pituitary is involved in T(4) modulation of somatotroph abundance. Somatotroph differentiation during normal development may be regulated by complex interactions of hormones produced by the embryonic thyroid and adrenal glands.

Animals↗
PubMedDate not supplied

Cholecystographic agents and drug binding to plasma albumin.

These studies have identified two separate sites for drug binding to human serum albumin (HSA). They began in an attempt to explain the persistence in plasma of iophenoxic acid, a now abandoned oral cholecystographic agent. This is identical to iopanoic acid save for -OH instead of -NH2 in the 3 position. Iophenoxate has a half-life in man of about three years, compared to several weeks for iopanoate. Both drugs are reversibly bound to HSA with high affinity. Attempts to determine the exact extent of binding were complicated by drug-radiolysis of 125I-labeled contrast agent. Once this was overcome, reproducible data were obtained, which yielded KD at the site of highest affinity of 0.15 microM for iopanoate and 0.013 microM for iophenoxic acid, thus making the latter the most tightly bound of known drugs. We then studied competitive binding, measuring free and bound drug and competitor. From analysis by computerized programs, iophenoxate binds most firmly at site I, iopanoate most firmly at the site II, both showing competition with each other. The findings are in agreement with Sudlow, Birkett, and Wade, who identified separate binding sites with completely different techniques. They have identified a large number of commonly used drugs that bind specifically to one site or the other. It is clear that drug binding to HSA will in the future be considered in reference to specific sites. It is not known at present to what extent the cholecystographic agents may participate in drug-drug interactions related to binding to HSA. The available data will be reviewed.

Binding Sites↗
PubMedDate not supplied

Observation on the metabolism of iopanoyl (Telepaque) glucuronide in dogs treated with antibiotics.

The purpose of our investigation was to determine whether iopanoyl glucuronide, the major metabolite of iopanoic acid (Telepaque), undergoes hydrolysis by bacterial beta-glucuronidase in dogs. The conjugated compound was identified and quantitated by elemental analysis, fluorescent excitation analysis, thin-layer chromatography, and high pressure liquid chromatography. The experiments were performed before and after combined antibiotic treatment with neomycin and vancomycin. It was first determined that reabsorption and excretion of sodium iopanoate was only minimally diminished during antibiotic treatment. Known amounts of iopanoyl glucuronide were infused into the small bowel of 4 awake dogs with chronic bile fistula, and bile was collected for 5--8 hours. The excretion of the recirculated conjugated compound was 4--5 times lower during antibiotic treatment. Incubation of ileal fluid with bile containing iopanoyl glucuronide suggested that beta-glucuronidase hydrolyzes the conjugated compound. Hydrolysis was markedly decreased after pretreatment with antibiotics. These findings suggest that the beta-glucuronidase produced by bacteria may be a major mechanism in enterohepatic recirculation of iopanoyl glucuronide. Mechanisms and possible implications are discussed.

Animals↗
PubMedDate not supplied

Hepatic excretion of cholecystopaques introduced into the canine jejunum.

The biliary excretion of five oral cholecystopaques was measured following their introduction into the jejunum of bile fistula dogs. The mean maximal iodine concentration in the bile ranged form a low of 2.2 +/- 0.55 mg per ml following a dose of 33 mg of iodine per kg of iopanoic acid to a high of 12.9 +/- 1.4 mg per ml after the same dose of sodium ipodate. Cumulative excretion at the end of three hours was over five times greater with sodium ipodate in comparison to ipoanoic acid. It is felt that the best explanation of this date is the ability of the more water soluble media to pass through the unstirred water layer of the intestine.

Animals↗
PubMed1989

Effect of a change in the luminal perfusion rate on intestinal drug absorption studied by a simple unified organ clearance approach.

A recently proposed simple, noncompartmental, unified organ clearance approach was employed to study the effect of change in luminal perfusion rate (Q) on the steady-state intestinal absorption extraction ratio (E) of drugs. The equation used for correlation or prediction is E = H/(Q + H), where H is the apparent intrinsic intestinal absorption clearance of drug and assumed to be constant under linear conditions. Reported experimental data from intestinal perfusion studies in rats were used to evaluate the applicability or accuracy of the above equation. It was found that the mean difference between the predicted and the reported E values for seven steroids with a very wide range of partition coefficients between n-octanol and water (P) was 4.37% as Q was reduced from 0.497 to 0.247 ml/min. Reported changes in E due to multiple variation in Q (up to about 10 times) for hydrocortisone, progesterone, and iopanoic acid were satisfactorily predicted. The relationship between H and log P and the potential limitation of the present absorption approach are discussed. The present limited study also indicates that the absorption of the steroids with higher lipophilicity is usually less flow dependent.

Animals↗
PubMed1989

Comparison of the nocturnal temporal profiles of N-acetyl-transferase and thyroxine 5'-deiodinase in rat pineal.

The nocturnal temporal patterns of pineal N-acetyltransferase (NAT) and type II thyroxine 5'-deiodinase (5'-D) were compared in the same animals. Both NAT and 5'-D had a similar rise to a midnight zenith with the same lag period but 5'-D rose to its peak 1 h before NAT. The temporal profiles of decrease in enzyme activities were quite different, with 5'-D declining long before NAT. Acute light exposure caused a rapid dramatic decrease in NAT but not in 5'-D. These data suggest that different mechanisms are in involved in the decrease of these two enzyme activities. The role of the antecedent rise in 5'-D activity in the nocturnal rise of NAT activity is apparently minor at most, since pretreatment with iopanoic acid completely blocked the nocturnal rise in 5'-D but had no effect on the nocturnal rise in NAT nor on the acute fall in NAT from its midnight zenith after exposure to light.

Acetylserotonin O-Methyltransferase↗
PubMed2006

Unliganded thyroid hormone receptor is essential for Xenopus laevis eye development.

Thyroid hormone receptors generally activate transcription of target genes in the presence of thyroid hormone (T(3)) and repress their transcription in its absence. Here, we investigated the role of unliganded thyroid hormone receptor (TR) during vertebrate development using an amphibian model. Previous studies led to the hypothesis that before production of endogenous T(3), the presence of unliganded receptor is essential for premetamorphic tadpole growth. To test this hypothesis, we generated a Xenopus laevis TR beta mutant construct ineffective for gene repression owing to impaired corepressor NCoR recruitment. Overexpression by germinal transgenesis of the mutant receptor leads to lethality during early development with numerous defects in cranio-facial and eye development. These effects correlate with TR expression profiles at these early stages. Molecular analysis of transgenic mutants reveals perturbed expression of genes involved in eye development. Finally, treatment with iopanoic acid or NH-3, modulators of thyroid hormone action, leads to abnormal eye development. In conclusion, the data reveal a role of unliganded TR in eye development.

Animals↗
PubMed1993

Automatic titrimetric determination of iodide in some pharmaceutical contrasting preparations.

Automatic titrimetric methods with catalytic, spectrophotometric and potentiometric monitoring of the course of titration were applied for determination of iodide content in iopanoic acid, 2-(3-amino-2,4,6-tri-iodobenzyl)butyric acid, as well as in the mixture of sodium amidotrizoate (sodium 3,5-diacetamido-2,4,6-tri-iodobenzoate), and meglumine amidotrizoate (N-methylglucamine salt of 3,5-diacetamido-2,4,6-tri-iodobenzoic acid), in some pharmaceutical contrasting preparations. After combustion of the sample in an oxygen atmosphere and absorption of products in hydrazine sulphate solution, the iodide present was titrated with a standard solution of silver nitrate. In catalytic titrations, the system persulphate-sulphanilic acid (acetate buffer pH 4.35) in the presence of 2,2'-bipyridine as an activator served as the indicator reaction. The results obtained were compared with those of the official methods. Amounts of iodide of about 1.2 mg per aliquot of analyte were determined with a standard deviation less than 1.9%.

Contrast Media↗
PubMed1990

Kinetic assessment of apparent facilitation by albumin of cellular uptake of unbound ligands.

Previous studies of the effect of albumin on initial uptake of ligands by isolated cell suspensions or cultures found that the apparent uptake for unbound ligand appeared larger in the presence of binding to the albumin than when albumin was absent. Furthermore, when ligand and albumin were increased in a fixed molar ratio, uptake appeared to be competitively inhibited by the excess albumin. We examined the kinetics underlying this apparent facilitation phenomenon by incorporating unbound fraction of ligand in the medium (fu1) into the general model for diffusion between two compartments. The analysis showed that even in the absence of facilitation by albumin, the apparent rate constant for uptake of unbound ligand (k/fu1) increases as albumin concentration increases but the uptake clearance of unbound ligand remains constant. This theoretical analysis was verified experimentally by measuring the effect of albumin on uptake rates of 14C-taurocholate (12, 24, 48, 60, and 96 microM, with and without 0.87 mM albumin) in a nonphysiological system consisting of two solutions separated by a cellulose membrane. Moreover, when the taurocholate and albumin concentrations were increased in a fixed molar ratio of 0.06 (taurocholate 12-96 microM, albumin 0.2-1.6 mM), the initial uptake rate exhibited the same nonlinear pattern as the previous studies that used living cells. This pattern was due not to saturation of a putative albumin receptor but simply to the concomitant decrease in fu1 which tended to offset the increase in uptake rate due to the increasing total taurocholate concentration. The model was also used to evaluate published data describing the effect of albumin on the uptake of iopanoic acid by cultured hepatocytes. In accordance with the model, k1/fu1 increased as albumin concentration increased, but uptake clearance was independent of albumin concentration. Therefore, the kinetic pattern found in this and other studies with isolated cell suspensions or cultures argues against a special role for albumin in facilitating cellular ligand uptake.

Animals↗
PubMed1990

Ontogenic characterization of type I and II thyroxine 5'-monodeiodinases in brown adipose tissue from fetal and newborn rabbits.

The ontogenic changes in thyroxine 5'-monodeiodinase (5'-MD) activity were examined in brown adipose tissue (BAT) of fetal (26, 28 and 30 days of gestation) and newborn (1-14 days old) rabbits. A near-maximum stimulation of BAT 5'-MD activity was reached at 1 mM of dithiothreitol (DTT). The kinetics of 5'-MD inhibition by propylthiouracil (PTU) was uncompetitive in fetal and noncompetitive in neonatal tissue. In fetal tissue the Ki was 3.2 mM independently of DTT concentration, in newborns from 0.5 to 8.25 mM at 1-10 mM of DTT. An apparent Km constant for T4 to T3 conversion in BAT of fetal rabbit amounted to 0.2, 0.67, 1.9 and 2.0 microM in the presence of 1, 2, 5 and 10 mM DTT, respectively. In neonatal rabbits Km was constant (0.72 microM) in various DTT concentrations. The presence of 5'-MDI and 5'-MDII in BAT of fetal and neonatal rabbit was identified. Using iopanoic acid and amiodarone as inhibitors, a decrease in the 5'-MDII:5'-MDI ratio from 8.9 to 2.7 after birth was observed. Changes in 5'-MD activity with advancing age were not correlated with the SH group content in the BAT.

Adipose Tissue, Brown↗