Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In contrast to the glucuronide conjugate, T3 sulfate (T3S) undergoes rapid deiodinative degradation in the liver and accumulates in rats and rat hepatocyte cultures if type I iodothyronine deiodinase activity is inhibited. We here report the RIA of plasma T3S in rats treated with the antithyroid drugs propylthiouracil (PTU) or methimazole (MMI), of which only PTU inhibits type I deiodinase. Male Wistar rats were treated acutely by ip injection with 1 mg PTU or MMI/100 g BW and subsequently for 4 days by twice daily injections with these drugs together with 0.5 microgram T4 or 0.25 microgram T3/100 g BW. Blood was obtained 4 h after the last injection, and plasma T4, rT3, T3, and T3S were determined by RIA and compared with pretreatment values. Serum concentrations (mean +/- SEM; nanomoles per liter) in untreated rats were: T4, 51 +/- 1; T3, 1.37 +/- 0.03; T3S, 0.09 +/- 0.01; and rT3, 0.03 +/- 0.002. Serum T3 was decreased, and T3S and rT3 were increased by acute PTU treatment [T3, 1.16 +/- 0.05 (P less than 0.01); T3S, 0.33 +/- 0.04 (P less than 0.001); rT3, 0.27 +/- 0.02 (P less than 0.001)], but unaffected by acute MMI treatment (T3, 1.37 +/- 0.05; T3S, 0.09 +/- 0.01; rT3, 0.02 +/- 0.003). In T4-treated rats, serum T3 was decreased and T4, T3S, and rT3 were increased by PTU vs. MMI [T4, 86 +/- 5 vs. 58 +/- 4 (P less than 0.001); T3, 0.51 +/- 0.07 vs. 0.88 +/- 0.06 (P less than 0.001); T3S, 0.38 +/- 0.03 vs. 0.12 +/- 0.01 (P less than 0.001); rT3, 0.86 +/- 0.19 vs. 0.08 +/- 0.01 (P less than 0.005)]. In T3-substituted rats T3S was increased by PTU vs. MMI (1.09 +/- 0.13 vs. 0.25 +/- 0.03; P less than 0.001). The T3S/T3 ratio in the PTU-treated T3 -replaced rats (0.60 +/- 0.09) was in agreement with that determined by HPLC of serum radioactivity in animals that in addition to this treatment also received about 10 microCi [125I]T3 with the last two injections (0.92 +/- 0.13). In conclusion, this investigation demonstrates the feasibility of the measurement of serum T3S by RIA. Our findings confirm previous observations with radioactive isotopes, suggesting that sulfation is an important pathway for the metabolism of T3 in rats. Analogous to rT3, the accumulation of T3S in PTU-treated rats indicates that this conjugate is metabolized predominantly by type I deiodination.
 ...
PMID:Increased plasma 3,5,3'-triiodothyronine sulfate in rats with inhibited type I iodothyronine deiodinase activity, as measured by radioimmunoassay. 291 98

Propylthiouracil (PTU) in maximally inhibitory doses for liver and kidney iodothyronine 5'-deiodinase activity (5'D-I), reduces extrathyroidal T4 to T3 conversion by only 60-70% in euthyroid rats. A second pathway of T4 to T3 conversion (5'D-II) has been found in pituitary, central nervous system, and brown adipose tissue. 5'D-II is insensitive to PTU and increases in hypothyroidism, whereas 5'D-I decreases in hypothyroid rats. Thyroxine (T4) and triiodothyronine (T3) kinetics were assessed in euthyroid and thyroidectomized rats by noncompartmental analysis after injecting [125I]T4 and [131I]T3. Neither the volume of distribution nor the rate of fractional removal of plasma T4 was affected by the thyroid status, but the fractional removal rate of T3 was approximately 50% reduced in hypothyroid rats (P less than 0.001). Fractional T4 to T3 conversion was 22% in euthyroid and 26% in hypothyroid rats. In euthyroid rats, sufficient PTU to inhibit liver and kidney 5'D-I greater than 90% reduced serum [125I]T3 after [125I]T4 (results given as percent dose per milliliter X 10(-3) +/- SEM): 4 h, control 16 +/- 2 vs. PTU 4 +/- 1, P less than 0.005, and 22 h, control 6.4 +/- 0.4 vs. PTU 3.6 +/- 0.7, P less than 0.025. In thyroidectomized rats, the same dose of PTU also inhibited 5'D-I in liver and kidney, but had no effect on the generation of serum [125I]T3 from [125I]T4. Similarly, after 1 microgram T4/100 g bw was given to thyroidectomized rats, serum T3 (radioimmunoassay) increased by 0.30 +/- 0.6 ng/ml in controls and 0.31 +/- 0.09 ng/ml in PTU-treated rats. However, when the dose of T4 was increased to 2-10 micrograms/100 g bw, PTU pretreatment significantly reduced the increment in serum T3. T3 clearance was not affected by PTU in hypothyroid rats. The 5'D-II in brain, pituitary, and brown adipose tissue was reduced to less than or equal to 60% of control by 30 micrograms/100 g bw reverse T3 (rT3), an effect that lasted for at least 3 h after rT3 had been cleared. In rT3-pretreated thyroidectomized rats, the generation of [125I]T3 from tracer [125I]T4 was reduced in the serum: 6 +/- 1 vs. 12 +/- 1 X 10(-3)% dose/ml, P less than 0.01, during this 3-h period. We conclude that virtually all the T3 produced from low doses of exogenous T4 given to hypothyroid rats is generated via a PTU-insensitive pathway, presumably catalyzed by the 5'D-II. This is a consequence of the enhanced activity of this low Km enzyme together with the concomitant decrease in the hepatic and renal 5'D-I characteristic of the hypothyroid state. The results indicate that in some circumstances, 5D-II activity may contribute to the extracellular, as well as intracellular, T3 pool.
 ...
PMID:Qualitative and quantitative differences in the pathways of extrathyroidal triiodothyronine generation between euthyroid and hypothyroid rats. 670 10

Enteric bacteria have been postulated to have a role in thyroid economy by promoting the hydrolysis of thyroid hormone conjugates of biliary origin, thus permitting the absorption and recycling of thyroxine (T4) and triiodothyronine (T3). An enterohepatic circulation of T3 might be more pronounced under conditions in which type I iodothyronine deiodinase activity (5'D-I) is inhibited, because this augments the accumulation of T3 sulfate conjugates in bile. This potential of increased gut reabsorption of T3 might explain, at least in part, the failure of serum T3 values to decrease appreciably when marked reductions in peripheral 5'D-I activity are induced by selenium deficiency or 6-anilino-2-thiouracil (ATU) administration. Thus, studies were performed to determine the effect of intestinal decontamination, in the absence and in the presence of 5'D-I inhibition, on plasma T4 and T3 concentrations. Groups of adult male rats received either enteric antibiotics or no antibiotics for 12 days and then, in half of the rats in each group, treatment for 10 days with ATU, a 5'D-I inhibitor that does not affect thyroid hormone synthesis. The activity of intestinal arylsulfatase and arylsulfotransferase, enzymes that catalyze hydrolysis of thyroid hormone conjugates, was reduced markedly by approximately 87% in rats that received antibiotics, regardless of whether or not they also received ATU. The ATU treatment markedly inhibited liver 5'D-I activity in antibiotic-treated as well as in non-antibiotic-treated rats (control = 399 +/- 32 U/mg protein (mean +/- SEM); ATU = 152 +/- 17: antibiotics = 351 +/- 29; antibiotics + ATU = 130 +/- 10; p < 0.01) and significantly increased plasma T4 and T3 sulfate (T4S, T3S) concentrations (control: T4S = 2.8 +/- 0.4 and T3S = 6.7 +/- 1.3 ng/dl; ATU: T4S = 6.2 +/- 1.4 and T3S = 10.6 +/- 2.1 ng/dl; antibiotics: T4S = 1.8 +/- 0.2 and T3S = 3.6 +/- 1.0 ng/dl; antibiotics + ATU: T4S = 6.8 +/- 0.7 and T3S = 9.7 +/- 1.8 ng/dl; p < 0.05). The ATU treatment was associated with a significant increase in plasma T4 and rT3 concentrations but did not affect plasma T3 concentrations, and intestinal decontamination did not alter these ATU-associated effects on circulating thyroid hormones. These results suggest that anaerobic enteric bacteria in the rat do not have an important role in recycling of thyroid hormones, either under normal conditions or in circumstances where 5'D-I activity is markedly reduced, and that increased gut absorption of T3 from T3S cannot explain the near-normal serum T3 values found when peripheral 5'D-I activity is markedly decreased.
 ...
PMID:Serum iodothyronine concentrations in intestinally decontaminated rats treated with a 5'-deiodinase type I inhibitor 6-anilino-2-thiouracil. 864 Mar 7

Sulfation is an important metabolic pathway facilitating the degradation of thyroid hormone by the type I iodothyronine deiodinase. Different human and rat tissues contain cytoplasmic sulfotransferases that show a substrate preference for 3,3'-diiodothyronine (3,3'-T2) > T3 > rT3 > T4. During investigation of the expression of plasma membrane transporters for thyroid hormone by injection of rat liver RNA in Xenopus laevis oocytes, we found uptake and metabolism of iodothyronines by native oocytes. Groups of 10 oocytes were incubated for 20 h at 18 C in 0.1 ml medium containing 500,000 cpm (1-5 nM) [125I]T4, [125I]T3, [125I]rT3, or [125I]3,3'-T2. In addition, cytosol prepared from oocytes was tested for iodothyronine sulfotransferase activity by incubation of 1 mg cytosolic protein/ml for 30 min at 21 C with 1 microM [125I]T4, [125I]T3, [125I]rT3, or [125I]3,3'-T2 and 50 microM 3'-phosphoadenosine-5'-phosphosulfate. Incubation media, oocyte extracts, and assay mixtures were analyzed by Sephadex LH-20 chromatography for production of conjugates and iodide. After 20-h incubation, the percentage of added radioactivity present as conjugates in the media and oocytes amounted to 0.9 +/- 0.2 and 1.0 +/- 0.1 for T4, less than 0.1 and less than 0.1 for T3, 32.5 +/- 0.4 and 29.3 +/- 0.2 for rT3, and 3.8 +/- 0.3 and 2.3 +/- 0.2 for 3,3'-T2, respectively (mean +/- SEM; n = 3). The conjugate produced from rT3 was identified as rT3 sulfate, as it was hydrolyzed by acid treatment. After injection of oocytes with copy RNA coding for rat type I iodothyronine deiodinase, we found an increase in iodide production from rT3 from 2.3% (water-injected oocytes) to 46.2% accompanied by a reciprocal decrease in rT3 sulfate accumulation from 53.7% to 7.1%. After 30-min incubation with cytosol and 3'-phosphoadenosine-5'-phosphosulfate, sulfate formation amounted to 1.8% for T4, less than 0.1% for T3, 77.9% for rT3, and 2.9% for 3,3'-T2. These results show that rT3 is rapidly metabolized in native oocytes by sulfation. The substrate preference of the sulfotransferase activity in oocytes is rT3 >> 3,3'-T2 > T4 > T3. The physiological significance of the high activity for rT3 sulfation in X. laevis oocytes remains to be established.
 ...
PMID:Rapid sulfation of 3,3',5'-triiodothyronine in native Xenopus laevis oocytes. 944 30