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PubMed1993

Inhibition of placental thyroxine 5-deiodinase activity decreases amniotic fluid concentration of 3,3',5'-triiodothyronine in rat.

We investigated whether the inhibition of placental T4 5-deiodinase (5-D) activity would decrease the amniotic fluid (AF) concentration of rT3. Iopanoic acid (IOP) was used to inhibit placental T4 5-D activity. From gestation days 14 to 17, a group of rats received IOP (10 mg/100 g bw/day, sc) once daily in experiment (exp) 1, and received it (40 mg/100 g bw/day) four times daily in exp 2. In exp 2, control dams received propylthiouracil (PTU; 2 mg/100 g bw/day) instead of IOP. Methimazole and T4 were also given to all dams in exp 1 and 2. On day 17 of gestation, we collected the liver, placenta, blood, and AF of each animal. In the IOP-treated group in both experiments, the serum T4 concentration was significantly increased. Hepatic T4 5'-deiodinase activity was significantly decreased by either PTU or IOP administration. In both experiments placental T4 5-D activity was significantly decreased in the IOP-treated group. The concentration of rT3 in AF was significantly decreased in the IOP-treated group in exp 2 (1.71 vs. 0.75 nmol/l, P < 0.01) despite a higher serum T4 concentration. There was a significant positive correlation between placental T4 5-D activity and the concentration of rT3 in AF in exp 2 (r = 0.62, P < 0.05). These observations indicate that the inhibition of placental T4 5-D activity decreases the concentration of rT3 in rat AF, and that placental T4 5-D and the T4 concentration in maternal serum plays important roles in maintaining the concentration of rT3 in rat AF.

Amniotic Fluid↗
PubMed1982

Evidence for two tissue-specific pathways for in vivo thyroxine 5'-deiodination in the rat.

Propylthiouracil (PTU) is a well known inhibitor of thyroxine (T(4)) to triiodothyronine (T(3)) conversion as evidenced by its effect in several in vitro systems and by the decrease in serum T(3) caused by this drug in either rats or man receiving T(4) replacement. However, the failure of PTU to decrease the intrapituitary T(3) concentration and to completely blunt the serum T(3) concentration in T(4)-replaced athyreotic rats suggest that there may be a PTU-insensitive pathway of T(4) to T(3) conversion in some tissues. To address this question, we have studied the in vivo effect of PTU treatment on the generation of [(125)I]T(3) from [(125)I]T(4) in the serum and cerebral cortex (Cx), cerebellum (Cm), liver (L), and anterior pituitary (P) of euthyroid rats. Whereas PTU decreased the concentration of [(125)I]T(3) in the serum, L homogenates, and L nuclei after [(125)I]T(4), it did not affect the concentration of [(125)I]T(3) in homogenates or nuclei of Cx, Cm, or P. Iopanoic acid pretreatment significantly reduced the [(125)I]T(3) concentration in serum, homogenates, and cell nuclei of all these organs. Neither agent affected the metabolism or tissue distribution of simultaneously injected [(131)I]T(3). The presence of PTU in these tissues was evaluated by in vitro assessment of iodothyronine 5'-deiodinating activity using both [(125)I]rT(3) and [(125)I]T(4) as substrates. In agreement with the in vivo findings, generation of [(125)I]T(3) from T(4) in vitro was not affected by PTU in Cx, Cm, P but it was inhibited by 76% in L. However, rT(3) 5'-deiodination, known to be sensitive to PTU in these tissues, was inhibited in all four indicating that the PTU given in vivo was present in significant amounts. These results demonstrate that in rat Cx, Cm, and P unlike liver, PTU does not inhibit T(4) to T(3) conversion in vivo despite the presence of the drug in the tissues in amounts that significantly inhibit reverse T(3) 5'-deiodination. These results show that in vivo 5'-deiodination of T(4) proceeds via a PTU-insensitive pathway in the central nervous system and pituitary, while this pathway is not quantitatively important in the L. This mechanism accounts for the "locally generated" T(3) in central nervous system and pituitary and could also provide the approximately one-third of extrathyroidally produced T(3) not blocked by PTU administration in athyreotic T(4)-replaced rat.

Animals↗
PubMed1998

Effect of 3,5-diiodo-L-thyronine on thyroid stimulating hormone and growth hormone serum levels in hypothyroid rats.

We have investigated the biological effects of physiological doses of 3,5-diiodo-L-thyronine (3,5-T2) and 3,3'-diiodo-L-thyronine (3,3'-T2) (at doses from 2.5 to 10 microg/100 g BW) on serum TSH and GH levels in rats made hypothyroid by propylthiouracil and iopanoic acid administration. In such animals deiodinase activities were inhibited and thyroid hormones serum levels strongly reduced. The effects of T2s were compared with those elicited by 3,5,3'-triiodo-L-thyronine (T3) (2.5 microg/100 g BW).The serum TSH level was much greater in hypothyroid rats than in euthyroid ones. T3 administration suppressed TSH by 88% compared to control (i.e, the level in hypothyroid rats); it thus reached a value not significantly different from that seen in the euthyroid rats. 3,5-T2 produced a similar effect, suppressing the TSH level by about 75% compared to control; it thus reached values not significantly different from those of the euthyroid and T3-treated rats. By contrast, 3,3'-T2 had no effect on TSH, whatever the dose. The serum GH level was much lower in hypothyroid rats than in euthyroid ones. T3 administration increased the GH level by about 5-fold, restoring it to the value seen in euthyroid rats. 3,5-T2-treated hypothyroid rats, at all the doses used (from 2.5 to 10 microg/100 g BW), showed increased serum GH levels: at a dose of 10 microg/100 g BW the level reached a value about 5-fold higher than that in hypothyroid rats. This value was not significantly different from those of euthyroid and T3-treated rats. 3,3'-T2 did not affect GH levels whatever the dose. Thus, 3,5-T2 (but not 3,3'-T2) seems to mimic the effects of T3 on serum TSH and GH levels in rats.

Animals↗
PubMed1989

The role of 3,5,3'-triiodothyronine in the physiological action of thyroxine in the premetamorphic tadpole.

In premetamorphic tadpoles precocious metamorphosis can be induced by immersion in water containing either T4 or T3. T3 5-deiodinase (5D) activity is present in most tissues, and T4 5'-deiodinase (5'D) activity is present in gut and skin; both systems can be inhibited by iopanoic acid (IOP). If conversion of T4 to T3 is important for the normal physiological action of T4 in these tadpoles, it follows that IOP should decrease the effects of T4 and increase those of T3 on metamorphic events. To test this, tadpoles were immersed in water containing either T4 or T3 (20 nM) with or without 1.75 microM IOP. Two indices of metamorphosis, increased leg length and hepatic carbamyl phosphate synthetase activity, were studied. In vehicle- or IOP-treated animals, change in leg length and carbamyl phosphate synthetase activity were minimal. Both indices were increased after exposure to T3 for 10 days or to T4 for 21 days. Moreover, the effects of T3 were significantly enhanced while those of T4 were inhibited when IOP was also present. Both 5'D and 5D activities determined in vitro were inhibited (95% and 60%, respectively) in IOP-treated tadpoles, and this was associated with an increase in the plasma concentration of hormone. In separate experiments, vehicle- and IOP-treated tadpoles received [125I]T4 or [125I]T3 ip. Plasma, liver, gut, and skin were examined 12-24 h later for 125I-labeled products. After [125I]T4 treatment [125I]T3 was found in skin and gut, but not in plasma or liver. After [125I]T3 treatment [125I]3,3'-diiodothyronine was identified in all extracts studied. In vivo generation of these products was reduced by 50% in IOP-treated tadpoles. These findings indicate that generation of T3 from T4 can take place in vivo in the premetamorphic tadpole and strongly support the hypothesis that this process plays an important role in the physiological action of T4 in this species.

Animals↗
PubMed1996

Role of thyroid hormones in early postnatal development of skeletal muscle and its implications for undernutrition.

Energy intake profoundly influences many endocrine axes which in turn play a central role in development. The specific influence of a short period of mild hypothyroidism, similar to that induced by undernutrition, in regulating muscle development has been assessed in a large mammal during early postnatal life. Hypothyroidism was induced by providing methimazole and iopanoic acid in the feed of piglets between 4 and 14 d of age, and controls were pair-fed to the energy intake of their hypothyroid littermates. Thyroid status was evaluated, and myofibre differentiation and cation pump concentrations were then assessed in the following functionally distinct muscles: longissimus dorsi (l. dorsi), soleus and rhomboideus. Reductions in plasma concentrations of thyroxine (T4; 32%, P < 0.01), triiodothyronine (T3; 48%, P < 0.001), free T3 (58%, P < 0.001) and hepatic 5'-monodeiodinase (EC 1.11.1.8) activity (74%, P < 0.001) occurred with treatment. Small, although significant, increases in the proportion of type I slow-twitch oxidative fibres occurred with mild hypothyroidism, in l. dorsi (2%, P < 0.01) and soleus (7%, P < 0.01). Nuclear T3-receptor concentration in l. dorsi of hypothyroid animals compared with controls increased by 46% (P < 0.001), a response that may represent a homeostatic mechanism making muscle more sensitive to low levels of circulating thyroid hormones. Nevertheless, Na+, K(+)-ATPase (EC 3.6.1.37) concentration was reduced by 15-16% in all muscles (l. dorsi P < 0.05, soleus P < 0.001, rhomboideus P < 0.05), and Ca(2+)-ATPase (EC 3.6.1.38) concentration was significantly reduced in the two slow-twitch muscles: by 22% in rhomboideus (P < 0.001) and 23% in soleus (P < 0.05). It is concluded that during early postnatal development of large mammals a period of mild hypothyroidism, comparable with that found during undernutrition, induces changes in myofibre differentiation and a down-regulation of cation pumps in skeletal muscle. Such changes would result in slowness of movement and muscle weakness, and also reduce ATP hydrolysis with a concomitant improvement in energetic efficiency.

Animals↗
PubMed1989

Serum triiodothyronine sulfate in man measured by radioimmunoassay.

In humans deiodination and perhaps glucuronidation are important pathways of thyroid hormone metabolism. In animals, sulfation plays an important role in T4 and especially in T3 metabolism, but little is known about sulfate conjugation of thyroid hormone in humans. In this study we used a specific T3 sulfate (T3S) RIA to address this question. Eight normal subjects were given oral T3 (1 microgram/day.kg BW) for 7 weeks. During the fifth week they also received propylthiouracil (PTU; four doses of 250 mg/day) for 2 days and during the seventh week iopanoic acid (IOP; 1 g/day) for 3 days. The mean pre-T3 serum iodothyronine values were: T4, 92 +/- 6 (+/- SE) nmol/L; rT3, 0.24 +/- 0.02 nmol/L; T3, 2.30 +/- 0.10 nmol/L; and T3S, less than 0.1 nmol/L (at or below the detection limit of the RIA). After 4 weeks of T3 administration the mean serum values were: T4, 39 +/- 6; rT3, 0.11 +/- 0.01; T3, 5.31 +/- 0.39; and T3S, 0.10 +/- 0.01 nmol/L. After 2 days of PTU administration, mean serum T4 increased to 48 +/- 7 (P less than 0.005), rT3 to 0.20 +/- 0.03 (P less than 0.025), and T3S to 0.13 +/- 0.01 nmol/L (P = NS), but serum T3 did not change (4.91 +/- 0.35 nmol/L). The effect of IOP was more pronounced; after its administration for 3 days the mean serum T4 was 49 +/- 8 (P less than 0.001), rT3 was 0.48 +/- 0.09 (P less than 0.005), and T3S was 0.29 +/- 0.04 nmol/L (P less than 0.005), and serum T3 decreased to 3.95 +/- 0.25 nmol/L (P less than 0.005). The T3S/T3 ratio was increased by PTU from 0.018 +/- 0.003 to 0.024 +/- 0.004 (P less than = NS) and by IOP to 0.055 +/- 0.007 (P less than 0.005). In conclusion, 1) serum T3S is virtually undetectable (less than 0.1 nmol/L) in normal subjects; 2) low serum T3S concentrations are detected in humans given T3; 3) serum T3S in T3-treated subjects is increased by inhibition of type I deiodinase activity with PTU and especially IOP; and 4) in comparison with previous estimates of the serum T3S/T3 ratio in rats, the low ratio in humans may indicate that sulfation is not an important mechanism of T3 metabolism in humans and/or the kinetics of plasma T3 and T3S differ in humans and rats.

Adult↗
PubMed1988

Dual mechanisms of regulation of type I iodothyronine 5'-deiodinase in the rat kidney, liver, and thyroid gland. Implications for the treatment of hyperthyroidism with radiographic contrast agents.

Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (5'DI). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (IOP) to broken cell preparations resulted in a competitive pattern of 5'DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 5'DI in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (V max) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5'DI activity was significantly increased in the liver and the kidney. The administration of IOP to these thyrotoxic animals resulted in a rapid loss of enzyme activity characterized by an approximate 80% decrease in 5'DI V max values in both tissues. Furthermore, this inhibitory effect persisted for longer than 60 h after a single IOP injection. IOP administration also decreased 5'DI V max levels in the thyroid gland by 52%. In other experiments, treatment of intact Reuber FAO hepatoma cells with IOP or rT3 induced a rapid decrease in 5'DI V max levels. In cells treated with cycloheximide, these agents enhanced the rate of disappearance of enzyme activity by greater than 12-fold, indicating a predominant effect on accelerating the rate of enzyme inactivation and/or degradation. These studies demonstrate that iodothyronines and other iodinated compounds have complex regulatory effects on 5'DI that entail alterations in the rates of both enzyme activation and inactivation. The previously accepted concept that rT3 and IOP impair thyroxine (T4) to T3 conversion in vivo by acting as competitive inhibitors is an oversimplification. Rather, the clinically beneficial effects of administering these agents to patients with hyperthyroidism may result primarily from the rapid and prolonged inactivation of 5'DI which occurs in the thyroid gland and peripheral tissues.

Animals↗
PubMed1990

Does a hidden pool of reverse triiodothyronine (rT3) production contribute to total thyroxine (T4) disposal in high T4 states in man.

A hidden pool of rT3 production represents a source of rT3 that is minimally reflected in circulating rT3 levels. To test for the existence of such a source of rT3 production in man, varying doses of the generalized deiodinase inhibitor iopanoic acid (IA) were administered to four hyperthyroxinemic subjects. The doses employed included low-IA (0.5-g load, then 0.5 g/day for 5 days), mid-IA (1.0-g load, then 1.0 g/day for 5 days), and high-IA (3.0-g load, then 3.0 g/day for 5 days). Each patient received 25 microCi [125I]rT3, iv, in the high T4 state and on day 3 of each IA dosing regimen. Serial blood and urine samples were obtained to determine serum rT3 clearance rates and the urinary thyronine metabolite patterns. Although total serum rT3 values were increased by all IA dosages (P less than 0.001), rT3 was lower with high-IA administration (P less than 0.02) than with low- or mid-IA regimens. Low-IA decreased rT3 clearance to 33 +/- 2 L/day (P less than 0.005), while increasing the daily rT3 production to 76 +/- 8 nmol/day (P less than 0.04) compared to the control values (150 +/- 10 L/day and 53 +/- 8 nmol/day, respectively). Mid-IA also reduced rT3 clearance (23 +/- 4 L/day; P less than 0.005) without changing rT3 production (50 +/- 10 nmol/day), while high-IA reduced both rT3 clearance (21 +/- 2 L/day; P less than 0.005) and production (39 +/- 9 nmol/day; P less than 0.04). Intravenously administered tracer rT3 could not be detected in the urine in the high T4 state, but rT3 could not be detected in the urine in the high T4 state, but was prominent after IA administration. It is concluded that a hidden pool of rT3 production exists in vivo in man. Further, low dose IA serves as a selective inhibitor of liver and kidney deiodinase systems, allowing reflection of this hidden rT3 pool in the blood and urine. It would appear that hypertrophy of this hidden pool of rT3 production occurs in high T4 states and may account for the majority of the unrecognized deiodinative metabolites of T4 generated in hyperthyroxinemia.

Adult↗
PubMed1994

3,5,3'-Triiodothyronine (T3) sulfate: a major metabolite in T3 metabolism in man.

Previous studies have suggested that T3 metabolism relies more on nondeiodinative conjugation than on direct deiodinative degradation for its disposal in man. To better define this process, tracer T3 kinetic studies were performed in five euthyroid subjects before and after iopanoic acid (IA) administration to selectively impair T3 deiodinative disposal. Both a low IA (0.5-g load, followed by 0.5 g/day for 7 days) and a high IA (3.0-g load, followed by 3.0 g/day for 7 days) dosing schedule were employed to achieve varying levels of deiodinase inhibition. Additionally, the high IA dose was repeated with simultaneous oral T3 administration (100 micrograms daily) to normalize serum T3 levels that were reduced by IA-induced inhibition of T4 to T3 conversion. The results demonstrated that baseline serum T3 (2.3 +/- 0.1 nmol/L) and T3/T4 (1.9 +/- 0.1 x 10(-2)) values were significantly reduced by both the low IA (1.5 +/- 0.1 nmol/L and 1.2 +/- 0.1 x 10(-2), respectively) and the high IA (1.5 +/- 0.1 nmol/L and 0.9 +/- 0.2 x 10(-2), respectively) dosing schedule and that the addition of oral T3 to the high IA regimen restored both the T3 and T3/T4 levels to near-normal values (2.9 +/- 0.3 nmol/L and 1.7 +/- 0.2 x 10(-2), respectively). Low IA also significantly decreased T3 clearance (30 +/- 4 to 18 +/- 2 L/day; P < 0.005) and fractional urinary tracer recovery (70 +/- 3% to 37 +/- 4%; P < 0.005), whereas high IA produced only a minimal further reduction in clearance (16 +/- 2 L/day; P < 0.01) and urinary tracer recovery (32 +/- 3%; P < 0.05). Surprisingly, oral administration of T3 to the high IA regimen significantly increased T3 clearance (23 +/- 4 L/day; P < 0.01) without changing urinary tracer recovery (34 +/- 5%) compared to the effects of high IA alone. Evaluation of the urinary T3 metabolite pattern demonstrated that the major products of T3 metabolism were T3 sulfate and 3,3-diiodothyronine sulfate. These observations confirm previous results suggesting that the majority of nondeiodinative T3 disposal occurs via T3 sulfate formation. The additional finding that such nondeiodinative disposal may also be influenced by the circulating T3 level leads us to propose that sulfotransferase enzyme systems may play an important role in regulating the prereceptor availability of this ligand.

Adult↗
PubMed1991

In vitro effect of thyroxine on cholinergic neurotransmission in rat sympathetic superior cervical ganglion.

This study aimed at examining the effect of thyroid hormones on cholinergic transmission in isolated rat superior cervical ganglia (SCG). In SCG explants incubated with 3H-choline, thyroxine (T4) and 3,3',5-triiodothyronine (T3) added to the medium before a second depolarization stimulus of 60 mM K+ resulted in a dose-dependent increase of S2/S1 ratio for 3H release. The concentration of hormone that produced 50% of maximal increase in K(+)-induced radioactivity release was 8 x 10(-9) M for T4 and 1.6 x 10(-8) M for T3 while 3,3',5,5'-tetraiodothyroacetic acid was almost ineffective. Preincubation of SCG with 10(-7) M iopanoic acid for 30 min before S2, although not affecting by itself S2/S1 ratio, effectively prevented the increase given by T4 or T3. 3H-acetylcholine release by SCG was augmented in a high K+, and the effect was amplified by T4 to a similar extent as that for total 3H release. When added to the incubation medium together with 60 mM K+ for 30 min, T4 (10(-7) M) increased significantly the activity of choline acetyltransferase (ChAT). T4 did not affect ChAT activity in SCG exposed to 4.7 mM K+, nor in SCG homogenates. 3H-choline uptake measured immediately after exposure of SCG to 60 mM K+ decreased by 25%, whereas it increased by 71% after a subsequent 30-min incubation with 4.7 mM K+. Addition of 10(-7) M T4 prevented the changes in choline uptake observed in a high K+ medium. These results indicate that T4 increases SCG cholinergic transmission.

Animals↗
PubMedDate not supplied

Effect of galactosamine-induced hepatic UDP-glucuronic acid depletion on acetaminophen elimination in rats. Dispositional differences between hepatically and extrahepatically formed glucuronides of acetaminophen and other chemicals.

Galactosamine (GAL) markedly depletes hepatic UDP-glucuronic acid (UDP-GA) whereas extrahepatic UDP-GA is minimally affected. This suggests that GAL predominantly inhibits hepatic glucuronidation. Therefore, the effect of GAL-induced hepatic UDP-GA depletion was examined in bile duct-cannulated rats to determine the role of hepatic glucuronidation in the disposition of acetaminophen (AA). GAL markedly altered the fate of AA-glucuronide but had little or no effect upon other AA metabolites. GAL decreased the biliary excretion of AA-glucuronide up to 92%, whereas reductions in blood levels and urinary excretion of AA-glucuronide did not exceed 50%. This suggests that AA-glucuronide excreted in bile is predominantly of hepatic origin whereas AA-glucuronide found in blood and urine is derived from both hepatic and extrahepatic tissues. Data in the present and previous studies [Gregus, Watkins, Thompson, Klaassen: J. Pharmacol. Exp. Ther. 225, 256, (1983)] indicate that GAL greatly reduced the biliary excretion of AA- and valproic acid-glucuronide whereas the biliary excretion of the glucuronides of phenolphthalein, iopanoic acid, bilirubin, and diethylstilbestrol was only partially decreased. This difference appears to be largely due to differential contributions by the liver and extrahepatic tissues in the glucuronidation of various compounds as well as the availability of glucuronides formed in extrahepatic tissues for biliary excretion. Specifically, the extrahepatically formed glucuronide conjugates of AA and valproic acid are not readily available for biliary excretion whereas the glucuronides of the other compounds are readily excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1996

Demonstration of in vivo metabolic effects of 3,5-di-iodothyronine.

The objective of the present study was to test in vivo the metabolic effects of 3,5-di-iodothyronine (3,5-T2) in unanesthetized and unrestrained male Sprague-Dawley rats. Amino acid and lipid metabolisms were investigated by breath tests using as tracers the 13C-carboxyl-labeled molecules of leucine, alpha-ketoisocaproic acid (KIC) and octanoic acid, in four different groups of rats: hypothyroid animals (receiving propylthiouracil (PTU) and iopanoic acid), hypothyroid animals treated with either a daily i.p. injection of 3,5-T2 (25 micrograms/100 g body weight), or tri-iodothyronine (T3) (1 microgram/100 g body weight), and control euthyroid animals receiving equivalent volumes of the vehicle solutions. Energy expenditure was measured by continuous monitoring of O2 consumption and CO2 production in these different groups. Daily energy expenditure was decreased by 30% in PTU-treated rats. The chronic treatments with 3,5-T2 and T3 restored daily energy expenditure to the control level. 13CO2 recovered in breath following the i.v. injection of octanoic acid-[1-13C] was decreased in hypothyroid animals compared with control animals (P < 0.05) and restored to control values by T3 and 3,5-T2 treatments. The 13CO2 recovered in breath after i.v. injection of leucine-[1-13C] was increased in PTU-treated compared with control animals (P < 0.05). Chronic treatment with either 3,5-T2 or T3 restored 13CO2 to control values. Excretion of 13CO2 recovered in breath following the i.v. injection of KIC-[1-13C] was increased in PTU-treated compared with control animals. Chronic treatments with either 3,5-T2 or T3 did not restore KIC decarboxylation. These results suggest that 3,5-T2 exerts metabolic effects on energy expenditure, on both lipid beta-oxidation and leucine metabolism in hypothyroid rats. We conclude that 3,5-T2 is a metabolically active iodothyronine.

Amino Acids↗
PubMed1983

The effect of taurocholate on canine bile flow, biliary excretion and concentration of ioglycamide.

The bile acid taurocholate increases the biliary excretion of organic anions, such as sulfobromophthalein (BSP), bilirubin and iopanoic acid. In the present study has been investigated the effect of taurocholate on 1. Canine biliary excretion and concentration of the i.v. contrast medium ioglycamide and 2. Canine bile flow. The experimental model consisted of cholecystectomized, anaesthetized dogs with a fistula, through which the common bile duct could be catheterized and drained. One hour after cannulation, i.v. infusion of ioglycamide at a rate of 4 mumol/min./kg. was started. Two hours after the infusion start a control group received i.v. infusion of saline, while in another a 1.5% sodium taurocholate infusion was started with stepwise increases with 30 min. intervals from 0.4 to 0.8, 1.6 and 3.2 mumol/min./kg. Compared with control, all rates of taurocholate infusion increased bile flow and decreased biliary ioglycamide concentration. Although the bile flow with increasing taurocholate infusion rates was enhanced, the biliary ioglycamide excretion did not increase. The results indicate that ioglycamide and taurocholate are excreted into bile by separate excretion mechanisms. As taurocholate increases the biliary excretion of some other organic anions, it supports the hypothesis that organic anions are excreted into bile by more than two excretion mechanisms, taurocholate affecting only some of them.

Animals↗
PubMed1994

12-O-tetradecanoylphorbol 13-acetate and fibroblast growth factor increase the 30-kDa substrate binding subunit of type II deiodinase in astrocytes.

Type II 5'-deiodinase (D-II) catalyzes the intracellular conversion of thyroxine (T4) to 3,5,3'-triiodothyronine (T3) in the brain. The D-II activity in astroglial cell cultures is induced by several pathways including cyclic AMP (cAMP), 12-O-tetradecanoylphorbol 13-acetate (TPA), and fibroblast growth factors (FGFs). We have examined the effect of TPA and FGFs on the 30-kDa substrate binding subunit of D-II, by affinity labeling with N-bromoacetyl-[125I]T4 in astroglial cells. TPA (0.1 microM), 20 ng/ml acidic FGF (aFGF), and 1 mM 8-bromo cyclic AMP all caused an increase in the 30-kDa protein. cAMP induced the greatest increase (fivefold) followed by TPA (3.2-fold) and FGF (2.8-fold). Glucocorticoids acted synergistically with cAMP and aFGF and promoted the effect of TPA. Affinity labeling was competitively inhibited by bromoacetyl-T4 > bromoacetyl-T3 > T4 > reverse T3 > iopanoic acid > T3 > 3,5,3'-triiodothyroacetic acid. The effect of TPA (0.1 microM) was maximum at 8 h and then gradually decreased. aFGF (20 ng/ml) plus heparin (17 micrograms/ml) induced a maximal 30-kDa increase at 8 h, which stayed stable for up to 24 h. The effect of aFGF was concentration dependent. Of the other growth factors studied, only basic FGF and platelet-derived growth factor induced small increases in the 30-kDa protein. Epidermal growth factor had little effect. In vitro labeling of cAMP, TPA, and aFGF-stimulated cell sonicates resulted in an increase in the 30-kDa protein that paralleled the increase in D-II activity.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1992

Adenosine 3',5'-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes.

We intend to develop in vitro model systems to study the hormonal regulation of uncoupling protein (UCP) and its role in brown adipose tissue (BAT) thermogenesis. We report here that UCP mRNA responses to adrenergic and thyroid hormone manipulations in freshly dispersed, mature brown adipocytes mimic in vivo observations. Studies were performed in brown adipocytes obtained from interscapular brown fat of euthyroid or hypothyroid rats. The tissue was dispersed with collagenase, and cells were isolated by floatation over 4% BSA. UCP mRNA in these cells is 2-3 times more abundant than that in the whole tissue, indicating a selection of cells expressing the gene. In cells from euthyroid rats, UCP mRNA is maximally elevated within 2 h of exposure to 1 microM forskolin and 50 ng T3/ml (77 nM total, 0.43 nM free). T3 significantly enhances the effect of forskolin. In the absence of stimulation, UCP mRNA rapidly disappears from euthyroid brown adipocytes, and this can be prevented with the addition of T3 by a mechanism not requiring on-going transcription. In cells from hypothyroid rats, forskolin or isoproterenol plus phenylephrine fail to stimulate UCP mRNA, but within 3 h of exposure to T3, cells recover full responsiveness. As in vivo, a high extracellular concentration of T3 is required for maximal responsiveness of UCP mRNA to cAMP, while T4 can restore responsiveness in physiological concentrations (40 pM). This effect of T4 is prevented by iopanoic acid, a compound that blocks the type II T4 5'-deiodinase. In conclusion, 1) freshly dispersed brown adipocytes retain all of the properties concerning UCP regulation by thyroid hormone and sympathetic nervous system described for brown fat in vivo; 2) the observations made in vivo, thus, represent direct action of norepinephrine and thyroid hormone on these cells; 3) as in vivo, T4 is a better source of intracellular T3 than extracellular T3 for brown adipocytes; hence, the in vivo findings are the result of the cell biology of 5'-deiodinase type II rather than dynamic factors inherent to the in vivo condition; 4) stabilization of mature UCP mRNA by T3 is an important mechanism to maintain the levels of this mRNA elevated under sustained stimulation; and 5) dispersed brown adipocytes and UCP gene products constitute a powerful model to study interactions between the sympathetic nervous system and thyroid hormone at a cellular or molecular level.

Adipose Tissue, Brown↗
PubMed1991

Hepatic 5'-deiodinase activity of Japanese quail using reverse-T3 as substrate: assay validation, characterization, and developmental studies.

Using rT3 as substrate, an in vitro 5'D assay was validated for use with liver tissue from adult Japanese quail, by defining conditions under which activity is proportional to enzyme (protein) concentration and is linear with incubation time. Activity was measured as the release of 125I from labeled rT3. Using validated assay conditions we found the following 5'D characteristics: maximal activity from 10 to 50 mM dithiothreitol (cofactor), an apparent Km of 0.52 microM rT3, pH optimum of 7.6-8.5, complete inhibition by 1 mM propylthiouracil and by 1.0 mM iopanoic acid, and substrate "preference" of rT3 greater than T4 greater than T3. Based on these characterizations the quail hepatic 5'D activity is like the Type I 5'D activity found in mammalian liver and kidney and embryonic chicken liver. To determine how previous unvalidated assays, that used high tissue and relatively low substrate (T4) concentrations, influenced 5'D studies we reevaluated 5'D development using an assay validated for each developmental stage with rT3 as substrate. We found extreme quantitative differences in the activities measured and in the proportional relationships between stages, and only limited qualitative similarity in the pattern of 5'D development when unvalidated T4 assay results were compared with validated rT3 assay results. Our data in this paper show good correspondence between whole liver 5'D activity per unit body weight and plasma T3/T4 ratios for the developmental stages sampled.

Animals↗
PubMed1983

Potential tumor- or organ-imaging agents XXIV: chylomicron remnants as carriers for hepatographic agents.

This paper describes the possible utility of plasma lipoproteins for the site-specific delivery of diagnostic agents. The class of lipoproteins known as chylomicrons was selected for this preliminary study, since they are known to be rapidly metabolized and taken up by the liver. Cholesteryl iopanoate (II), an iodinated analogue of a normal constituent of the hydrophobic core of chylomicrons, was synthesized from cholesterol and iopanoic acid (I) and subsequently radiolabeled with ioidine-125. Whereas intravenous administration of II in physiological saline resulted in the appearance of approximately 31% of the dose in the liver at 0.5 hr, prior incorporation of II into chylomicrons resulted in an almost threefold (87%) increase in the liver accumulation of II in the same time period. A more gradual appearance of II in steroid-secreting tissues was consistent with the association of II with high-density lipoproteins following administration.

Animals↗