Biliary Excretion Of Thyroxine Research Articles

Polychlorinated Biphenyl Congeners that Increase the Glucuronidation and Biliary Excretion of Thyroxine Are Distinct from the Congeners that Enhance the Serum Disappearance of Thyroxine

Polychlorinated biphenyl (PCB) congeners differentially reduce serum thyroxine (T(4)) in rats, but little is known about their ability to affect biliary excretion of T(4). Thus, male Sprague-Dawley rats were orally administered Aroclor-1254, Aroclor-1242 (32 mg/kg per day), PCB-95, PCB-99, PCB-118 (16 mg/kg per day), PCB-126 (40 μg/kg per day), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (3.9 μg/kg per day), or corn oil for 7 days. Twenty-four hours after the last dose, [(125)I]T(4) was administered intravenously, and blood, bile, and urine samples were collected for quantifying [(125)I]T(4) and in bile [(125)I]T(4) metabolites. Serum T(4) concentrations were reduced by all treatments, but dramatic reductions occurred in response to Aroclor-1254, PCB-99 [phenobarbital (PB)-type congener], and PCB-118 (mixed-type congener). None of the treatments increased urinary excretion of [(125)I]T(4). Aroclor-1254, PCB-118, TCDD, and PCB-126 (TCDD-type congener) increased biliary excretion of T(4)-glucuronide by 850, 756, 710, and 573%, respectively, corresponding to marked induction of hepatic UDP-glucuronosyltransferase (UGT) activity toward T(4). PCB-95 and PCB-99 did not induce UGT activity; therefore, the increased biliary excretion of T(4)-glucuronide was related to the affinity of congeners for the aryl hydrocarbon receptor. The disappearance of [(125)I]T(4) from serum was rapid (within 15-min) and was increased by Aroclor-1254, PCB-99 and PCB-118. Thus, reductions in serum T(4) in response to PCBs did not always correspond with UGT activity toward T(4) or with increased biliary excretion of T(4)-glucuronide. The rapid disappearance of [(125)I]T(4) from the serum of rats treated with PB-like PCBs suggests that increased tissue uptake of T(4) is an additional mechanism by which PCBs may reduce serum T(4).

Inducible thyroid lesions in the rat with special reference to mediation or interactions with other organ systems.

Several unrelated compounds are known to induce thyroid follicular lesions in the rat, some acting directly on the epithelium and others acting indirectly. The frequent observation of hyperplastic and neoplastic changes of the thyroid follicles in chronic toxicity studies using rats is further evidence of the sensitivity of this epithelium in this species. TSH responses in man, to changes in thyroxine levels are often insignificant (Hill, Erdreich, Paynter, Roberts, Rosenthal and Wilkinson 1989). In the rats these responses are known to be prompt and strong. The increased sensitivity of rat thyroid is attributable to several species-specific features. They include; comparatively low half-life of active thyroxine; absence of thyroxine binding globulin in rat plasma to bind the free thyroxine, considerably greater plasma levels of TSH; markedly greater TSH responses and greater biliary excretion of thyroxine in rat compared to man.

The effect of phenobarbital on the metabolism and excretion of thyroxine in rats

The effect of phenobarbital on thyroid function and the metabolism and biliary excretion of thyroxine in rats was determined. Phenobarbital, administered for 2 weeks at a dose of 100 mg/kg/day, resulted in an increase in hepatic and thyroid gland weights, decreased circulating levels of T 4, T 3 and rT 3, and increased TSH levels in male and female rats. After 3 months of treatment liver and thyroid weights were still increased; however, hormone values were not as markedly affected indicating that the rats had partially compensated for the effect on thyroid function. In thyroidectomized rats the plasma clearance of thyroxine was increased with phenobarbital. In bile duct cannulated phenobarbital-treated male rats the hepatic uptake at 4 hr was markedly increased. Bile flow was increased and the 4-hr cumulative biliary excretion of administered radioactivity was increased by 42%. Most of the increase in the excretion (76%) was accounted for by an increase in the excretion of thyroxine-glucuronide in phenobarbital-treated rats. Hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats expressed as picomoles per milligram of protein was increased by 40%; enzyme activity per gram of liver was increased by about twofold which, coupled with increased hepatic weight, resulted in about a threefold increase in total hepatic thyroxine-glucuronyltransferase activity in phenobarbital-treated rats as compared to that of controls. Qualitatively similar effects on metabolism, excretion, and enzyme induction were noted in female rats; however, the magnitude of increase was less than that observed in male rats. It is concluded that the effect of phenobarbital on thyroid function in rats is primarily a result of its effects on the hepatic disposition of thyroid hormone. The induction of thyroxine-glucuronyltransferase appears to play an important role in the increased metabolism and excretion of thyroxine in phenobarbital-treated rats.

Effect of adrenaline on biliary excretion of triiodothyronines in rats mediated by alpha 1-adrenoceptors and related to the inhibition of 5'-monodeiodination in liver.

Biliary excretion of thyroxine (T4),3,5,3'-triiodothyronine (T3),3,3,5'-triiodothyronine (rT3) and diiodothyronines (3,3'-T2,3,5-T2 and 3',5'-T2) was estimated with the aid of radioimmunoassay in 3-4 subsequent 2-h samples of bile obtained from pentobarbital anesthetized rats through the tubing inserted in bile duct. The excretion of T3 was significantly decreased during 4-h infusion of 2400 ng/kg/min adrenaline in normal rats or during 6-h infusion of the latter dose in the animals preinjected with 2 micrograms T4. Moreover, the excretion of rT3 was significantly increased after the infusion of 1200 and 2400 ng/kg/min adrenaline. Such increase after 1200 and 2400 ng/kg/min adrenaline was prevented by a single dose of 10 mg/kg phentolamine (alpha 1-2-antagonist) and that after 2400 ng/kg/min adrenaline also by 2.5 mg/kg prazosin (alpha 1-antagonist) injected at the beginning of the infusion, but not by 6 mg/kg yohimbine (alpha 2-antagonist) injected every 60 min during 4-h infusion. In addition, increased rT3 excretion was found during the infusion of alpha 1-agonist methoxamine (1.5 mg/kg/4 h), while no such effect of the infusion of alpha 2-agonist azepexol (10 mg/kg/4 h) was observed. It may be suggested that the effect of adrenaline was mediated predominantly by alpha 1-adrenoceptors and that the observed changes in biliary excretion of T3 and rT3 were related to the inhibition of 5'-monodeiodination in the liver.

The biliary excretion of thyroxine and glucuronic acid conjugate in normal and Gunn rats.

Eighteen hr after ip injection of 125I-thyroxine (T4) in homozygous Gunn rats, the 125I bile:plasma (B/P) ratios and plasma clearance of T4 into bile were one—third of normal. Paper chromatography revealed a gross deficiency in the amount of T4-glucuronide (T4-G) present in the bile, with a relative excess in the quantities of I∼ and free T4. Normal rats excreted 7.8% of iv injected 131I-T4 into the bile in 200 min compared to only 3.8% in Gunn rats. 125I-T4-G was prepared biosynthetically. Normal rats were injected with 125I-T4, bile was collected and chromatographed on paper and the T4-G region was eluted. The 125I-T4-G was reasonably radiochemically pure as shown by 2-dimensional paper chromatography and by its hydrolysis to free T4 with ²-glucuronidase. Intravenously injected 125I-T4-G was very rapidly excreted into the bile in both normal and Gunn rats. In both initial B/P ratios around 200 were observed and 50% of the dose was excreted in the bile in the first 20 min; virtually all was excreted by 3...

RELATION BETWEEN THE BILIARY EXCRETION OF THYROXINE AND ITS BINDING BY THE SERUM PROTEINS IN MONKEYS.

Nonradioactive thyroxine (T4) and sodium salicylate were injected intravenously into monkeys given intravenous 13lI-labeled T4 24 hr before the injection. Nearly all the m I in the bile, before and after the injections, was in the form of glucuronides or sulfate esters, both of which require intracellular enzymes for their synthesis. Injections of T4 caused an increase in the proportion of free to bound T4 by decreasing the concentration of free binding sites on the serum thyroxine-binding globulin (TBG), a fall in the plasma concentration of radioactive protein-bound iodine (PB131I), and a rise in the concentration of 13lI in the bile. T4 had no effect on bile flow. Salicylate, injected after nonradioactive T4, increased the proportion of free to bound T4 in the plasma by displacing T4 from albumin, and caused a fall in the plasma PB131I concentration and a rise in the concentration of mI in the bile. Salicylate stimulated the bile flow. These findings are consistent with the hypothesis that only the fre...

Effect of salicylate on the biliary excretion of thyroxine in rats.

In rats in which the plasma thyroxine is labeled with I131, injections of salicylate cause an increase in the ratio of the concentrations of radioactivity in bile and plasma (B/P ratio) and a fall in plasma radioactivity. It is suggested that both effects are due to displacement of thyroxine from the main thyroxine- binding protein of the plasma by salicylate. The greatest effect produced by salicylate on the B/P ratio is not as great as the effect of injections of exogenous thyroxine. This finding is considered in relation to the mechanism whereby the biliary excretion of thyroxine increases at high plasma thyroxine concentrations.