Effect of Starvation on the Production and Peripheral Metabolism of 3,3′,5′-Triiodothyronine in Euthyroid Obese Subjects*

173

A B S T R A C T As judged from both paper and column chromatography, slices or homogenates of liver from rats fasted for 48 h displayed a lesser rate of generation of 1251-labeled 3,5,3'-triiodothyronine (T3) from 1251-labeled thyroxine (T4) added to incubation media than did preparations from normal chow-fed animals. A similar defect in the conversion of T4 to T3 in the livers of fasted animals was observed when preparations were incubated with substrate concentrations of T4 so that T3 generation could be assessed by radioimmunoassay. The effect offasting could be prevented, wholly or in part, by administration of glucose in the drinking water to otherwise fasted animals, and the degree ofprevention appeared to be proportional to the concentration of glucose employed. Diminished generation of T3 from T4 was similarly evident in the livers of animals with streptozotocin-induced diabetes mellitus, and this defect was overcome by the provision of insulin in vivo, but not in vitro. Decreased formation of T3 from T4 was also observed in preparations of liver from animals given dexamethasone, amiodarone, and propylthiouracil. In no case could these effects on the net formation of T3 from T4 be explained by effects of the experimental conditions on the degradation of the T3 generated, as judged from the rate of degradation of exogenous 125I-T3 measured in parallel incubates.An analysis of the rate of disappearance of 125I-T4 from reaction mixtures in relation to the rate of appearance of 125I-T3 and 1251-iodide was employed to estimate the activity of the 5-monodeiodinating pathway of T4 metabolism that leads to the formation of 3,3',5'-triiodothyronine (reverse T3). Such estimates indicated that reverse T3 formation was actively proceeding in the preparations studied, was slightly enhanced by Received for publication 9 November 1977 and in revised form 14 March 1978. fasting, was unaffected by dexamethasone and amiodarone, and was markedly inhibited by propylthiouracil.In view ofthe similarities between the effect ofthese experimental manipulations on the generation of T3 from T4 by rat liver in vitro to their effects on the production rates and serum concentrations of T3 in man, it is concluded that the rat liver system provides a suitable model for the study of factors that influence the conversion of T4 to T3 in man. In addition, the findings strongly indicate that this process, at least in the liver, is closely linked to the utilization of carbohydrate. INTRODUCTION Recent studies have provided convincing evidence that 3,5,3'-triiodothyronine (T3)l contributes a major portion to the overall metabolic action of the thyroid hormones within the peripheral tissues. It is evident, moreover, that much of the T3 found in the blood of normal man arises, not by direct secretion from the thyroid gland, but rather from the peripheral monodeiodination of thyroxine (T4) in its outer ring at the 5'-position. It is generally agreed that this reaction results in activation of the hormone molecule, as T3 is several times more ...

supporting

confidence: 86%

The Influence of Fasting, Diabetes, and Several Pharmacological Agents on the Pathways of Thyroxine Metabolism in Rat Liver

Balsam¹,

Ingbar²,

Sexton³

1978

173

“…For example, under certain circumstances, the sum of the apparent production rates of T3 and rT3 is far less than the overall rate of deiodination of T4. This is characteristically true in several clinical conditions that lead to impaired peripheral production of T3, such as starvation (28,29), and hepatic cirrhosis (30,31). Here, the overall degradation of T4 is unchanged and T3 production is markedly reduced, while rT3 production rates are only slightly increased, findings that suggest that T4 metabolism has been diverted to other pathways.…”

Section: Discussionmentioning

confidence: 82%

Formation of diiodotyrosine from thyroxine. Ether-link cleavage, an alternate pathway of thyroxine metabolism.

Balsam¹,

Sexton²,

Borges³

et al. 1983

A B S T R A C T Studies were performed to elucidate the nature of the pathway of hepatic thyroxine (T4) metabolism that is activated by inhibitors of liver catalase. For this purpose, the metabolism of T4 in homogenates of rat liver was monitored with T4 labeled with '25I either at the 5'-position of the outer-ring ('251-#-T4) or uniformly in both the outer and inner rings (125I-U-T4). In homogenates incubated with 125I-0-T4 in an atmosphere of 02, the catalase inhibitor aminotriazole greatly enhanced T4 degradation, promoting the formation of large proportions of '25I-labeled iodide (125I1 I-) and chromatographically immobile origin material (1251-OM), but only a minute proportion of '25I-labeled 3,5,3'-triiodothyronine ('25I-T3) (T3 neogenesis). In an atmosphere of N2, in contrast, homogenates produced much larger proportions of 1251-T3, and aminotriazole had no effect. In incubations with 125I-U-T4, under aerobic conditions, control homogenates degraded T4 slowly; formation of 1251-labeled 3,5-diiodotyrosine ('25I-DIT) was seen only occasionally and in minute proportions. However, in homogenates incubated under 02, but not N2, aminotriazole consistently elicited the formation of large proportions of 1251-DIT, indicating that the ether link of T4 was being cleaved by an 02-dependent process.Formation of 125j-DIT in the presence of aminotriazole and 02 was markedly inhibited by the substrates of peroxidase, aminoantipyrine, and guaiacol. GSH greatly attenuated the increase in DIT formation induced by aminotriazole, whereas the sulfhydryl inhibitor N-ethylmaleimide (NEM) activated the DIT-generating pathway, even in the absence of aminotriazole.This work has been published in abstract form in 1979, Clin. Res., 27:247A.Received for publication 18 May 1982 and in revised form 3 May 1983. Activation of the in vitro formation of 125I-DIT from 125I-U-T4was also produced by the in vivo administration of aminotriazole or bacterial endotoxin, an agent that reduces hepatic catalase activity. Studies with 125I-DIT as substrate revealed it to be rapidly deiodinated by liver homogenates under aerobic conditions. Recovery of 125I-DIT from 125I-U-T4 was increased by the addition of the inhibitor of iodotyrosine dehalogenase, 3,5-dinitrotyrosine. However, as judged from studies conducted in parallel with radioiodinelabeled DIT and 1251-U-T4 as substrates, none of the factors that altered the proportion of 1251-DIT found after incubations with 125I-U-T4 did so by altering the degradation of the 125I-DIT formed.The factors that influenced DIT formation from T4 in rat liver had opposite effects on T3 neogenesis. Thus, aminotriazole, endotoxin, NEM, and an aerobic atmosphere, all of which enhanced DIT formation, were inhibitory to T3 neogenesis. In contrast, anaerobiosis and GSH inhibited ether-link cleavage of T4, but facilitated T3 neogenesis.The foregoing results suggest that a pathway for the ether-link cleavage of T4 to yield DIT is present in rat liver. Activity of this pathway, which appears to be peroxidase mediated, i...

“…A decrease in the serum concentration of T3 (6)(7)(8)(9)(10) and the production of T3 from T4 (11)(12)(13) have been demonstrated in man under a variety of circumstances. An increase in serum rT3 concentration almost always occurs in these states (9,10,14,15), probably due to a decrease in rT3 clearance rather than enhanced rT3 production (11,16,17). In animals, the in vitro conversion of T4 to T3 was first reported by Larson et al (18) in 1955 in rat kidney slices, but the significance of these findings was not immediately recognized.…”

Section: Introductionmentioning

confidence: 99%

The Role of Sulfhydryl Groups on the Impaired Hepatic 3′,3,5-Triiodothyronine Generation from Thyroxine in the Hypothyroid, Starved, Fetal, and Neonatal Rodent

Harris¹,

Fang²,

Hinerfeld³

et al. 1979

A B S T R A C T The role of nonprotein sulflhydryl groups (NPSH) in the decreased in vitro hepatic 3',3,5-triiodothyronine (T3) generation from thyroxine (T4) in the starved, hypothyroid, fetal and 1-to 4-d-old neonatal rat and dwarf mouse was assessed. NPSH were measured in fresh 25% liver homogenates prepared in 0.1 M P04/10 mM EDTA buffer. As 516 4-d-old neonates, but had little or no effect in the fetal and hypothyroid rat and dwarf mouse. Liver homogenates stored for 6 mo at -20°C lost their capacity to generate T3 from T4. NPSH concentrations in the frozen homogenates decreased progressively with increasing storage and were absent by 6 mo. 5'-Deiodinase activity correlated with NPSH concentration in the stored homogenates (r = 0.95, P < 0.005). Addition of DTT partially restored hepatic T3 generation in the frozen homogenate. It is concluded that NPSH are important for the action of the liver 5'-deiodinase. The decreased hepatic T3 generation in the starved rat is associated with decreased NPSH but not with a decrease in the absolute quantity of 5'-deiodinase because provision of sulfhydryl groups restored hepatic T3 generation to normal. In contrast, the decreased hepatic T3 generation in the adult hypothyroid rodent and in the fetal rat is probably due to a decrease in the enzyme concentration per se. In the 1-and 4-d neonatal rat, the decrease in hepatic T3 generation is secondary to a decrease in NPSH and the deiodinating enzyme.