The integrity of the ether linkage during thyroxine metabolism in man

Pittman, Constance S.; Read, Virginia H.; Chambers, Joseph B.; Nakafuji, Haruyoshi

doi:10.1172/jci106246

Cited by 10 publications

(3 citation statements)

References 13 publications

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“…Hence, according to this formulation, inhibition of catalase would favor DIT formation by permitting the accumulation of H202, thereby promoting peroxidase-mediated cleavage of the ether bond of T4. Conversely (21)(22)(23) showed that after the administration of T4 variously labeled with either 14C or 3H in its outer ring, inner ring, or alanine side chain, a major fraction of administered radioactivity was recovered in urinary metabolites containing radionuclides from the three portions of the T4 molecule. Although these studies clearly suggested that the major pathways of T4 metabolism do not involve the cleavage of the ether bond, they were not strictly quantitative and could not rigorously exclude, therefore, the possibility that some portion of T4 was metabolized by cleavage of the ether link to yield DIT.…”

Section: Discussionmentioning

confidence: 99%

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

Balsam¹,

Sexton²,

Borges³

et al. 1983

J. Clin. Invest.

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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...

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Section: Discussionmentioning

confidence: 99%

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

Balsam¹,

Sexton²,

Borges³

et al. 1983

J. Clin. Invest.

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“…Since the clearance rate of Tetrac was reported to be slower than that of T3 by some early studies, the higher serum concentrations of "4C-labeled Tetrac could not be interpreted to mean a higher production rate for Tetrac than for T3 in man (25). Recently, Pittman, Read, Chambers, and Nakafuji (13) ratios of the urine were the same as the 3H/'4C ratios of the T4 dose suggesting that the deiodinated metabolites of T4 retained an intact diphenyl ether structure. Therefore, most likely the T3 and Tetrac formed from T4 metabolism are in turn deiodinated before urinary excretion without undergoing cleavage of the diphenyl ether.…”

Section: Discussionmentioning

confidence: 99%

“…The purity of radioactive T4 and T3 was 98% or greater before use. They were prepared for injection in a sterile solution of 1% ethanol, 0.9% scdium chloride, and 1% human albumin as described previously (13). Every thyroxine dose was chromatographed in at least two solvent systems and the presence of triiodothyronine was assayed directly in a liquid scintillation counter as de- Subjects.…”

Section: Methodsmentioning

confidence: 99%

The extrathyroidal conversion rate of thyroxine to triiodothyronine in normal man

Pittman¹,

Chambers²,

Read³

1971

J. Clin. Invest.

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214

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A B S T R A C T Eight normal subjects were administered tracer amounts of a 14C-labeled thyroxine, L-[tyrosyl-14C] T4, by multiple injections. Then serial blood samples were collected for isolation of the thyroxine, triiodothyronine, and tetraiodothyroacetic acid fractions by a combination of column and paper chromatographies. The chromatographic artifacts were corrected by adding to the sera a purified 3H-labeled thyroxine, D,L-[a,,f-3H] T4 immediately after the separation of sera from blood. 1-2% of the serum 14C radioactivity was observed in the triiodothyronine fraction and 2-4% of the serum 14C radioactivity was observed in the tetraiodothyroacetic acid fraction. Complete kinetic studies of thyroxine and triiodothyronine were compared in the same individual in four of the subjects. The extrathyroidal conversion rates of thyroxine to triiodothyronine were calculated from data obtained during both the injection and the postinjection periods as functions of the 14C-labeled thyroxine and triiodothyronine remaining in the body at time t and their fractional turnover rates. The average daily rate of the extrathyroidal conversion of thyroxine to triiodothyronine was 4% of the extrathyroidal thyroxine pool or 33% of the total thyroxine production. The amount of triiodothyronine generated by this pathway (22 ,ug/day) was found to contribute 31% of the extrathyroidal triiodothyronine pool or 41% of the daily triiodothyronine production. This pathway is a major source of triiodothyronine production. The extrathyroidal conversions of thyroxine to triiodothyronine and tetraiodothyroacetic acid are major metabolic pathways of thyroxine in normal man.

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