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

Abstract

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...

Measurement of Polybrominated Diphenyl Ethers and Metabolites in Mouse Plasma after Exposure to a Commercial Pentabromodiphenyl Ether Mixture

“…The mechanism proposed for such reactions involves a HO radical attacking the carbon–oxygen bond. A similar mechanism has been reported to cleave the thyroxine diphenyl ether bond in vitro by incubation with rat liver homogenates (Balsam et al 1983). In the case of PBDEs, the intermediate product then cleaves into a brominated phenol and a phenoxy radical, which can abstract hydrogen to form another brominated phenol.…”

Effect of Alterations in Thyroid Status on the Metabolism of Thyroxine and Triiodothyronine by Rat Pituitary Gland In Vitro

“…The nature of the non-T3 generating pathway for T4 metabolism in rat pituitary whose activity varies directly with thyroid hormone status is not clearly proven. We have been unable to detect a pathway for the oxidative cleavage of the ether-link of the T4 molecule with loss of outer ring iodine (15), since no labeled iodotyrosines were detected after incubation of hemipituitaries with biosynthetically derived, uniformly labeled T4. On the otherhand, we have demonstrated generation of ['25I]rT3 from ['25I]T4 during short term (15 min) incubations.…”

Properties of 5′-deiodinase of 3,3′,5′-triiodothyronine in rat skeletal muscle

“…However, rT3 5'D in skeletal muscle may partially help regulate circu¬ lating rT3 concentration, since skeletal muscle is widely distributed throughout the body. We recently reported a pathway for ether-link cleavage of T4, T3 or rT:i to be present in rat skeletal muscle as well as in the liver (Balsam et al 1983), phagocytosing leukocyte (Burger et al 1983) and white adipose tissue (Maeda et al 1983a) on the basis of results of incubation in the absence of sulfhydryl agents (Tsukahara et al 1984). Further, white adipose tissue contains PTU-sensitive rT3 5'D, although deiodination of T4 and T3 does not occur (Maeda et al 1983a,b).…”