Autoregulation of 3, 3′,5′-triiodothyronine production by rat liver microsomes

Kamiński, Tadeusz; Köhrle, Josef; Ködding, R.; Hesch, R. D.

doi:10.1530/acta.0.0980240

Cited by 5 publications

(2 citation statements)

References 10 publications

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“…Up to now, no clear demonstration of rT3 function has been observed apart from its role during glial cell-mediated neuronal guidance in mammalian brain development (11). The initial hypothesis that rT3 might act as potent inhibitor of DIO1 or DIO2 during T3 formation (12,13) could not be supported by in vivo experiments due to its short half-life and insufficient local concentrations (14). These observations did not support the hypothesis of rT3 acting as an autonomous regulator of extrathyroidal T3 formation under (patho-)physiological conditions.…”

Section: Introduction Endogenous Thyroid Hormones and Their Metabolitesmentioning

confidence: 99%

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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Structural formula of the "Janus-faced" THM 3,5-diiodo-L-thyronine (left), which has the same 3,5-iodine substitution pattern as its putative precursors L-T4 and L-T3 at the tyrosyl-ring, but lacks the iodine substitution in 3 ′-position of the phenolic ring which is essential for binding classical T3-receptors and conveying canonical and non-canonical thyromimetic effects. The roman god Janus symbolized "duality" and "jani" were ceremonial gateways in ancient Rome typically used for symbolically auspicious entrances or exits. Janus-face (right) source: This image comes from the 4th edition of Meyers Konversationslexikon (1885-90). The copyrights have expired and this image is in the public domain. Wikimedia, Meyers_b9_s0153_b1.png. HYPOTHESES AND THEORY a. 3,5-T2 is an endogenous metabolite of thyroid hormones T4 and T3 b. 3,5-T2 might represent the precursor of 3-iodothyronamine c. 3,5-T2 acts like T3 via canonical activation of T3 receptors albeit with lower potency d. 3,5-T2 exerts actions distinct from those of thyromimetically active T3 i) via mitochondrial targets ii) by its intrahepatic accumulation iii) by its intracrine mode of action e. 3,5-T2 formation and action might be altered in patients on T4 replacement therapy and causes adverse effects if abused.

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Section: Introduction Endogenous Thyroid Hormones and Their Metabolitesmentioning

confidence: 99%

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

et al. 2020

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“…A possible mechanism could be the pH-dependent production of regulatory iodothyronines rT3 and/or 3'5'-T2, which were shown to inhibit T3 production by the L-thyroxine 5'-deiodinase in pH-dependent manner in microsomal fractions in vitro (Kaminski et al, 1981).…”

Section: Discussionmentioning

confidence: 99%

pH-dependency of iodothyronine metabolism in isolated perfused rat liver

Köhrle¹,

Müller²,

Ködding³

et al. 1982

Biochemical Journal

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1. Isolated livers from fed male rats were perfused for 2h with T4 (L-thyroxine), T3 (L-3,3',5-tri-iodothyronine) or rT3 (L-3,3',5'-tri-iodothyronine) at different pH values (7.1-7.6) in a fully synthetic medium, whereby normal metabolic functions were maintained without addition of rat blood constituents or albumin. 2. T3 output into the medium and net T3 production reached a maximum at a pH of the medium of 7.2 and significantly decreased with alteration of the pH when livers were perfused with T4 as a substrate. 3. However, the net T4 and T3 uptake by the liver, as well as the hepatic T4 and T3 content after perfusion, were not dependent on the pH of the perfusion when livers were offered T4 or T3 as substrates respectively. 4.Determination of intracellular pH by the analysis of the distribution of the weak acid dimethyloxazolidinedione allows the conclusion that the pH optimum of iodothyronine 5'-deiodinase in the intact perfused liver corresponds to the maximum determined in vitro for the membrane-bound enzyme localized in the endoplasmic reticulum. 5. The rapid 5'-deiodination of rT3 to 3,3'-T2 (L-3,3'-di-iodothyronine), the fast disappearance of 3,3'-T2, and the fact that no net rT3 production from T4 could be detected, supports the hypothesis that in rat liver iodothyronine 5'-deiodinase activity seems to predominate over iodothyronine 5-deiodinase activity. 6. Thus the rat liver can be considered in normal physiological situations as an organ forming T3 from T4 and deiodinating rT3 originating from extrahepatic tissues, whereby the cellular iodothyronine 5'-deionination rate is controlled by the intracellular pH.Extrathyroidal enzymic deiodination of the thyroid hormone L-thyroxine (T4) to other iodothyronines results in both activation and inactivation of T4. One product, L-3,3',5-tri-iodothryonine (T3) represents a compound that is more active, in terms of metabolic action and effects, than T4, whereas the other product, L-3,3',5'-tri-iodothyronine (rT3) is regarded as calorigenically inactive (Jorgensen, 1978). The (two) enzyme(s) iodothyronine 5'-deiodinase and 5-deiodinase forming these different tri-iodothyronines exhibit different pH optima in rat liver microsomal fractions and liver homogenates in vitro [for a review, see Kohrle (1981)1. Uptake, deiodination and conjugation of iodothyronines by isolated perfused rat liver was initially detected by paper chromatography of the radiolabelled compounds (Briggs et al

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Iodothyronine Deiodinases

Köhrle¹

2002

Methods in Enzymology

167

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Autoregulation of 3, 3′,5′-triiodothyronine production by rat liver microsomes

Cited by 5 publications

References 10 publications

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

3,5-T2—A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action

pH-dependency of iodothyronine metabolism in isolated perfused rat liver

Iodothyronine Deiodinases

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