pH-dependency of iodothyronine metabolism in isolated perfused rat liver

Abstract

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

Reduced Activation and Increased Inactivation of Thyroid Hormone in Tissues of Critically Ill Patients

“…Liver D1 activity showed a very strong negative correlation with plasma total bilirubin, whereas no correlation was shown with inflammation as reflected by an elevated CRP level. To our knowledge, there are no previous data suggesting a relation between deiodinase activity and tissue hypoxia, but a pH dependence of D1 activity has been shown in perfused rat livers (32). Because D1 is responsible for the activation and D3 for the inactivation of thyroid hormone, regulation of deiodinase activities by cellular hypoxia may be a tissuespecific way to alter thyroid hormone bioactivity during limited oxygen supply.…”

Reverse 3,3′,5′‐Triiodothyronine Suppresses Increase in Free Fatty Acids in Chickens Elicited by Dexamethasone or Adrenaline

“…The dose of rT 3 applied in these experiments was the same as described previously (Bobek et al., 1996, 1997). Since rT 3 disappeared rapidly from the circulation (Köhrle et al., 1982; Pearce et al., 1985), as could be deduced from the half‐time of rT 3 in the blood plasma of chickens: 43.7 ± 1.98 min (cf. 147.0 ± 6.0 min for T 3 ) (Bobek et al., 1996), it was decided to repeat treatment with rT 3 5 h after the first injection in the experiment with Dex.…”

3,5-T2 - An Endogenous Thyroid Hormone Metabolite As Promising Lead Substance in Anti-Steatotic Drug Development?

“…10 g wet weight) in a similar experimental setup, but with a fully synthetic fluorocarbon medium acting as oxygen carrier [15]. In contrast, this TH metabolite 3,3'-T2 was readily formed after perfusion with rT3 (3 nmol/200 ml; estimated half-life 8.7 min) [15,16] , a clear indication of functional 5'-Dio1 activity of these livers, which also produced T3 during perfusion with T4 (26 nmol/200ml) with an apparent conversion rate of 13% at pH 7.2. 3,5-T2 formation or its hepatic content after perfusion with the potential precursors T4 or T3 was not analysed then, but the high stability of T3 (estimated half-life ca.…”