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Cited by 179Thyroid Disorders and TreatmentsChemical Analysis and Environmental ImpactThyroid Cancer Diagnosis and Treatment

Phenolic and Tyrosyl Ring Deiodination of Iodothyronines in Rat Brain Homogenates

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Kaplan, Michael M., Yaskoski, Kimberlee A.·1980·Journal of Clinical Investigation
DOI 10.1172/jci109887PMC PMC371684
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Abstract

Conversion of thyroxine (T(4)) to 3,5,3'-triiodothyronine (T(3)) in rat brain has recently been shown in in vivo studies. This process contributes a substantial fraction of endogenous nuclear T(3) in the rat cerebral cortex and cerebellum. Production of T(4) metabolites besides T(3) in the brain has also been suggested. To determine the nature of these reactions, we studied metabolism of 0.2-1.0 nM [(125)I]T(4) and 0.1-0.3 nM [(131)I]T(3) in whole homogenates and subcellular fractions of rat cerebral cortex and cerebellum. Dithiothreitol (DTT) was required for detectable metabolic reactions: 100 mM DTT was routinely used. Ethanol extracts of incubation mixtures were analyzed by paper chromatography in t-amyl alcohol:hexane:ammonia and in 1-butanol:acetic acid. Rates of production of iodothyronines from T(4) and T(3) were greater at pH 7.5 than at 6.4 or 8.6 and greater at 37 degrees C than at 22 degrees or 4 degrees C. Lowering the pH, reducing the protein or DTT concentrations, and preheating homogenates to 100 degrees C all increased excess I(-) production but reduced iodothyronine production. In cerebral cortical homogenates from normal rats, products of T(4) degradation were as follows (percent added T(4)+/-SEM in nine experiments): T(3), 1.9+/-0.5%; 3,3',5'-triiodothyronine (rT(3)), 34.0+/-2.4%; 3,3'-diiodothyronine (3,3'-T(2)), 5.8+/-1.6%; 3'-iodothyronine (3'-T(1)), </=2.5%; and excess I(-), 4.7+/-1.2%. In the same experiments, products of T(3) degradation were 3,3'-T(2), 63.3+/-5.5%, and 3'-T(1), 12.6+/-1.4%. Cerebral cortical homogenates from hyperthyroid rats and normals were similar in regard to T(4) to T(3) deiodination. In contrast, in cerebral cortical homogenates from hypothyroid rats, phenolic ring deiodination rates were increased and tyrosyl ring deiodination rates were decreased compared with normals.T(4) to T(3) conversion rates in cerebellar homogenates were greater than rates in cerebral cortical homogenates from the same normal rats and less than rates in cerebellar homogenates from hypothyroid rats. T(4) and T(3) tyrosyl ring deiodination rates were greatly diminished in cerebellar homogenates compared with cerebral cortical homogenates in normal and hypothyroid rats. High-speed (1,000-160,000 g) pellets from cerebral cortical homogenates were enriched in phenolic and tyrosyl ring deiodinating activities relative to cytosol. Fractional conversion of T(4) to T(3) was inhibited by T(4), iopanoic acid, and rT(3), but not by T(3). Tyrosyl ring deiodination reactions were inhibited by T(3), T(4), and iopanoic acid, but not by rT(3). These studies demonstrate separate phenolic and tyrosyl ring iodothyronine deiodinase enzymes in rat brain. The brain phenolic ring deiodinase serves in vivo as a T(4) 5'-deiodinase and closely resembles anterior pituitary T(4) 5'-deiodinase in physiological and biochemical characteristics. The physiological significance of the tyrosyl ring iodothyronine deiodinase enzyme is unclear; it shares several properties with rat hepatic T(4) 5-deiodinase.

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  • In healthy adults, D3 expression is found predominantly in the brain and skin.

    “In healthy adults, D3 expression is found predominantly in the brain and skin (24,25).”

    From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [24]

    The Discussion (page unavailable) reports substantial iodothyronine 5-deiodinase activity in rat brain tissue. It does not establish D3 expression in healthy adults or compare expression in brain and skin, so the claimed human tissue distribution is unsupported. (LLM, conf=0.79)

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  • An increase in serum T3 could upregulate DIO3 expression in the brain, increasing local T3 clearance, forming another local feedback control of T3.

    “an increase in serum T3 could upregulate DIO3 expression in the brain, increasing local T3 clearance, forming another local feedback control of T3 (41–43).”

    From Intrathyroidal feedforward and feedback network regulating thyroid hormone synthesis and secretion (2022) · cites this paper as [41]

    The Results (p. 555) report that T3 degradation in cerebral-cortex homogenates was greatest in hyperthyroid rats, and the Discussion suggests that this activity could provide intracellular T3 disposal. The study does not show that a rise in serum T3 upregulates DIO3 expression or establish an in vivo feedback mechanism; the hyperthyroid rats were given T4. (LLM, conf=0.86)

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Research works printed but not linked: 1

  1. Brasel, J. A., and D. B. Boyd. 1975. Influence of thyroid hormone on fetal brain growth and development. In Perinatal Thyroid Physiology and Disease. D. A. Fisher and G. N. Burrow, editors. Raven Press, New York. 59-71.

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Authors
Kaplan, M. M., & Yaskoski, K. A.
Affiliations
Harvard University (US)
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
1980-09-01
Volume
66
Issue
3
Pages
551-562
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci109887
PMC
PMC371684
OpenAlex
W2072073963
Cited by
179
References
53
Citations by year
2024: 1 · 2023: 3 · 2022: 1 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 5
FWCI
11.96
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Chemical Analysis and Environmental Impact
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
Keywords
thyroxine, triiodothyronine, deiodination, reverse T3, 3,3'-diiodothyronine, cerebral cortex, cerebellum, hyperthyroidism
MeSH terms
Animals, Brain, Dithiothreitol, Hydrogen-Ion Concentration, Hyperthyroidism, Hypothyroidism, Iodine, Iopanoic Acid, Male, Subcellular Fractions, Temperature, Thyronines, Thyroxine, Time, Triiodothyronine, Rats, In Vitro Techniques

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