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Cited by 397Thyroid Disorders and TreatmentsDrug Transport and Resistance MechanismsIon Transport and Channel Regulation

Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability

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Hennemann, Georg, Docter, Roelof, Friesema, Edith C. H., de Jong, Marion, Krenning, Eric P., Visser, Theo J.·2001·Endocrine Reviews
DOI 10.1210/edrv.22.4.0435
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Abstract

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis- Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level.

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  • Serum from patients with NTIS inhibits T4 uptake in rat hepatocytes, mediated in part by increased non-esterified fatty acids (NEFA) and bilirubin and by decreased albumin.

    “Using deiodination of T4 as a measure of cellular transport of T4 into rat hepatocytes, various older studies [4, 5, 6] reported that serum from patients with NTIS inhibits T4 uptake, mediated in part by increased non-esterified fatty acids (NEFA) and bilirubin and by decreased albumin.”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [4]

  • In muscle, local conversion of T4 to T3 by DIO2 is important for muscle function both in rodents and in humans.

    “In muscle, local conversion of T4 toT3 by DIO2 is important for muscle function both in rodents and in humans [4, 26, 27].”

    From An update on non-thyroidal illness syndrome (2021) · cites this paper as [4]

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Authors
Hennemann, G., Docter, R., Friesema, E. C. H., de Jong, M., Krenning, E. P., & Visser, T. J.
Affiliations
  • Erasmus MC (NL)
  • Department of Internal Medicine (R.D., E.C.H.F., T.J.V.), Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
  • Department of Nuclear Medicine (G.H., M.d.J., E.P.K.), Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
ORCID
Venue
Endocrine Reviews
Publisher
The Endocrine Society
Published
2001-08-01
Volume
22
Issue
4
Pages
451-476
ISSN
  • 0163-769X (ISSN-L)
  • 1945-7189
DOI
10.1210/edrv.22.4.0435
OpenAlex
W2108671981
Cited by
394
References
255
Citations by year
2026: 5 · 2025: 5 · 2024: 7 · 2023: 14 · 2022: 12 · 2021: 8 · 2020: 14 · 2019: 19 · 2018: 13 · 2017: 16 · 2016: 21 · 2015: 17 · 2014: 18 · 2013: 23 · 2012: 15
FWCI
2.00
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Endocrine Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Keywords
thyroid hormone transport, plasma membrane transport, thyroid hormone uptake, triiodothyronine, thyroxine, carrier-mediated transport, system L amino acid transporter, organic anion transporters, blood-brain barrier, low T3 syndrome, starvation
MeSH terms
Animals, Binding Sites, Biological Availability, Biological Transport, Active, Brain, Carrier Proteins, Cell Membrane, Humans, Species Specificity, Starvation, Thyroid Hormones, Hepatocytes

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