Best Practice & Research Clinical Endocrinology & MetabolismVol. 21, No. 2, pp. vii–viii, 2007

doi:10.1016/j.beem.2007.04.005available online at http://www.sciencedirect.com

Preface

The concept that cellular entry of thyroid hormone does not take place by simple dif-fusion but is mediated by transporters located in the plasma membrane has been es-tablished by experimental studies over the last three decades, but the evidence hasbeen received with considerable reservation to say the least. This was largely basedon the belief that diffusion of the lipophilic hormone through the lipid bilayer of thecell membrane is perfectly feasible. However, this ignored the fact that the cell mem-brane not only has a lipid core but also polar surfaces. Also the structure of thyroidhormone is amphipathic with the hydrophobic aromatic rings and iodine substituentsas well as a hydrophilic alanine side chain. Therefore, diffusion of thyroid hormone intothe cell must be strongly hindered by unfavorable interactions of the hormone withthe different parts of the plasma membrane.

The scepticism regarding the idea that transporters are required to get thyroid hor-mone into cells was much reduced after the identification of mutations in a T3 trans-porter (MCT8) in male patients with severe X-linked psychomotor retardation andelevated serum T3 levels. The severe neurological phenotype appears to be explainedby an impaired uptake of T3 in central neurons, thus preventing its action in these cellswhich is so important for normal brain development.

Transporters are not only involved in thyroid hormone uptake into cells but thesame and/or other transporters are also required for cellular efflux of the hormoneand its metabolites. These transporters are essential factors regulating the intracellularthyroid hormone levels available for binding to the receptors but also for conversionby the iodothyronine deiodinases. Transporters are thus crucial for both the actionand metablism of thyroid hormone.

Although we are still at the initial stages of identifying the relevant thyroid hormonetransporters and their role in the tissue-specific regulation of thyroid hormone avail-ability, we felt that it was timely to present the state of the art in this field in this specialissue of Best Practice and Research Endocrinology and Metabolism. Chapters written byPaul Chen and Josef Koehrle provide current knowledge regarding the mechanisms ofaction and metabolism of thyroid hormone as a necessary background to the chaptersdealing with different aspects of thyroid hormone transport. Different types of trans-porters involved in thyroid hormone transport are discussed, including the organic an-ion transporters by Bruno Hagenbuch, the heterodimeric amino acid transporters byPeter Taylor and the ‘‘monocarboxylate’’ transporters by Edward Visser and colleagues.

The importance of thyroid hormone transport into the brain for normal brain de-velopment is discussed by Heike Heuer and colleages. However, transport of maternal

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viii Preface

thyroid hormone across the placenta is also an essential step in the supply of thyroidhormone to the fetal brain at the time when the fetal thyroid is not functional yet, andthis aspect is discussed by Mark Kilby and colleages.

Charles Schwartz and Roger Stevenson discuss in detail the finding of mutations inthe MCT8 gene in patients with the so-called Allan-Herndon-Dudley syndrome(AHDS), first described by the latter authors in 1944 in one of the first reports ofX-linked mental retardation. The latter syndrome is regarded as a form of thyroidhormone resistance due to a defect in the cellular uptake of thyroid hormone. Thisis compared in the chapter of Samuel Refetoff and Alexandra Dumitrescu with thephenotypes of other forms of thyroid hormone resistance due to mutations in aT3 receptor or in a protein necessary for the expression of deiodinases and otherselenoproteins.

The rate limiting role of transporters in determining the intracellular conversion ofthe prohormone T4 to the active hormone T3 is discussed by Georg Hennemann andEric Krenning, and the chapter by Wendy van der Deure and colleagues focuses on thepossible effects of genetic variations in transporters on serum thyroid hormone andrelated biological endpoints in human subjects.

We doubt that the state-of-the-art in the thyroid hormone transporter field willbe static in the coming years. We hope that this issue will provide a useful guide tothe interested clinical and experimental endocrinologist to assist in following futuredevelopments in this area.

Theo J. VisserDepartment of Internal Medicine,

Erasmus University Medical Center,Room Ee 502, Dr Molewaterplein 50,3015 GE Rotterdam, The Netherlands

Tel.: þ31 10 463 5463; Fax: þ31 10 463 5430.E-mail address: t.j.visser@erasmusmc.nl