Loading…

Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways

Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and...

Full description

Saved in:
Bibliographic Details
Published in:Toxicology and applied pharmacology 2012-04, Vol.260 (1), p.81-88
Main Authors: Vickers, Alison E.M., Heale, Jason, Sinclair, John R., Morris, Stephen, Rowe, Josh M., Fisher, Robyn L.
Format: Article
Language:English
Subjects:
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Drug induced thyroid effects were evaluated in organotypic models utilizing either a rat thyroid lobe or human thyroid slices to compare rodent and human response. An inhibition of thyroid peroxidase (TPO) function led to a perturbation in the expression of key genes in thyroid hormone synthesis and release pathways. The clinically used thiourea drugs, methimazole (MMI) and 6-n-propyl-2-thioruacil (PTU), were used to evaluate thyroid drug response in these models. Inhibition of TPO occurred early as shown in rat thyroid lobes (2h) and was sustained in both rat (24–48h) and human (24h) with ≥10μM MMI. Thyroid from rats treated with single doses of MMI (30–1000mg/kg) exhibited sustained TPO inhibition at 48h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (~15–84μM), thus demonstrating a close correlation between in vivo and ex vivo thyroid effects. A compensatory response to TPO inhibition was demonstrated in the rat thyroid lobe with significant up-regulation of genes involved in the pathway of thyroid hormone synthesis (Tpo, Dio1, Slc5a5, Tg, Tshr) and the megalin release pathway (Lrp2) by 24h with MMI (≥10μM) and PTU (100μM). Similarly, thyroid from the rat in vivo study exhibited an up-regulation of Dio1, Slc5a5, Lrp2, and Tshr. In human thyroid slices, there were few gene expression changes (Slc5a5, ~2-fold) and only at higher MMI concentrations (≥1500μM, 24h). Extended exposure (48h) resulted in up-regulation of Tpo, Dio1 and Lrp2, along with Slc5a5 and Tshr. In summary, TPO was inhibited by similar MMI concentrations in rat and human tissue, however an increased sensitivity to drug treatment in rat is indicated by the up-regulation of thyroid hormone synthesis and release gene pathways at concentrations found not to affect human tissue. ► Novel model of rat thyroid or human thyroid slices to evaluate pathways of injury. ► TPO inhibition by MMI or PTU altered hormone synthesis and release genes. ► Rat thyroid was more sensitive to the drug effects than human tissue.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2012.01.029