title: Thyroid organotypic rat and human cultures used to investigate drug effects on thyroid function, hormone synthesis and release pathways.
abstract: 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 (2 h) and was sustained in both rat (24-48 h) and human (24 h) with ≥ 10 μM MMI. Thyroid from rats treated with single doses of MMI (30-1000 mg/kg) exhibited sustained TPO inhibition at 48 h. The MMI in vivo thyroid concentrations were comparable to the culture concentrations (~15-84 μM), 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 (≥ 10 μM) and PTU (100 μM). 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 (≥ 1500 μM, 24h). Extended exposure (48 h) 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.
authors.affiliation: Drug Safety Evaluation, Allergan Inc., 2525 Dupont Dr, Irvine, CA 92612, USA. vickers_alison@allergan.com
authors.forename: Alison E M
authors.initials: AE
authors.lastname: Vickers
authors.forename: Jason
authors.initials: J
authors.lastname: Heale
authors.forename: John R
authors.initials: JR
authors.lastname: Sinclair
authors.forename: Stephen
authors.initials: S
authors.lastname: Morris
authors.forename: Josh M
authors.initials: JM
authors.lastname: Rowe
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Fisher
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D013956:Antithyroid Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008713:Methimazole / Q000008:administration & dosage / Q000494:pharmacology*; D008875:Middle Aged; D011441:Propylthiouracil / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013960:Thyroid Function Tests; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013963:Thyroid Hormones / Q000096:biosynthesis*; D013997:Time Factors; D046509:Tissue Culture Techniques; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D013956:Antithyroid Agents; D013963:Thyroid Hormones; D008713:Methimazole; D011441:Propylthiouracil