Effects of Microsomal Enzyme Inducers on Thyroid Follicular Cell Proliferation and Thyroid Hormone Metabolism

Abstract

The effects of microsomal enzyme inducers on thyroid hormone homeostasis and the thyroid gland are of concern. We have investigated the effects of microsomal enzyme inducers on thyroid follicular cell proliferation and thyroid hormone metabolism in rats. We have shown that small increases in serum TSH can result in large increases in thyroid follicular cell proliferation. Furthermore, only those microsomal enzyme inducers that increase serum TSH--that is, phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN)-increase thyroid follicular cell proliferation, whereas those microsomal enzyme inducers that do not increase serum TSH--that is, 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB)-do not increase thyroid follicular cell proliferation. Deiodination does not appear to be the reason why serum T3 concentrations are maintained in microsomal enzyme inducer-treated rats. We have also shown that those microsomal enzyme inducers that increase serum TSH increase T3 UDP-glucuronosyltransferase (UGT) activity, whereas those microsomal enzyme inducers that do not increase serum TSH do not increase T3 UGT activity. This finding suggests that induction of T3 glucuronidation, rather than T4 glucuronidation, mediates increases in serum TSH of microsomal enzyme inducer treated rats.

Clofibrate Increases Hepatic Triiodothyronine (T3)- and Thyroxine (T4)-Glucuronosyltransferase Activities and Lowers Plasma T3and T4Concentrations in Pigs

“…The finding that mRNA concentrations of TSH receptor, sodium iodide symporter, thyroid peroxidase, and cathepsin B, all genes responsive to TSH, were moderately increased by 40 to 70% suggests that the thyroid was stimulated by the increased plasma concentration of TSH. This suggestion is confirmed by a study that showed that TSH plasma concentrations are increased by microsomal enzyme inducers, which stimulate the glucuronidation of T 3 (Klaassen and Hood, 2001). Our study further shows that expression levels of dual oxidase 2, a hydrogen peroxide-generating system that constitutes the rate-limiting step of thyroid hormone synthesis, and of thyroglobulin, a protein involved in thyroid hormone synthesis and storage, are not altered by clofibrate treatment.…”

Thyroid dysfunction in sea bass (Dicentrarchus labrax): Underlying mechanisms and effects of polychlorinated biphenyls on thyroid hormone physiology and metabolism

“…In our experiment no effect of PCB exposure on T 4 UGT could be observed, whereas other studies have reported marked induction in rats following exposure to individual PCB congeners (Adams et al, 2000;Brown et al, 2004b;Morse et al, 1993;Spear et al, 1990;Visser et al, 1993) and mixtures (Hood, 1999;Klaassen and Hood, 2001;Morse et al, 1996). In most of these reports reduced T 4 levels in the same animal accompanied an increased T 4 UGT activity and negative correlations between those two parameters suggested a causal relationship.…”

“…In most of these reports reduced T 4 levels in the same animal accompanied an increased T 4 UGT activity and negative correlations between those two parameters suggested a causal relationship. Generally, phenolic PCBs undergo detoxification by glucuronidation and induce hepatic UGTs to facilitate excretion of PCBs (Klaassen and Hood, 2001;Visser et al, 1993). Although there was no increase in hepatic T 4 -UGT activity in our experiment.…”

“…PCB exposure also induces the expression and activity of 0166-445X/$ -see front matter © 2011 Elsevier B.V. All rights reserved. doi: 10.1016/j.aquatox.2011.07.019 the phase-II enzymes glucuronosyltransferase and sulfotransferase that also utilize thyroid hormones as conjugate group acceptors and increase T 4 conjugation (Klaassen and Hood, 2001;Visser et al, 1993). These actions facilitate T 4 clearance by hepatic metabolism, reducing the biological half-life of T 4 .…”

Stoffmonographie für 1,2-Cyclohexandicarbonsäure-di-isononylester (Hexamoll® DINCH®) – HBM-Werte für die Summe der Metabolite Cyclohexan-1,2-dicarbonsäure-mono-hydroxyisononylester (OH-MINCH) und Cyclohexan-1,2-dicarbonsäure-mono-carboxy­isooctylester (cx-MINCH) im Urin von Erwachsenen und Kindern

“…Die erhöhten γ-Glutamyltransferase-und TSH-Werte, die erhöhten Organgewichte der Leber und Schilddrüse wie auch die follikuläre Hyperplasie/Hypertrophie der Schilddrüse wurden von den Autoren einer gemeinsamen Pathogenese über die Induktion von Enzymen zugeordnet und als toxikologisch nicht relevant eingestuft. So zeigen zusätz-liche Untersuchungen zur Wirkung von DINCH [37,38], dass Schilddrüseneffek-te über einen indirekten Mechanismus vermittelt werden: Induktion von Phase-II-Enzymen [39][40][41], hier insbesondere der UDP-Glucuronyltransferase, führt zu erhöhter Elimination von Schilddrüsen-hormonen [42] und damit sekundär zu Schilddrüseneffekten. Diese Schilddrü-seneffekte werden aus folgenden Grün-den als nicht relevant für den Menschen betrachtet [16]: Der Ratte fehlt das Thyroxin-bindende Globin (TBG).…”