In vitro thyroid hormone metabolism: effects of nuclear receptor activation on the metabolic profiles of thyroxine in rat and human hepatocytes

Richardson, Vicki

In vitro thyroid hormone metabolism: effects of nuclear receptor activation on the metabolic profiles of thyroxine in rat and human hepatocytes

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March 21, 2019

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Richardson, Vicki
- Affiliation: School of Medicine, Curriculum in Toxicology

Abstract

Thyroid hormones are critical in the normal growth and development of amphibians, birds, fish, and mammals. There are numerous xenobiotics that interfere with thyroid hormone homeostasis; therefore, exposure to these xenobiotics could be detrimental to the growth and development.. Xenobiotics categorized as thyroid hormone disruptors have been defined by their ability to reduce circulating concentrations of thyroid hormone in serum. It is has been proposed that thyroid hormone disruption occurs through the induction of thyroxine (T4) glucuronidation and biliary elimination which ultimately results in reduced serum T4 concentrations. This mode of action has been described using animal models, but the relevance to humans has not been determined. This research tests the hypothesis that there are species differences in the hepatic metabolism of thyroid hormones and these differences occur via nuclear receptor activation. Here we demonstrate the utility of sandwich-cultured rat and human hepatocytes in measuring T4 metabolism following the activation of Aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR) or pregnane x receptor (PXR). The relationship between T4 metabolism and nuclear receptor activation was studied through the establishment of an in vitro assay for the qualitative and quantitative measurement of T4 metabolites. Here we report that hepatic glucuronidation may be a more important pathway for T4 metabolism in rats whereas T4 deiodination may be a favored pathway in humans. Following nuclear receptor activation, glucuronidation is a primary route of T4 metabolism in rat and humans hepatocytes. Agonists of CAR/PXR are more consistent in the induction of T4 glucuronidation in rat and human hepatocytes. We also show similarities in the in vivo and in vitro effect on T4 metabolism in response to the environmental contaminant, 2,2',4,4'-tetrabromodiphenyl ether (BDE 47). These results indicate possible species differences in hepatic T4 metabolism and these differences may be based on nuclear receptor activation.

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