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Species Differences in Nuclear Receptor Activation and Hepatic Thyroid Hormone Metabolism
Citation:
Richardson, V. Species Differences in Nuclear Receptor Activation and Hepatic Thyroid Hormone Metabolism. BASF Thyroid Mini Symposium, Virtual, NC, December 09, 2021. https://doi.org/10.23645/epacomptox.17209241
Impact/Purpose:
Presentation to the BASF Thyroid Mini Symposium December 2021. This presentation describes the quantitative species differences in nuclear receptor activation and the conequent increase in thyroid hormone clearance.
Description:
Thyroid hormones are essential to many physiological processes during development; therefore, xenobiotics that alter thyroid hormone homeostasis have potential to be developmental toxicants. One proposed mode of action (MoA) for hypothyroxinemia consists of the activation of the aryl hydrocarbon (AhR), constitutive androstane (CAR) and/or pregnane X (PXR) nuclear receptors in the liver, which increases metabolism and biliary elimination of thyroxine (T4) through induction of xenobiotic metabolizing enzymes. This MoA has been examined in rodents; however, the relevance to humans is unclear. Fresh sandwich-cultured hepatocytes from human or male Sprague-Dawley rats were treated with AhR, CAR or PXR activators. After 72h, culture medium was replaced with physiological concentrations of [125I]-T4 (0.05 µM (rat) or 0.1 µM (human)) and incubated for 24h. The resulting culture media were then collected and analyzed for T4 glucuronide (T4G) and sulfonated (T4S) metabolites. Although T4S was unchanged in the media of treated rat or human hepatocytes, T4G increased in culture media of rat hepatocytes exposed to AhR, CAR, or PXR agonists and human hepatocytes exposed to CAR or PXR agonists. These results highlight the utility of hepatocytes in evaluating the potential species differences in the effects of nuclear receptor activators on thyroid hormone metabolism. This abstract may not necessarily reflect official EPA policy.
URLs/Downloads:
DOI: Species Differences in Nuclear Receptor Activation and Hepatic Thyroid Hormone Metabolism
RICHARDSON.BASF THYROID MINI SYMPOSIUM 120621_M.PDF (PDF, NA pp, 1718.291 KB, about PDF)