Marked differences in thyroxine (T4) metabolism following in vitro exposure of Wistar rat and human hepatocytes to several reference CAR/PXR nuclear receptor activators.
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引用次数: 0
Abstract
Our study builds upon previous findings (Baze et al., 2024) by investigating species differences in thyroxine (T4) metabolism regulation by CAR/PXR activators using cryopreserved primary Wistar rat hepatocytes (PRH) and human hepatocytes (PHH) in 2D-sandwich over a 7-day treatment period. Daily exposure of PRH to phenobarbital, 5-Pregnen-3β-ol-20-one-16α‑carbonitrile (PCN) or dexamethasone increased T4 clearance over the last 24 h exposure (up to 60 %, 79 % and 67 % over control, respectively) and secretion of T4-glucuronide (T4-G; up to 463, 661 and 545 pmol/106 cells over control, respectively). Effects were concentration-dependent for phenobarbital and PCN and highest at the lowest concentration for dexamethasone, while rifampicin barely affected T4 clearance and T4-G secretion. None of the compounds, at any tested concentration, affected these parameters in PHH. Additionally, mRNA expression data were consistent with the species-specific and concentration-dependent regulation of phase I Cyp/CYP, phase II Ugt/UGT and phase III Mrp2/MRP2 pathways occurring in rat and human liver following CAR/PXR activation. T4-UGT relative activity increased in PRH only, specifically by PCN, dexamethasone and phenobarbital. The comparison of PRH and PHH responses to compounds represents an important step towards using in vitro methods to reduce animal testing. We recommend using relative T4-UGT activity thresholds observed in PRH as benchmarks for defining compound-related effects across species, helping determine the human relevance of thyroid effects in rodents.
期刊介绍：
Toxicology in Vitro publishes original research papers and reviews on the application and use of in vitro systems for assessing or predicting the toxic effects of chemicals and elucidating their mechanisms of action. These in vitro techniques include utilizing cell or tissue cultures, isolated cells, tissue slices, subcellular fractions, transgenic cell cultures, and cells from transgenic organisms, as well as in silico modelling. The Journal will focus on investigations that involve the development and validation of new in vitro methods, e.g. for prediction of toxic effects based on traditional and in silico modelling; on the use of methods in high-throughput toxicology and pharmacology; elucidation of mechanisms of toxic action; the application of genomics, transcriptomics and proteomics in toxicology, as well as on comparative studies that characterise the relationship between in vitro and in vivo findings. The Journal strongly encourages the submission of manuscripts that focus on the development of in vitro methods, their practical applications and regulatory use (e.g. in the areas of food components cosmetics, pharmaceuticals, pesticides, and industrial chemicals). Toxicology in Vitro discourages papers that record reporting on toxicological effects from materials, such as plant extracts or herbal medicines, that have not been chemically characterized.
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