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Transcriptional comparisons of stem cell-derived hepatocytes (hiPS-Hep), HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury

ABSTRACT: Three current hepatic in vitro cell systems were compared at the gene expression level in order to determine their suitability for investigations of hepatotoxicity. For mechanistic investigations we focussed on the PHH spheroid system, treating them with IC10 concentrations of either aflatoxin B1, amiodarone or chlorpromazine for up to 2 weeks and investigating the transcriptional changes induced by each of the compounds. We observed significant alterations in genes regulating carcinogenic, steatotic and cholestatic pathologies respectively.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93840 | GEO | 2017/05/22

SECONDARY ACCESSION(S): PRJNA362580

REPOSITORIES: GEO

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Project description:Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles Amiodarone, a potent antiarrhythmic agent, is a highly active oxidant, exerting cytotoxic effects on thyrocytes at pharmacological concentrations. Patients receiving amiodarone usually remain euthyroid, but occasionally develop thyroid dysfunction, such as amiodarone-associated hypothyroidism or amiodarone-induced thyrotoxicosis. To elucidate the mechanism by which amiodarone elicits thyroid dysfunction, human thyroid follicles were cultured with TSH and amiodarone at therapeutic (1-2 microM) and pharmacological (10-20microM) concentrations, and the drug-induced effect on whole human gene expression was analyzed by cDNA microarray. Amiodarone at 1-2microM decreased the expression level of the sodium-iodide symporter (NIS) to nearly half, but did not affect genes participating in thyroid hormonogenesis (thyroid peroxidase, thyroglobulin, pendrin, NADPH oxidase). Higher concentrations (10-20 microM) decreased the expression of all these genes, accompanied by increased expression of antioxidant proteins such as heme oxygenase 1 and ferritin. When thyroid follicles obtained from a patient with Graves’ disease who had been treated with amiodarone for 2 months before thyroidectomy were cultured in amiodarone-free medium, TSH-induced thyroid function was intact, suggesting that amiodarone at a maintenance dose did not elicit any cytotoxic effect on thyrocytes. The ultrastructural features of cultured thyroid follicles were compatible with these in vitro findings. These in vitro and ex vivo findings suggest that patients taking maintenance doses of amiodarone usually remain euthyroid, probably due to escape from the Wolff-Chaikoff effect mediated by decreased expression of NIS mRNA. Furthermore, amiodarone is not cytotoxic for thyrocytes at therapeutic concentrations but elicits cytotoxicity through oxidant activity at supra-physiological concentrations. Keywords: Cultured human thyroid follicles

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Transcriptional comparisons of stem cell-derived hepatocytes (hiPS-Hep), HepaRG cells and 3D human hepatocyte spheroids as predictive in vitro systems for drug-induced liver injury

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