【摘 要】
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Recent advances in stem cell technologies offer the opportunity to overcome the lack of in vitro toxicity testing models, in vitro differentiated hepatocytes from human pluripotent stem cells (hPSCs)
【机 构】
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Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon, Republic of Korea
【出 处】
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2016(第二届)毒性测试替代方法与转化毒理学(国际)学术研讨会暨有害结局路径(AOP)与风险评估培训会议
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Recent advances in stem cell technologies offer the opportunity to overcome the lack of in vitro toxicity testing models, in vitro differentiated hepatocytes from human pluripotent stem cells (hPSCs) have emerged as the most potential source for the prediction of drug and xenobiotic toxicity.However, human pluripotent stem cell-derived hepatocyte like cell (HLC) is not currently available for toxicity testing due to insufficient expressions and activities of major drug metabolizing enzymes (DMEs).In this study, we measured the mRNA expression levels of DMEs in HLCs compared to adult and fetal hepatocytes via global gene expression profiles.The mRNA expression levels of most DMEsassociated with drug and xenobiotic metabolism wereconsiderably low in HLCs.On the other hand, the mRNA expression levels of CYP1A1 and CYP1B1 regulated by aryl hydrocarbon receptor (AHR)were comparable to those in human primary hepatocyte (PHH).In addition, several signaling components of AHR were constitutively expressed in HLC.Quantitative real-time polymerase chain reaction (qRT-CPR) analysis revealed strong induction of both CYP1A1 and CYP1Blgenes by several AHR agonists including benzo(a)pyrene (BaP), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3-MC), and 2-(1H-indole-3-carbonyl)-thiazole-4-ca rboxylicacid methyl ester (ITE).Moreover, 6,2,4-trimethoxyflavone (TMF), a known AHR antagonist, exhibited inhibitory effect on the transcriptional activation of CYP1A1 and CYP1B1.These results indicated that AHR signaling pathway is active in HLC.Therefore, HLC can be used a valuable model for screening toxic substances triggering human AHR signaling pathway.
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