A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk.
A modified multiparametric assay using HepaRG cells for predicting the degree of drug-induced liver injury risk.
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使用 HepaRG 细胞进行改良的多参数测定，用于预测药物引起的肝损伤风险程度。
DOI：
10.1002/jat.3371
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发表时间：
2017
期刊：
影响因子：
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通讯作者：
Yoshihiro Konno.
中科院分区：
文献类型：
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作者：
Takafumi Tomida;Hayao Okamura;Tsuyoshi Yokoi;Yoshihiro Konno.
采用改良的多参数法，利用HepaRG细胞定量研究了预测药物性肝损伤（DILI）风险程度的方法。根据美国食品和药物管理局（FDA）批准的药物标签，将38种药物的DILI风险分为5类：撤回（WDN）、黑框警告（BW）、警告和注意事项（WP）、不良反应（AR）和不匹配（NM）。此外，WP被分为高关注和低关注两类。分化后的HepaRG细胞用药物处理24 h。最大浓度设定为治疗最大血浆浓度（Cmax）的100倍。药物处理后，测定细胞活力、谷胱甘肽含量、caspase 3/7活性、乳酸脱氢酶漏出量和白蛋白分泌量。作为每个参数的修改截断值，计算TC50（使反应降低50%的毒性浓度）和EC200（使反应等于对照的200%的有效浓度）。并计算毒性评分（各参数细胞毒性水平的总和评分）。这种改进的多参数分析方法预测DILI风险的敏感性为87%，特异性为87%。毒性评分对WDN、BW和WP（高度关注）类别具有良好的预测性能[截止值：评分≥1；受试者工作特征曲线下面积（ROC - AUC）： 0.88]，以及WDN和BW类别（截止值：评分≥3；ROC - AUC: 0.88）。这项新研究表明，在改良的HepaRG细胞多参数试验中，通过评估毒性评分，可以定量预测DILI风险程度。版权所有©2016 John Wiley & Sons， Ltd。
The approach for predicting the degree of drug‐induced liver injury (DILI) risk was investigated quantitatively in a modified multiparametric assay using HepaRG cells. Thirty‐eight drugs were classified by DILI risk into five categories based on drug labels approved by the Food and Drug Administration (FDA) as follows: withdrawn (WDN), boxed warning (BW), warnings and precautions (WP), adverse reactions (AR), and no match (NM). Also, WP was classified into two categories: high and low concern. Differentiated HepaRG cells were treated with drugs for 24 h. The maximum concentration was set at 100‐fold the therapeutic maximum plasma concentration (Cmax). After treatment with drugs, the cell viability, glutathione content, caspase 3/7 activity, lactate dehydrogenase leakage and albumin secretion were measured. As modified cut‐off values of each parameter, the TC50(toxic concentration that decreased the response by 50%) and EC200(effective concentration giving a response equal to 200% of controls) were calculated. In addition, the toxicity score (total sum score of the cytotoxic level of each parameter) was calculated. This modified multiparametric assay showed an 87% sensitivity and 87% specificity for predicting the DILI risk. The toxicity score showed a good predictive performance for WDN, BW and WP (high concern) categories [cut‐off: score ≥ 1; area under a receiver operating characteristic curve (ROC‐AUC): 0.88], and for WDN and BW categories (cut‐off: score ≥ 3; ROC‐AUC: 0.88). This study newly indicated that the degree of DILI risk might be predictable quantitatively by assessing the toxicity score in the modified multiparametric assay using HepaRG cells. Copyright © 2016 John Wiley & Sons, Ltd.