Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, USA.
Division of Toxicology, Office of Applied Research and Safety Assessment, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, Laurel, MD, USA.
Food Chem Toxicol. 2020 Jun;140:111313. doi: 10.1016/j.fct.2020.111313. Epub 2020 Mar 30.
Anthraquinones are found in a variety of consumer products such as dietary supplements, traditional Chinese medicines, and drugs. Along with their widespread use, potential safety concerns have emerged, especially liver toxicity. Therefore, there is a need to conduct rapid and inexpensive safety assessment for anthraquinones due to a lack of animal and human toxicological data. Here, a combined in vitro cytotoxicity and in silico reverse dosimetry approach was adopted to consider the potential human liver toxicity of 16 anthraquinones and derivatives. First, cytotoxicity (EC) in two human liver cell lines (HepG2/C3A and HuH-7) was measured under two conditions (single and repeated dosing, 72 h). Second, toxic doses (D) required to yield plasma steady-state concentrations (C) equal to in vitro EC values were predicted by reverse dosimetry simulation using a PBPK model. Finally, D was compared to literature-derived estimated daily intake (EDI) of anthraquinones to assess safety. Among the 16 anthraquinones, rhein was identified as a potential hepatotoxicant due to a combination of cytotoxicity, plasma concentration, and daily intake level. These in vitro and in silico findings provide preliminary data and guidance for further animal and clinical studies to confirm liver toxicity of anthraquinones.
蒽醌类化合物存在于各种消费产品中，如膳食补充剂、中药和药物。随着它们的广泛使用，出现了潜在的安全问题，特别是肝毒性。因此，由于缺乏动物和人体毒理学数据，需要对蒽醌类化合物进行快速和廉价的安全性评估。在这里，采用了体外细胞毒性和计算反剂量测定相结合的方法，以考虑 16 种蒽醌类化合物及其衍生物对人类肝脏的潜在毒性。首先，在两种人肝细胞系（HepG2/C3A 和 HuH-7）中测量了在两种条件（单次和重复给药，72 小时）下的细胞毒性（EC）。其次，通过使用 PBPK 模型进行反剂量模拟，预测了产生与体外 EC 值相等的血浆稳态浓度（C）所需的毒性剂量（D）。最后，将 D 与文献中蒽醌类化合物的估计每日摄入量（EDI）进行比较，以评估安全性。在 16 种蒽醌类化合物中，由于细胞毒性、血浆浓度和每日摄入量水平的综合作用，大黄素被确定为一种潜在的肝毒物。这些体外和计算结果为进一步的动物和临床研究提供了初步数据和指导，以确认蒽醌类化合物的肝毒性。
