Liver toxicity of anthraquinones: A combined in vitro cytotoxicity and in silico reverse dosimetry evaluation.

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.