Discrimination of active and inactive substances in cytotoxicity based on Tox21 10K compound library: Structure alert and mode of action.

In vitro cytotoxicity assay is an ideal alternative method for the in vivo toxicity in the risk assessment of pollutants in environment. However, modes of action (MOAs) of cytotoxicity have not been investigated for a wide range of compounds. In this paper, binomial and recursive partitioning analysis were carried out between the cytotoxicity and molecular descriptors for 8981 compounds. The results showed that cytotoxicity is strongly related to the chemical hydrophobicity and excess molar refraction, indicating the bio-uptake and chemical-receptor interaction through π and n electron pair play important roles in the cytotoxicity. The decision tree derived from recursive partitioning analysis revealed that the studied compounds could be divided into 25 groups and their structural characteristics could be used as structure alert to identify active and inactive compounds in cytotoxicity. The descriptors used in the decision tree revealed that chemical ionization and bioavailability could affect the cytotoxicity for ionizable and highly hydrophobic compounds. Comparison of MOAs based on Verhaar's classification scheme showed that many inert or less inert compounds were inactive substance, and many reactive or specifically-acting compounds were active substances in the cytotoxicity. In vitro toxicity assay instead of in vivo toxicity assay can be used in the environmental hazard and risk assessment of organic pollutants. The descriptors used in the binomial equation and decision tree reveal that chemical hydrophobicity, ionization and solubility play very important roles for identification of active and inactive compounds. The results obtained in this paper are valuable for understanding the modes of action in cytotoxicity and in vivo-in vitro toxicity relationship.