Host: The Japanese Society of Toxicology
Name : The 50th Annual Meeting of the Japanese Society of Toxicology
Date : June 19, 2023 - June 21, 2023
The liver is exposed to many toxicants. Past studies have suggested that hepatotoxicity is affected by reactive functional groups, and metabolic activation. Various prediction tools have been developed, but their accuracy remains to be improved.
We built a hepatotoxicity database of mainly pesticides, with information of their mode of action (MoA) and ADME. We analyzed the data to gain insights to improve hepatotoxicity prediction. The substances were grouped into three: High toxicity (“high”) group, which showed low LOEL values and severe hepatotoxicity-related findings, low toxicity (“low”) group, which showed high LOEL values and minor findings, and others.
First, we subjected them to two known QSAR tools, and found more than half showed false-negative results, suggesting the difficulty of structural alert-based hepatotoxicity prediction. Therefore, we explored possible factors useful for prediction in terms of structure, physical properties, ADME and MoA.
It turned out that some structural features associated with hepatic accumulation, metabolic difficulties are more common in the “high” group. Two groups were also differed in their physical properties (MW or log P) and ADME values (T1/2, Tmax, etc.) Moreover, we found that combining MW and log P could be a possible screening for hepatotoxicity.
On the other hand, we found that the “high” group contains more pesticides that target mitochondria or cytochrome P450, both are abundant in the liver. Furthermore, considering these factors enabled to detect hepatotoxic risk of a part of false-negative substances.
