Cytochrome P450 inhibition correlates with hepatotoxicity of pesticides: Analysis using repeated-dose toxicity data in rats.

Drug-induced liver injury (DILI) remains a significant challenge in drug development and safety assessment, requiring a deeper understanding of its underlying mechanisms. We recently reported that the inhibition of cytochrome P450 (P450) enzymes CYP1A1 and CYP1B1 is associated with DILI; however, it is unclear whether this association extends to non-pharmaceutical chemicals with structurally and pharmacologically diverse properties. In this study, we aimed to clarify the relationship between P450 inhibition and the hepatotoxicity of pesticides by using the results of rat repeated-dose toxicity studies and in vitro assays. A test set of 126 pesticides was evaluated for inhibitory activity against six rat P450s using recombinant enzymes and luminescent substrates. Statistical analyses revealed that the inhibition of CYP1A1 and CYP2C6 was significantly (p < 0.05) associated with liver hypertrophy-related findings, including weight increase and centrilobular hepatocyte hypertrophy, and dyslipidemia characterized by elevated blood cholesterol levels. In addition, simple regression analysis demonstrated that CYP2C6-inhibitory activity correlated with the lowest observed adverse effect level (LOAEL) values for the hypertrophy and dyslipidemia in carbamates. These results suggest that hepatotoxicity associated with CYP1A1 inhibition is a common phenomenon across chemical classes, and that CYP2C6 inhibition is specifically linked to liver hypertrophy and dyslipidemia in pesticides.