Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
Hepatotoxicity is a major cause of drug development discontinuation, and its reliable evaluation method is highly needed. Recently, we have found that CYP1A1 inhibition may cause liver injury via AHR activation. In this study, we analyzed the relationship between hepatotoxicity and CYP1A1 inhibition using pesticides to clarify whether the relationship was observed with a different class of compounds. The results of rat 2-year RDT studies of 126 pesticides were obtained from the evaluation reports published by the Food Safety Commission Japan. If each hepatotoxicity endpoint (EP) was observed at any dose, the EP was considered positive. In addition, 5 group EPs (gEPs) were defined by grouping similar EPs, and if any of the EPs within a gEP was positive, the gEP was considered positive. The inhibitory activity against rat CYP1A1 was measured using its recombinant enzyme and a luminescent substrate, and a pesticide was considered positive if its inhibitory activity was ≥15%. The association analysis using Fisher's exact test showed associations of CYP1A1 inhibition with gEPs on hypertrophy and dyslipidemia as well as increased liver absolute weight, centrilobular hepatocyte hypertrophy, and increased blood cholesterol. Welch's t-test showed significant differences in the inhibitory activity between the positives and negatives for the above gEPs and EPs, except for centrilobular hepatocyte hypertrophy. These results corroborate our previous findings that CYP1A1 inhibition is associated with hepatotoxicity and CYP1A1 inhibition assay is useful for evaluating hepatotoxicity.
