Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
Hepatotoxicity is one of the most common toxicities observed in non-clinical safety studies of drug candidates, and it is important to understand the mechanism of hepatotoxicity in animals to assess the risk of drug-induced liver injury in humans. In this study, we tried to elucidate the mechanism of hepatotoxicity caused by Compound A, a drug candidate that showed hepatotoxicity characterized by centrilobular hypertrophy and centrilobular/mid-zonal lipid accumulation in hepatocytes in a 4-week oral repeated-dose toxicity study in male rats. In the liver samples of rats administered Compound A for 4 weeks, the expression of aryl hydrocarbon receptor (AHR) target genes, including Cyp1a1, was up-regulated, however, Compound A showed only minimal AHR activation in in vitro reporter assays. Therefore, we investigated the possibility that Compound A enhanced AHR activation by endogenous AHR agonists through inhibiting the CYP1 enzyme-dependent clearance of the agonists. In in vitro assays, Compound A showed inhibitory effects on both rat and human CYP1A1. In addition, Compound A enhanced rat and human AHR-mediated reporter gene expression induced by FICZ, a well-known endogenous AHR agonist. These results suggest that CYP1A1 inhibition-mediated AHR activation is involved in the hepatotoxicity caused by Compound A, and that the Compound A-induced hepatotoxicity is also possible in humans. Furthermore, this mechanism may explain hepatotoxicity caused by compounds that inhibit CYP1A1.
