Diagnosis of drug-induced liver injury in model mice by studying the inhibitory effect of serum components on P450 inhibition assay

Abstract

Drug-induced liver injury (DILI) causes abortive drug development in both clinical and non-clinical phases. Therefore, it is important to develop an evaluation system that can be used to accurately and easily assess DILI during drug development and at an early stage. The diagnosis of diseases using P450 inhibition assays, with focus on changes in cytochrome P450 (CYP, P450) during disease onset, has been previously validated in mouse models of ulcerative colitis and type 2 diabetes. In this study, we tested the effectivity of the P450 inhibition assay in a DILI mouse model treated with acetaminophen (APAP). We found that TNF-α expression was upregulated in the APAP-treated group, and CYP2E1 gene expression was significantly decreased at 8 h after treatment. In the P450 inhibition assay, in which sera were used, significant changes in CYP2E1 and CYP3A5 levels were observed 8 and 24 h after APAP administration, respectively. Receiver operating characteristic curve analysis showed significant inhibition rate changes; the area under the curve values of CYP2E1 and CYP3A5 were above 0.8, at 0.832 and 0.849, respectively. In conclusion, we suggest that P450 inhibition assay could be used for the diagnosis of liver diseases, such as acute DILI.