Authors: Yifan Bao, Pei Wang, Xueyan Shao, Junjie Zhu, Jingcheng Xiao, Jian Shi, Lirong Zhang, Hao-Jie Zhu, Xiaochao Ma, Jose E. Manautou, Xiao-bo Zhong
Summary: Drug-induced liver injury (DILI) is a global medical problem. The risk of DILI is often related to expression and activities of drug-metabolizing enzymes, especially cytochrome P450s (P450s). However, changes on expression and activities of P450s after DILI have not been determined. The aim of this study is to fill this knowledge gap. Acetaminophen (APAP) was used as a model drug to induce DILI in C57BL/6J mice at different ages of day 10 (infant), 22 (child), and 60 (adult). DILI was assessed by levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in plasma with a confirmation by H&E staining on liver tissue sections. The expression of selected P450s at mRNA and protein levels was measured by RT-PCR and LC-MS/MS, respectively. The activities of these P450s were determined by the formation of metabolites from probe drugs for each P450 using UPLC-QTOFMS. DILI was induced at mild to severe levels in a dose-dependent manner in 200, 300, and 400 mg/kg APAP treated groups at child and adult ages, but not at the infant age. Significantly decreased expression at mRNA and protein levels as well as enzymatic activities of CYP2E1, 3A11, 1A2, and 2C29 was found at child and adult ages. Adult male mice were more susceptible to ALIL than female mice with more decreased expression of P450s. These results implicate that altered levels of P450s in severely injured livers caused by drugs may affect the therapeutic efficacy of drugs, which are metabolized by P450s, more particularly for males.
Source: Drug Metabolism and Disposition, 2020; dmd.119.089557