RT Journal Article
SR Electronic
T1 Acetaminophen-induced Liver Injury Alters Expression and Activities of Cytochrome P450 Enzymes in an Age-dependent Manner in Mouse Liver
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.119.089557
DO 10.1124/dmd.119.089557
A1 Yifan Bao
A1 Pei Wang
A1 Xueyan Shao
A1 Junjie Zhu
A1 Jingcheng Xiao
A1 Jian Shi
A1 Lirong Zhang
A1 Hao-Jie Zhu
A1 Xiaochao Ma
A1 Jose E. Manautou
A1 Xiao-bo Zhong
YR 2020
UL http://dmd.aspetjournals.org/content/early/2020/02/24/dmd.119.089557.abstract
AB 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.SIGNIFICANCE STATEMENT The current study in an animal model demonstrates that AILI results in decreased expression and enzyme activities of several examined drug-metabolizing P450s. The extent of such decreases is correlated to the degree of liver injury severity. The generated data may be translated to human health for patients who have DILI with decreased capability to metabolize drugs by certain P450s.