Study on Early Toxicity of Paracetamol to Drug-induced Liver Injury in Mice Based on Lipid Metabonomics Research / 中国药房

ABSTRACT

OBJECTIVE： To study early toxicity of paracetamol （APAP） to drug-induced liver injury in mice based on lipid metabonomics research， and to provide reference for finding potential biological marker. METHODS： Totally 20 mice were randomly divided into normal group and APAP liver injury group， with 10 mice in each group. APAP liver injury group was given intraperitoneal injection of APAP 300 mg/kg to establish acute liver injury model； normal group was given constant volume of normal saline intraperitoneally. 1 h later， the blood of mice was collected to isolate plasma. UPLC-Triple-TOF-MS method was used to detect plasma metabolites and perform metabonomics analysis. PCA， PLS-DA and OPLS-DA analysis distinguished the difference of metabolism profiles between groups. The lipid metabolites were screened and identified according to HMDB， Metlin and LIPID MAPS databases. Meanwhile， the changes of APAP level in plasma of mice were detected. The lipid metabolites with variable influence in the projection （VIP） greater than 1 and P＜0.05 in OPLS-DA analysis were identified as differential metabolites. The correlation between lipid differential metabolites and plasma APAP level was analyzed. RESULTS： PCA， PLS-DA and OPLS-DA results showed that sample points in normal group and APAP liver injury group were located in different areas with good differentiation. Compared with liver injury group and normal group， levels of 5 fatty acid metabolites were significantly increased or decreased； levels of 8 glycerophospholipids were significantly decreased and one sphingolipids was significantly increased. 9-thiastearic acid， tetradecanedioic acid， 9-hydrogen peroxide-10，12-octadecadienoic acid， L-myristoyl carnitine （fatty acid） and scyphostation A （sphingolipids） levels had a significant correlation with APAP level in plasma. CONCLUSIONS： The plasma lipid metabolomics showed abnormal changes 1 hour after acetaminophen exposure. A total of 14 related lipid differential metabolites are found， and 5 of which are significantly correlated with APAP level in plasma.