Study On Indiyidual Susceptible Biomarker To Acetaminophen-induced Liver Injury Using Systems Toxicology Approaches

Acetaminophen(APAP)-induced liver injury is a leading cause of drug-induced hepatotoxicity, which has evident individual susceptibility in clinic. Therefore, it is of great benefit to screen the individual susceptible biomarkers to improve the safety of APAP. This study aims to identify and validate individual susceptible biomarkers on liver injury by analyzing the difference of innate gene expression and metabolite profiling of susceptible and resistant rats prior to administration using toxicogenomic and metabonomic approaches.1. Total RNA of rats’peripheral blood was extracted to detect the expression of innate genes before exposure to APAP, and30genes were identified as potential gene markers by integrated analysis of microarray data. A new set of rats were applied to validate the gene markers by conducting the Real-time fluorescent quantitative PCR analysis. The results suggested that rats with low expression of Incenp、Rpgripl、Hapln2%Cxadr in blood might be susceptible to APAP liver injury, and these genes might be gene markers to APAP induced liver injury.2. A GC-MS based metabonomic approach was applied to analyze the urine of rats obtained before exposure to APAP, and then analysis of metabonomic data of susceptible and resistant group of five rats was performed using SPSS software. The results suggessted that Propanedioic acid, L-threonine,3,4-dihydroxy butyric acid, L-methionine, glycine, galactose, uridine and β-D-glucopyranoside might be metabolite markers to APAP induced liver injury.The study suggests that innate gene expression and metabolite content prior to administration might be correlated with the liver injury induced by APAP, and can be as biomarker, more importantly, the current findings, which provide a novel methodology to predict individual susceptibility to liver injury induced by compounds, can be applied to studies of other hepatotoxicants and other species.