Interindividual variation in gene expression responses and metabolite formation in acetaminophen-exposed primary human hepatocytes.

摘要: Acetaminophen (APAP) is a readily available over-the-counter drug and one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, exact underlying factors causing this variability are still largely unknown. The aim study was to better understand response APAP by evaluating differences gene expression changes metabolite formation primary human hepatocytes (PHH) from several donors (n = 5) exposed vitro non-toxic toxic dose range. To evaluate variation, data/levels metabolites were plotted against dose/donor. correlation between calculated comparing data points donor all other using Pearson-based analysis. From that, score/donor for each gene/metabolite defined, representing similarity omics PHH particular donors. top 1 % highest variable genes selected further evaluation set overrepresentation biological processes which with high involved include regeneration, inflammatory responses, mitochondrial stress hepatocarcinogenesis, cell cycle, efficacy. Additionally, these could be associated levels hydroxyl/methoxy-APAP C8H13O5N-APAP-glucuronide. before-mentioned or their derivatives have also reported blood humans therapeutic doses. Possibly findings can contribute elucidating causative APAP.