Abstract
Acetaminophen (APAP) is a readily available over-the-counter drug and is one of the most commonly used analgesics/antipyretics worldwide. Large interindividual variation in susceptibility toward APAP-induced liver failure has been reported. However, the exact underlying factors causing this variability in susceptibility are still largely unknown. The aim of this study was to better understand this variability in response to APAP by evaluating interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes (PHH) from several donors (n = 5) exposed in vitro to a non-toxic to toxic APAP dose range. To evaluate interindividual variation, gene expression data/levels of metabolites were plotted against APAP dose/donor. The correlation in APAP dose response between donors was calculated by comparing data points from one donor to the data points of all other donors using a Pearson-based correlation analysis. From that, a correlation score/donor for each gene/metabolite was defined, representing the similarity of the omics response to APAP in PHH of a particular donor to all other donors. The top 1 % highest variable genes were selected for further evaluation using gene set overrepresentation analysis. The biological processes in which the genes with high interindividual variation in expression were involved include liver regeneration, inflammatory responses, mitochondrial stress responses, hepatocarcinogenesis, cell cycle, and drug efficacy. Additionally, the interindividual variation in the expression of these genes could be associated with the variability in expression levels of hydroxyl/methoxy-APAP and C8H13O5N-APAP-glucuronide. The before-mentioned metabolites or their derivatives have also been reported in blood of humans exposed to therapeutic APAP doses. Possibly these findings can contribute to elucidating the causative factors of interindividual susceptibility toward APAP. Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-015-1545-2) contains supplementary material, which is available to authorized users.
Highlights
Acetaminophen (APAP) is one of the most commonly used analgesics/antipyretics worldwide
The aim of this study is to evaluate the interindividual differences in gene expression changes and APAP metabolite formation in primary human hepatocytes of several donors (n = 5) exposed to a non-toxic to toxic APAP dose range
Interindividual variation in gene expression is a very common phenomenon; we have focused on the gene expression changes that are most different between individuals in response to APAP exposure
Summary
Acetaminophen (APAP) is one of the most commonly used analgesics/antipyretics worldwide. Thereby, it is a readily available over-the-counter drug. Apart from its beneficial effects as a pharmaceutical, APAP is the most common cause of acute liver toxicity in Europe and the USA (Lee 2007). Cytochrome P450 enzymes in the liver metabolize APAP to the oxidative metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is thought to cause the toxic effects of APAP through protein adduct formation, leading to oxidative stress and liver damage (Dahlin et al 1984a). The main body of our knowledge on the toxicological, or more specific hepatotoxic, mechanisms of compounds, Arch Toxicol (2016) 90:1103–1115 including APAP, is based on data collected from studies using animal models (Hinson et al 2010). There is a growing need for human in vitro models such as hepatic cell lines, liver slices, or primary hepatocytes cultures, to facilitate human-based research
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