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

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.

Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans

“…Previous studies suggested that DMEs were the most important proteins accounting for the inter-individual variability of APAP-induced hepatotoxicity and the development of adaptive tolerance (Adjei et al 2008; Court et al 2001; Jetten et al 2016; McKillop et al 1999; Strubelt et al 1979). Since un-biased gene expression analyses revealed that genes encoding DMEs and NRs were highly dysregulated after APAP treatment, detailed expression profiles of key DMEs involved in the APAP metabolism were examined.…”

“…Further, we demonstrated that introduction of exogenous hsa-miR-320a, hsa-miR-449a, or hsa-miR-877-5p rescued hepatic cells from APAP-induced hepatotoxicity. Compared to previous studies reporting the gene or miRNA expression profiles associated with APAP-induced hepatotoxicity (Jetten et al 2015; Morishita et al 2006; Wang et al 2009), the present study comprehensively and systematically examined the whole-genome expression of miRNAs and protein-coding genes affected by APAP-induced hepatotoxicity, validated the regulatory network between genes and miRNAs, and thus is relevant to understanding the role of miRNAs in regulating CYP450 expression in development of adaptive tolerance in APAP-induced hepatotoxicity.…”

“…Glutathione (GSH) conjugation by GSTT1, GSTP1, and GSTM1 efficiently detoxifies NAPQI, but is depleted by exposures to large doses of APAP, resulting in increased covalent binding of NAPQI to proteins (Zhao and Pickering 2011). Despite this existing body of knowledge, few studies have examined molecular mechanisms underlying inter-individual variability and the adaptive tolerance effect in APAP-induced hepatotoxicity (Adjei et al 2008; Court et al 2001; Jetten et al 2016; McKillop et al 1999; Strubelt et al 1979). …”

Microarray Expression Analysis for the Paradoxical Roles ofAcanthopanax senticosusHarms in Treating α-Synucleinopathies

“…Pcdh20, Cldn22, and Rnd1 may participate in cell adhesion, and the genetic variations in this process can cause synaptic dysfunction in PD (Chapman, ). The dysregulations of Psd, Cntnap1, and Capn11 can induce cytoskeletal abnormalities (Garcia‐Fresco et al ., ; Jetten et al ., ; Sironi et al ., ), which is linked to the pathogenesis of PD (Mila et al ., ). Nmbr can regulate the functions of 5‐hydroxytryptamine system (Yamano et al ., ), which may be involved in the development of PD through its interaction with the basal ganglia (Miguelez et al ., ).…”

“…Pcdh20, Cldn22, and Rnd1 may participate in cell adhesion, and the genetic variations in this process can cause synaptic dysfunction in PD (Chapman, 2014). The dysregulations of Psd, Cntnap1, and Capn11 can induce cytoskeletal abnormalities (Garcia-Fresco et al, 2006;Jetten et al, 2015;Figure 3. Pathway analysis of lncRNA/mRNA targets involved in the anti-α-synucleinopathies mechanism of AS.…”