Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems

Rodrigues, Robim Marcelino; Heymans, Anja; Boe, Veerle De; Sachinidis, Agapios; Chaudhari, Umesh; Govaere, Olivier; Roskams, Tania; Vanhaecke, Tamara; Rogiers, Vera; Kock, Joery De

doi:10.1016/j.toxlet.2015.10.014

Cited by 46 publications

(36 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To validate the effects of APAP on UDP-glucuronosyltransferases and sulfotransferases, we extracted the expression data of the key genes, including genes encoding UDP-glucuronosyltransferases and sulfotransferases, in HepaRG cells from the GSE74000 data set (gene expression data affected by sub-cytotoxic concentration of APAP) (Rodrigues et al 2016), and observed similar “shut-down” response (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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

Gill

et al. 2017

Arch Toxicol

View full text Add to dashboard Cite

Acetaminophen (APAP) overdose is the leading cause of acute liver failure. Yet the mechanisms underlying adaptive tolerance toward APAP-induced liver injury are not fully understood. To better understand molecular mechanisms contributing to adaptive tolerance to APAP is an underpinning foundation for APAP-related precision medicine. In the current study, the mRNA and microRNA (miRNA) expression profiles derived from next generation sequencing data for APAP-treated (5 and 10 mM) Hep-aRG cells and controls were analyzed systematically. Putative miRNAs targeting key dysregulated genes involved in APAP hepatotoxicity were selected using in silico prediction algorithms, un-biased gene ontology, and network analyses. Luciferase reporter assays, RNA electrophoresis mobility shift assays, and miRNA pull-down assays were performed to investigate the role of miRNAs affecting the expression of dysregulated genes. Levels of selected miRNAs were measured in serum samples obtained from children with APAP overdose (58.6–559.4 mg/kg) and from healthy controls. As results, 2758 differentially expressed genes and 47 miRNAs were identified. Four of these miRNAs (hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p) suppressed drug metabolizing enzyme (DME) levels involved in APAP-induced liver injury by downregulating HNF1A, HNF4A and NR1I2 expression. Exogenous transfection of these miRNAs into HepaRG cells effectively rescued them from APAP toxicity, as indicated by decreased alanine aminotransferase levels. Importantly, hsa-miR-320a and hsa-miR-877-5p levels were significantly elevated in serum samples obtained from children with APAP overdose compared to health controls. Collectively, these data indicate that hsa-miR-224-5p, hsa-miR-320a, hsa-miR-449a, and hsa-miR-877-5p suppress DME expression involved in APAP-induced hepatotoxicity and they contribute to an adaptive response in hepatocytes.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Gill

et al. 2017

Arch Toxicol

View full text Add to dashboard Cite

show abstract

“…73 However, other studies showed a reduced sensitivity of HepaRG cells to the detection of hepatotoxic drugs. 74 These findings are in line with the discrepancy observed between HepaRG cells and PHH in the activation of apoptosis or necrosis upon exposure to acetaminophen.…”

Section: Applications Of Liver Cell Lines In In Vitro Researchmentioning

confidence: 99%

Cell sources forin vitrohuman liver cell culture models

Zeilinger

Freyer

Damm

et al. 2016

Exp Biol Med (Maywood)

186

160

View full text Add to dashboard Cite

In vitro liver cell culture models are gaining increasing importance in pharmacological and toxicological research. The source of cells used is critical for the relevance and the predictive value of such models. Primary human hepatocytes (PHH) are currently considered to be the gold standard for hepatic in vitro culture models, since they directly reflect the specific metabolism and functionality of the human liver; however, the scarcity and difficult logistics of PHH have driven researchers to explore alternative cell sources, including liver cell lines and pluripotent stem cells. Liver cell lines generated from hepatomas or by genetic manipulation are widely used due to their good availability, but they are generally altered in certain metabolic functions. For the past few years, adult and pluripotent stem cells have been attracting increasing attention, due their ability to proliferate and to differentiate into hepatocyte-like cells in vitro. However, controlling the differentiation of these cells is still a challenge. This review gives an overview of the major human cell sources under investigation for in vitro liver cell culture models, including primary human liver cells, liver cell lines, and stem cells. The promises and challenges of different cell types are discussed with a focus on the complex 2D and 3D culture approaches under investigation for improving liver cell functionality in vitro. Finally, the specific application options of individual cell sources in pharmacological research or disease modeling are described.

show abstract

“…In vitro assay systems using human hepatocytes have been developed in order to solve these problems (5,6). Toxicogenomic systems should be effective at predicting hepatotoxicity based on the expression of various genes that respond hepatotoxicity (7,8). However, these in vitro assay systems still present problems in terms of the collection of mammalian cells and differences in conditions from those in vivo.…”

Section: Introductionmentioning

confidence: 99%

Using silkworms to establish alternative animal models for evaluation of drug-induced tissue injury

Inagaki

Matsumoto

Sekimizu

2016

DD&T

View full text Add to dashboard Cite

Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems

Cited by 46 publications

References 21 publications

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

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

Cell sources forin vitrohuman liver cell culture models

Using silkworms to establish alternative animal models for evaluation of drug-induced tissue injury

Contact Info

Product

Resources

About