ArticleToxicological sciences : an official journal of the Society of Toxicology2021
Spatial Reconstruction of the Early Hepatic Transcriptomic Landscape After an Acetaminophen Overdose Using Single-Cell RNA-Sequencing.
Article in Toxicological sciences : an official journal of the Society of Toxicology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 37 citations in OpenAlex.
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- Disparities and trends in drug-related adverse reaction mortality in the United States, 1999-2020.Therapeutic advances in drug safety · 2026Article
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- Progress in toxicogenomics to protect human health.Nature reviews. Genetics · 2025Review
- Advanced omics approaches in liver transplant settings: current applications and future prospectives.Frontiers in immunology · 2025Review
- Central Mechanisms of Acetaminophen Hepatotoxicity: Mitochondrial Dysfunction by Protein Adducts and Oxidant Stress.Drug metabolism and disposition: the biological fate of chemicals · 2024Review
- The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice.Archives of toxicology · 2024Article
- The p21Toxicology · 2024Article
- Reconstruction of the Hepatic Microenvironment and Pathological Changes Underlying Type II Diabetes through Single-Cell RNA Sequencing.International journal of biological sciences · 2024Article
- Spatial Transcriptomics: A Powerful Tool in Disease Understanding and Drug Discovery.Theranostics · 2024Review
- Article
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- Multi-omics approach reveals dysregulated genes during hESCs neuronal differentiation exposure to paracetamol.iScience · 2023Article
- Spatial transcriptomics analysis of zone-dependent hepatic ischemia-reperfusion injury murine model.Communications biology · 2023Article
- Single-cell transcriptomics shows dose-dependent disruption of hepatic zonation by TCDD in mice.Toxicological sciences : an official journal of the Society of Toxicology · 2023Article
- Illuminating HBV with multi-scale modeling.Frontiers in systems biology · 2023Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
An acetaminophen (APAP) overdose is the most common cause of acute liver failure in the United States. A hallmark characteristic of APAP hepatotoxicity is centrilobular necrosis. General, innate mechanisms such as lower amounts of GSH and higher cytochrome P450 2e1 expression in pericentral (PC) hepatocytes are known to contribute to the differences in susceptibility to cell injury between periportal (PP) hepatocytes and PC hepatocytes. Although a sequence of molecular events involving formation of the reactive metabolite N-acetyl-p-benzoquinone imine, GSH depletion, oxidative stress, and c-Jun N-terminal kinase activation define the early cell stress trajectory following APAP exposure, their activation in PC versus PP hepatocytes is not well characterized. By using single-cell RNA-sequencing, we provide the first reconstruction of the early transcriptomic APAP liver lobule after validation of our methodology using human liver single-cell RNA-sequencing data. Two hours after APAP treatment, we find that PP hepatocytes progress along the APAP stress axis to oxidative stress, before resolving injury due to innate and adaptive mechanisms. However, PC hepatocytes continue along this stress axis as indicated by activation of mitogen-activated protein kinase genes, which is absent in PP hepatocytes. We also identify a population of glutamine synthetase enriched PC hepatocytes in close proximity to the central vein, where a stepwise induction of a stress program culminated in cell death. Collectively, these findings elucidate a molecular sequence of events distinguishing the differential response to APAP exposure between PP and PC hepatocytes and identify a subset of uniquely susceptible PC hepatocytes.
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