ArticlePLoS computational biology2016
Coordinating Role of RXRα in Downregulating Hepatic Detoxification during Inflammation Revealed by Fuzzy-Logic Modeling.
Article in PLoS computational biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 40 citations in OpenAlex.
- Regulation of Renal Transporters by Pro-Inflammatory Cytokines in Human Proximal Tubular Epithelial Cells: Identification of the Perpetrator and Mechanisms.ACS pharmacology & translational science · 2026Article
- Enhancing therapeutic strategies and drug development for patients with kidney disease.Expert opinion on drug safety · 2026Review
- Regulation of Renal Transporters by Pro-inflammatory Cytokines in Human Proximal Tubular Epithelial Cells: Identification of the Perpetrator and Mechanisms.bioRxiv : the preprint server for biology · 2025Article
- Severe acute respiratory syndrome coronavirus 2-mediated dysregulation of drug processing genes is dependent on pathogenic variants, target site of infection, age, and sex.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- The impact of the exposome on cytochrome P450-mediated drug metabolism.Frontiers in pharmacology · 2025Review
- Suppression of NNK Metabolism by Anthocyanin-Rich Haskap Berry Supplementation Through Modulation of P450 Enzymes.Pharmaceuticals (Basel, Switzerland) · 2024Article
- A multi-omics approach to elucidate okadaic acid-induced changes in human HepaRG hepatocarcinoma cells.Archives of toxicology · 2024Article
- Effects of marine biotoxins on drug-metabolizing cytochrome P450 enzymes and their regulation in mammalian cells.Archives of toxicology · 2024Review
- Pharmacokinetics, Pharmacodynamics, and Side Effects of Midazolam: A Review and Case Example.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Dysregulation of the mRNA Expression of Human Renal Drug Transporters by Proinflammatory Cytokines in Primary Human Proximal Tubular Epithelial Cells.Pharmaceutics · 2024Article
- Gut microbiota trigger host liver immune responses that affect drug-metabolising enzymes.Frontiers in immunology · 2024Review
- Okadaic Acid Activates JAK/STAT Signaling to Affect Xenobiotic Metabolism in HepaRG Cells.Cells · 2023Article
- Pharmacokinetics under the COVID-19 storm.British journal of clinical pharmacology · 2023Article
- Managing Cancer Drug Resistance from the Perspective of Inflammation.Journal of oncology · 2022Review
- Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition.Pharmaceutics · 2021Review
- Therapeutic Drug Monitoring of Second- and Third-Generation Antipsychotic Drugs-Influence of Smoking Behavior and Inflammation on Pharmacokinetics.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Signal Transducer and Activator of Transcription-3 Modulation of Cardiac Pathology in Chronic Chagasic Cardiomyopathy.Frontiers in cellular and infection microbiology · 2021Article
- Article
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- Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment.Pharmacology & therapeutics · 2020Review
Corrections and comments
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
During various inflammatory processes circulating cytokines including IL-6, IL-1β, and TNFα elicit a broad and clinically relevant impairment of hepatic detoxification that is based on the simultaneous downregulation of many drug metabolizing enzymes and transporter genes. To address the question whether a common mechanism is involved we treated human primary hepatocytes with IL-6, the major mediator of the acute phase response in liver, and characterized acute phase and detoxification responses in quantitative gene expression and (phospho-)proteomics data sets. Selective inhibitors were used to disentangle the roles of JAK/STAT, MAPK, and PI3K signaling pathways. A prior knowledge-based fuzzy logic model comprising signal transduction and gene regulation was established and trained with perturbation-derived gene expression data from five hepatocyte donors. Our model suggests a greater role of MAPK/PI3K compared to JAK/STAT with the orphan nuclear receptor RXRα playing a central role in mediating transcriptional downregulation. Validation experiments revealed a striking similarity of RXRα gene silencing versus IL-6 induced negative gene regulation (rs = 0.79; P<0.0001). These results concur with RXRα functioning as obligatory heterodimerization partner for several nuclear receptors that regulate drug and lipid metabolism.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.