ReviewCritical reviews in toxicology2014
Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: A case study with phenobarbital as a model constitutive androstane receptor (CAR) activator.
Review in Critical reviews in toxicology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 79 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
79 citing papers in PubMed, 259 citations in OpenAlex.
- The use of cultured human hepatocytes as a test system to evaluate cell proliferation as a key event in nongenotoxic carcinogenesis.Archives of toxicology · 2026Article
- Mechanistic insights into CAR-mediated repression of the HNF4α-FABP1 axis and inhibition of HepG2 cell proliferation.Pharmacological research · 2026Article
- Reviewing the thoroughness of human safety testing for succinate dehydrogenase inhibitors: fluopyram as a case study.Archives of toxicology · 2026Review
- Cytochrome P450 enzymes as modulators of oncogenic signaling via the Wnt/β-catenin signaling pathway.Archives of toxicology · 2026Review
- The Pivotal Role of GR-CAR Pathway in Fetal Programming of Hepatic Cytochrome P450 3A Alteration in Adulthood.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Systematic evaluation of the evidence base on ethylCurrent research in toxicology · 2026Review
- Nucleophosmin 1 induction is an early event in a Phenobarbital induced proliferation response in rat but not human liver 3D microtissues.Toxicology reports · 2025Article
- Effects of Crocus sativus and its active constituents on cytochrome P450: a review.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- An evaluation of the human relevance of the hepatocellular tumors observed in mice treated with synthetic fungicide, pyridachlometyl, based on mode of action.Archives of toxicology · 2025Article
- A proposal of criteria to support the EU classification on endocrine disruption for the thyroid modality and their application to four data-rich case studies.Archives of toxicology · 2025Article
- Dose-response modeling of effects in mice after exposure to a polyfluoroalkyl substance (Nafion byproduct 2).Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- The potent human CAR activator CITCO is a non-genotoxic hepatic tumour-promoting agent in humanised constitutive androstane receptor mice but not in wild-type animals.Archives of toxicology · 2025Article
- Differential hepatic activation of mouse and human peroxisome proliferator-activated receptor-α by perfluorohexane sulfonate.Toxicological sciences : an official journal of the Society of Toxicology · 2025Article
- The fungicide propiconazole induces hepatic steatosis and activates PXR in a mouse model of diet-induced obesity.Archives of toxicology · 2025Article
- Tetrabromobisphenol A: MAK Value Documentation - Translation of the German version from 2023.The MAK collection for occupational health and safety · 2025Review
- Constitutive androstane receptor (CAR) functions as a tumor suppressor via regulating stemness in liver cancer.Scientific reports · 2024Article
- In vitro and in vivo investigation of a thyroid hormone system-specific interaction with triazoles.Scientific reports · 2024Article
- Assessing human carcinogenicity risk of agrochemicals without the rodent cancer bioassay.Frontiers in toxicology · 2024Article
- Investigating open access new approach methods (NAM) to assess biological points of departure: A case study with 4 neurotoxic pesticides.Current research in toxicology · 2024Article
- Increased Cell Proliferation as a Key Event in Chemical Carcinogenesis: Application in an Integrated Approach for the Testing and Assessment of Non-Genotoxic Carcinogenesis.International journal of molecular sciences · 2023Review
19 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
17 authors at 15 institutions in 8 countries.
Funding
Abstract
The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are important nuclear receptors involved in the regulation of cellular responses from exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non-genotoxic indirect CAR activator, which induces cytochrome P450 (CYP) and other xenobiotic metabolizing enzymes and is known to produce liver foci/tumors in mice and rats. From literature data, a mode of action (MOA) for PB-induced rodent liver tumor formation was developed. A MOA for PXR activators was not established owing to a lack of suitable data. The key events in the PB-induced liver tumor MOA comprise activation of CAR followed by altered gene expression specific to CAR activation, increased cell proliferation, formation of altered hepatic foci and ultimately the development of liver tumors. Associative events in the MOA include altered epigenetic changes, induction of hepatic CYP2B enzymes, liver hypertrophy and decreased apoptosis; with inhibition of gap junctional intercellular communication being an associative event or modulating factor. The MOA was evaluated using the modified Bradford Hill criteria for causality and other possible MOAs were excluded. While PB produces liver tumors in rodents, important species differences were identified including a lack of cell proliferation in cultured human hepatocytes. The MOA for PB-induced rodent liver tumor formation was considered to be qualitatively not plausible for humans. This conclusion is supported by data from a number of epidemiological studies conducted in human populations chronically exposed to PB in which there is no clear evidence for increased liver tumor risk.
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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.