{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:20:26Z","timestamp":1790799626038,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T00:00:00Z","timestamp":1589155200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Azole fungicides, especially triazole compounds, are widely used in agriculture and as pharmaceuticals. For a considerable number of agricultural azole fungicides, the liver has been identified as the main target organ of toxicity. A number of previous studies points towards an important role of nuclear receptors such as the constitutive androstane receptor (CAR), the pregnane-X-receptor (PXR), or the aryl hydrocarbon receptor (AHR), within the molecular pathways leading to hepatotoxicity of these compounds. Nuclear receptor-mediated hepatic effects may comprise rather adaptive changes such as the induction of drug-metabolizing enzymes, to hepatocellular hypertrophy, histopathologically detectable fatty acid changes, proliferation of hepatocytes, and the promotion of liver tumors. Here, we present a comprehensive review of the current knowledge of the interaction of major agricultural azole-class fungicides with the three nuclear receptors CAR, PXR, and AHR in vivo and in vitro. Nuclear receptor activation profiles of the azoles are presented and related to histopathological findings from classic toxicity studies. Important issues such as species differences and multi-receptor agonism and the consequences for data interpretation and risk assessment are discussed.<\/jats:p>","DOI":"10.3390\/cells9051192","type":"journal-article","created":{"date-parts":[[2020,5,11]],"date-time":"2020-05-11T12:26:30Z","timestamp":1589199990000},"page":"1192","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["The Connection of Azole Fungicides with Xeno-Sensing Nuclear Receptors, Drug Metabolism and Hepatotoxicity"],"prefix":"10.3390","volume":"9","author":[{"given":"Philip","family":"Marx-Stoelting","sequence":"first","affiliation":[{"name":"German Federal Institute for Risk Assessment, Department Pesticides Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constanze","family":"Knebel","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Braeuning","sequence":"additional","affiliation":[{"name":"German Federal Institute for Risk Assessment, Department Food Safety, Max-Dohrn-Str. 8-10, 10589 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"EFSA (2009). Scientific Opinion on Risk Assessment for a Selected Group of Pesticides from the Triazole Group to Test Possible Methodologies to Assess Cumulative Effects from Exposure through Food from these Pesticides on Human Health. EFSA J., 7, 1167.","DOI":"10.2903\/j.efsa.2009.1167"},{"key":"ref_2","first-page":"135","article-title":"Fundamental Concepts of Azole Compounds and Triazole Antifungals: A Beginner\u2019s Review","volume":"37","year":"2018","journal-title":"PR Health Sci. J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S1369-5274(98)80087-8","article-title":"Antifungals: Mechanism of action and resistance, established and novel drugs","volume":"1","author":"Georgopapadakou","year":"1998","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.taap.2006.02.015","article-title":"Gene expression profiling in liver and testis of rats to characterize the toxicity of triazole fungicides","volume":"215","author":"Tully","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1093\/toxsci\/kfp098","article-title":"Mode of action for reproductive and hepatic toxicity inferred from a genomic study of triazole antifungals","volume":"110","author":"Goetz","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1093\/toxsci\/kfp076","article-title":"Discrimination of tumorigenic triazole conazoles from phenobarbital by transcriptional analyses of mouse liver gene expression","volume":"110","author":"Nesnow","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1111\/j.1365-2605.2007.00838.x","article-title":"Endocrine-disrupting properties in vivo of widely used azole fungicides","volume":"31","author":"Taxvig","year":"2008","journal-title":"Int. J. Androl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.reprotox.2012.05.088","article-title":"Triazole induced concentration-related gene signatures in rat whole embryo culture","volume":"34","author":"Robinson","year":"2012","journal-title":"Reprod. Toxicol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.toxlet.2013.05.011","article-title":"Dose-response involvement of constitutive androstane receptor in mouse liver hypertrophy induced by triazole fungicides","volume":"221","author":"Tamura","year":"2013","journal-title":"Toxicol. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/j.fct.2015.01.021","article-title":"Involvement of constitutive androstane receptor in liver hypertrophy and liver tumor development induced by triazole fungicides","volume":"78","author":"Tamura","year":"2015","journal-title":"Food Chem. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1093\/toxsci\/kfm012","article-title":"Induction of cytochrome P450 1A1 by ketoconazole and itraconazole but not fluconazole in murine and human hepatoma cell lines","volume":"97","author":"Korashy","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/toxsci\/kfj173","article-title":"Identification of new human pregnane X receptor ligands among pesticides using a stable reporter cell system","volume":"91","author":"Lemaire","year":"2006","journal-title":"Toxicol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.tox.2017.04.002","article-title":"Itraconazole cis-diastereoisomers activate aryl hydrocarbon receptor AhR and pregnane X receptor PXR and induce CYP1A1 in human cell lines and human hepatocytes","volume":"383","author":"Stepankova","year":"2017","journal-title":"Toxicology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1128\/AAC.01900-12","article-title":"Coordinated roles of pregnane X receptor and constitutive androstane receptor in autoinduction of voriconazole metabolism in mice","volume":"57","author":"Ohbuchi","year":"2013","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2488","DOI":"10.1158\/1078-0432.CCR-06-1592","article-title":"Activated pregnenolone X-receptor is a target for ketoconazole and its analogs","volume":"13","author":"Wang","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1007\/s00204-019-02445-2","article-title":"Pregnane X receptor mediates steatotic effects of propiconazole and tebuconazole in human liver cell lines","volume":"93","author":"Knebel","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1021\/acs.chemrestox.8b00112","article-title":"Adverse Outcome Pathway-Driven Analysis of Liver Steatosis in Vitro: A Case Study with Cyproconazole","volume":"31","author":"Luckert","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"801","DOI":"10.2131\/jts.41.801","article-title":"A crucial role of constitutive androstane receptor (CAR) in liver tumor development by imazalil in mice","volume":"41","author":"Tamura","year":"2016","journal-title":"J. Toxicol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/toxsci\/kfm154","article-title":"Mouse liver effects of cyproconazole, a triazole fungicide: Role of the constitutive androstane receptor","volume":"99","author":"Peffer","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e002","DOI":"10.1621\/nrs.13002","article-title":"Identification of chemical modulators of the constitutive activated receptor (CAR) in a gene expression compendium","volume":"13","author":"Oshida","year":"2015","journal-title":"Nucl. Recept. Signal"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1016\/j.bcp.2009.08.008","article-title":"Constitutive androstane receptor transcriptionally activates human CYP1A1 and CYP1A2 genes through a common regulatory element in the 5\u2019-flanking region","volume":"79","author":"Yoshinari","year":"2010","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.toxlet.2012.06.001","article-title":"Ligand dependent hepatic gene expression profiles of nuclear receptors CAR and PXR","volume":"212","author":"Tojima","year":"2012","journal-title":"Toxicol. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1038\/sj.tpj.6500087","article-title":"Specific and overlapping functions of the nuclear hormone receptors CAR and PXR in xenobiotic response","volume":"2","author":"Wei","year":"2002","journal-title":"Pharmacogenom. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1016\/j.bbagrm.2016.04.010","article-title":"RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome","volume":"1859","author":"Cui","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.taap.2015.02.004","article-title":"Effects of currently used pesticides and their mixtures on the function of thyroid hormone and aryl hydrocarbon receptor in cell culture","volume":"284","author":"Ghisari","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_26","first-page":"18","article-title":"RNA-protein correlation of liver toxicity markers in HepaRG cells","volume":"19","author":"Braeuning","year":"2020","journal-title":"ExCli J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.jhazmat.2014.05.083","article-title":"Two azole fungicides (carcinogenic triadimefon and non-carcinogenic myclobutanil) exhibit different hepatic cytochrome P450 activities in medaka fish","volume":"277","author":"Lin","year":"2014","journal-title":"J. Hazard. Mater."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.tiv.2017.02.023","article-title":"Development of a common carp (Cyprinus carpio) pregnane X receptor (cPXR) transactivation reporter assay and its activation by azole fungicides and pharmaceutical chemicals","volume":"41","author":"Lange","year":"2017","journal-title":"Toxicol. In Vitro"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1002\/tox.20701","article-title":"Multiple biomarkers responses in juvenile rainbow trout, Oncorhynchus mykiss, after acute exposure to a fungicide propiconazole","volume":"28","author":"Li","year":"2013","journal-title":"Environ. Toxicol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1007\/s00204-016-1925-2","article-title":"Hepatotoxic effects of cyproconazole and prochloraz in wild-type and hCAR\/hPXR mice","volume":"91","author":"Ganzenberg","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3471","DOI":"10.1007\/s00204-018-2321-x","article-title":"Propiconazole is an activator of AHR and causes concentration additive effects with an established AHR ligand","volume":"92","author":"Knebel","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1093\/toxsci\/kfy026","article-title":"Unexpected Effects of Propiconazole, Tebuconazole, and Their Mixture on the Receptors CAR and PXR in Human Liver Cells","volume":"163","author":"Knebel","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.tox.2014.03.003","article-title":"Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action","volume":"321","author":"Currie","year":"2014","journal-title":"Toxicology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1080\/15376516.2017.1333555","article-title":"Bromuconazole-induced hepatotoxicity is accompanied by upregulation of PXR\/CYP3A1 and downregulation of CAR\/CYP2B1 gene expression","volume":"27","author":"Abdelhadya","year":"2017","journal-title":"Toxicol. Mech. Meth."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.toxlet.2008.11.009","article-title":"CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides","volume":"184","author":"Sergent","year":"2009","journal-title":"Toxicol. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.toxlet.2004.10.006","article-title":"Propiconazole-induced cytochrome P450 gene expression and enzymatic activities in rat and mouse liver","volume":"155","author":"Sun","year":"2005","journal-title":"Toxicol. Lett."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.fct.2018.11.039","article-title":"The azole fungicide tebuconazole affects human CYP1A1 and CYP1A2 expression by an aryl hydrocarbon receptor-dependent pathway","volume":"123","author":"Knebel","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1390","DOI":"10.1124\/dmd.115.068619","article-title":"Establishment of In Silico Prediction Models for CYP3A4 and CYP2B6 Induction in Human Hepatocytes by Multiple Regression Analysis Using Azole Compounds","volume":"44","author":"Nagai","year":"2016","journal-title":"Drug Metabol. Disp."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1093\/toxsci\/kfs086","article-title":"The hepatocarcinogenic conazoles: Cyproconazole, epoxiconazole, and propiconazole induce a common set of toxicological and transcriptional responses","volume":"127","author":"Hester","year":"2012","journal-title":"Toxicol. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1080\/01926230601047832","article-title":"Transcriptional profiles in liver from mice treated with hepatotumorigenic and nonhepatotumorigenic triazole conazole fungicides: Propiconazole, triadimefon, and myclobutanil","volume":"34","author":"Ward","year":"2006","journal-title":"Toxicol. Pathol."},{"key":"ref_41","unstructured":"(2020, April 24). Assessment Report of the Active Substance Propiconazole (Finland), Available online: www.efsa.europa.eu."},{"key":"ref_42","unstructured":"WHO\/JMPR (2004). Propiconazole, WHO. Available online: https:\/\/apps.who.int\/pesticide-residues-jmpr-database\/pesticide?name=PROPICONAZOLE."},{"key":"ref_43","unstructured":"European Commission (2003). Review Report for the Active Substance Propiconazole, European Commission. Available online: https:\/\/ec.europa.eu\/food\/plant\/pesticides\/eu-pesticides-database\/public\/?event=activesubstance.detail&language=EN&selectedID=1770."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/toxsci\/kfq118","article-title":"Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo","volume":"116","author":"Ross","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/bj3290017","article-title":"Zonation of hepatic cytochrome P-450 expression and regulation","volume":"329","author":"Oinonen","year":"1998","journal-title":"Biochem. J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"5051","DOI":"10.1111\/j.1742-4658.2006.05503.x","article-title":"Differential gene expression in periportal and perivenous mouse hepatocytes","volume":"273","author":"Braeuning","year":"2006","journal-title":"FEBS J."},{"key":"ref_47","first-page":"506","article-title":"Selective centrilobular expression of the aryl hydrocarbon receptor in rat liver","volume":"280","author":"Lindros","year":"1997","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.devcel.2006.03.015","article-title":"Apc tumor suppressor gene is the \u201czonation-keeper\u201d of mouse liver","volume":"10","author":"Benhamouche","year":"2006","journal-title":"Dev. Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1002\/hep.21523","article-title":"Liver-specific loss of beta-catenin results in delayed hepatocyte proliferation after partial hepatectomy","volume":"45","author":"Sekine","year":"2007","journal-title":"Hepatology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5318","DOI":"10.1093\/nar\/gkv423","article-title":"Signal integration by the CYP1A1 promoter--a quantitative study","volume":"43","author":"Schulthess","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.tox.2014.08.010","article-title":"Cooperation of structurally different aryl hydrocarbon receptor agonists and beta-catenin in the regulation of CYP1A expression","volume":"325C","author":"Vaas","year":"2014","journal-title":"Toxicology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.tox.2013.03.019","article-title":"The time point of beta-catenin knockout in hepatocytes determines their response to xenobiotic activation of the constitutive androstane receptor","volume":"308","author":"Ganzenberg","year":"2013","journal-title":"Toxicology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1093\/toxsci\/kfr080","article-title":"Coordinate regulation of cytochrome P450 1a1 expression in mouse liver by the aryl hydrocarbon receptor and the beta-catenin pathway","volume":"122","author":"Braeuning","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/toxsci\/kfr166","article-title":"Gender-specific interplay of signaling through beta-catenin and CAR in the regulation of xenobiotic-induced hepatocyte proliferation","volume":"123","author":"Braeuning","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1515\/bc.2010.012","article-title":"beta-Catenin as a multilayer modulator of zonal cytochrome P450 expression in mouse liver","volume":"391","author":"Braeuning","year":"2010","journal-title":"Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1124\/dmd.108.026179","article-title":"Inducibility of drug-metabolizing enzymes by xenobiotics in mice with liver-specific knockout of Ctnnb1","volume":"37","author":"Braeuning","year":"2009","journal-title":"Drug Metab. Dispos."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1021\/acs.chemrestox.5b00208","article-title":"Adverse Outcome Pathways and Drug-Induced Liver Injury Testing","volume":"28","author":"Vinken","year":"2015","journal-title":"Chem. Res. Toxicol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"111283","DOI":"10.1016\/j.fct.2020.111283","article-title":"An adverse outcome pathway-based approach to assess steatotic mixture effects of hepatotoxic pesticides in vitro","volume":"139","author":"Lichtenstein","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3109\/10408444.2013.835786","article-title":"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","volume":"44","author":"Elcombe","year":"2014","journal-title":"Crit. Rev. Toxicol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1016\/j.bcp.2005.02.004","article-title":"Ah receptor- and TCDD-mediated liver tumor promotion: Clonal selection and expansion of cells evading growth arrest and apoptosis","volume":"69","author":"Bock","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1080\/17425255.2020.1746268","article-title":"Nuclear receptor CAR-mediated liver cancer and its species differences","volume":"16","author":"Shizu","year":"2020","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1007\/s00204-016-1712-0","article-title":"Is the question of phenobarbital as potential liver cancer risk factor for humans really resolved?","volume":"90","author":"Braeuning","year":"2016","journal-title":"Arch. Toxicol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9660","DOI":"10.3390\/ijerph110909660","article-title":"Combination effects of (tri)azole fungicides on hormone production and xenobiotic metabolism in a human placental cell line","volume":"11","author":"Rieke","year":"2014","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1007\/s00204-019-02502-w","article-title":"Assessment of mixture toxicity of (tri)azoles and their hepatotoxic effects in vitro by means of omics technologies","volume":"93","author":"Seeger","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s00204-017-2087-6","article-title":"Hepatotoxic combination effects of three azole fungicides in a broad dose range","volume":"92","author":"Heise","year":"2018","journal-title":"Arch. Toxicol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s00204-014-1336-1","article-title":"Hepatotoxic effects of (tri)azole fungicides in a broad dose range","volume":"89","author":"Heise","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_67","unstructured":"EFSA (2008). Conclusion regarding the peer review of epoxiconazole. EFSA J., 138, 1\u201380."},{"key":"ref_68","unstructured":"(2020, April 24). Assessment Report on the Active Substance Epoxiconazole (Germany), Available online: www.efsa.europa.eu."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.tox.2016.05.018","article-title":"Combination effects of azole fungicides in male rats in a broad dose range","volume":"355\u2013356","author":"Schmidt","year":"2016","journal-title":"Toxicology"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"EFSA (2010). Conclusion on the peer review of the risk assessment of the active substance cyproconazole. EFSA J., 8, 1897.","DOI":"10.2903\/j.efsa.2010.1897"},{"key":"ref_71","unstructured":"(2020, April 24). Assessment Report on the Active Substance Cyproconazole (Ireland), Available online: www.efsa.europa.eu."},{"key":"ref_72","unstructured":"WHO\/JMPR (2010). Tebuconazole, WHO. Available online: https:\/\/apps.who.int\/pesticide-residues-jmpr-database\/pesticide?name=TEBUCONAZOLE."},{"key":"ref_73","unstructured":"EFSA (2008). Conclusion regarding the peer review of the pesticide risk assessment of the active substance tebuconazole. EFSA J., 176, 1\u2013109."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"EFSA (2011). Conclusion on the peer review of the risk assessment of the active substanz prochloraz. EFSA J., 9, 2323.","DOI":"10.2903\/j.efsa.2011.2323"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/toxsci\/kfu038","article-title":"Phenobarbital induces cell cycle transcriptional responses in mouse liver humanized for constitutive androstane and pregnane x receptors","volume":"139","author":"Luisier","year":"2014","journal-title":"Toxicol. Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1093\/carcin\/16.6.1271","article-title":"Inhibition of apoptosis during 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated tumour promotion in rat liver","volume":"16","author":"Stinchcombe","year":"1995","journal-title":"Carcinogenesis"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1093\/carcin\/15.6.1143","article-title":"Effects of 2,3,7,8-tetrachloro- and 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin on the proliferation of preneoplastic liver cells in the rat","volume":"15","author":"Buchmann","year":"1994","journal-title":"Carcinogenesis"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/0378-4274(95)03465-X","article-title":"Role of cell proliferation at early stages of hepatocarcinogenesis","volume":"82\u201383","author":"Schwarz","year":"1995","journal-title":"Toxicol. Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"443","DOI":"10.2131\/jts.43.443","article-title":"Acceleration of murine hepatocyte proliferation by imazalil through the activation of nuclear receptor PXR","volume":"43","author":"Yoshimaru","year":"2018","journal-title":"J. Toxicol. Sci."},{"key":"ref_80","unstructured":"WHO\/JMPR (2018). Imazalil, WHO. Available online: https:\/\/apps.who.int\/pesticide-residues-jmpr-database\/pesticide?name=IMAZALIL."},{"key":"ref_81","unstructured":"EFSA (2010). Conclusion regarding the peer review on the active substance imazalil. EFSA J., 8, 1526."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"111306","DOI":"10.1016\/j.fct.2020.111306","article-title":"Hepatotoxicity of the pesticides imazalil, thiacloprid and clothianidin-Individual and mixture effects in a 28-day study in female Wistar rats","volume":"140","author":"Alarcan","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1093\/toxsci\/kfr191","article-title":"Multi-species analyses of direct activators of the constitutive androstane receptor","volume":"123","author":"Omiecinski","year":"2011","journal-title":"Toxicol. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1773","DOI":"10.1007\/s00204-019-02481-y","article-title":"Satirical contribution: Non-linear endocrine no-dose effects-towards a new paradigm in toxicology","volume":"93","author":"Portant","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3109\/03602532.2012.738687","article-title":"Xenobiotic receptor humanized mice and their utility","volume":"45","author":"Scheer","year":"2013","journal-title":"Drug Metabol. Rev."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1210\/me.2004-0046","article-title":"Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR","volume":"18","author":"Huang","year":"2004","journal-title":"Mol. Endocrinol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2375","DOI":"10.1007\/s00204-017-1948-3","article-title":"Human pregnane X receptor is activated by dibenzazepine carbamate-based inhibitors of constitutive androstane receptor","volume":"91","author":"Jeske","year":"2017","journal-title":"Arch. Toxicol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/5\/1192\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:27:39Z","timestamp":1760174859000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/9\/5\/1192"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,11]]},"references-count":87,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["cells9051192"],"URL":"https:\/\/doi.org\/10.3390\/cells9051192","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,11]]}}}