title: Hepatotoxic effects of cyproconazole and prochloraz in wild-type and hCAR/hPXR mice.
abstract: The agricultural fungicides cyproconazole and prochloraz exhibit hepatotoxicity in rodent studies and are tumorigenic following chronic exposure. Both substances are suspected to act via a CAR (constitutive androstane receptor)/PXR (pregnane-X-receptor)-dependent mechanism. Human relevance of these findings is under debate. A 28-day toxicity study was conducted in mice with humanized CAR and PXR (hCAR/hPXR) with two dose levels (50 or 500 ppm) of both substances, using the model CAR activator phenobarbital as a reference. Results were compared to wild-type mice. A treatment-related increase in liver weights was observed for all three substances at least at the high-dose level. Changes in the expression of classic CAR/PXR target genes such as Cyp2b10 were induced by cyproconazole and phenobarbital in both genotypes, while prochloraz treatment resulted in gene expression changes indicative of additional aryl hydrocarbon receptor activation, e.g. by up-regulation of Cyp1a1 expression. Cyproconazole-induced effects on CAR-dependent gene expression, liver weight, and hepatic lipid accumulation were more prominent in wild-type mice, where significant genotype differences were observed at the high-dose level. Moreover, high-dose cyproconazole-treated mice from the wild-type group responded with a marked increase in hepatocellular proliferation, while hCAR/hPXR mice did not. In conclusion, our data demonstrate that cyproconazole and PB induce CAR/PXR downstream effects in hepatocytes in vivo via both, the murine and human receptors. At high doses of cyproconazole, however, the responses were clearly more pronounced in wild-type mice, indicating increased sensitivity of rodents to CAR agonist-induced effects in hepatocytes.
authors.affiliation: Department of Pesticides Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.|Institute for Biochemistry, Technical University of Berlin, Straße des 17. Juni 153, 10623, Berlin, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Marx-Stoelting
authors.affiliation: Department of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Ganzenberg
authors.affiliation: Department of Pesticides Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
authors.forename: Constanze
authors.initials: C
authors.lastname: Knebel
authors.affiliation: Department of Pesticides Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
authors.forename: Flavia
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Department of Pesticides Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Rieke
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Hammer
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: Natural and Medical Sciences Institute at the University of Tübingen, Markwiesenstr. 55, 72770, Reutlingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Pötz
authors.affiliation: Department of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.affiliation: Department of Toxicology, University of Tübingen, Wilhelmstr. 56, 72074, Tübingen, Germany. Albert.Braeuning@bfr.bund.de.|Department of Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, 10589, Berlin, Germany. Albert.Braeuning@bfr.bund.de.
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D000090702:Constitutive Androstane Receptor; D004305:Dose-Response Relationship, Drug; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010634:Phenobarbital / Q000494:pharmacology; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000090702:Constitutive Androstane Receptor; D005659:Fungicides, Industrial; D007093:Imidazoles; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014230:Triazoles; C093628:cyproconazole; C045362:prochloraz; D010634:Phenobarbital
keywords: Aryl hydrocarbon receptor; Constitutive androstane receptor; Cytochrome P450; Liver; Phenobarbital; Tumor promotion