title: Mouse liver effects of cyproconazole, a triazole fungicide: role of the constitutive androstane receptor.
abstract: Cyproconazole, a triazole fungicide, causes hepatocellular adenomas and carcinomas in CD-1 mice at dose levels of 100 and 200 ppm. The constitutive androstane receptor (CAR) has been shown to play a significant role in the overall mode of action for several nongenotoxic rodent carcinogens such as phenobarbital. The liver effects of dietary cyproconazole or phenobarbital were investigated after 2, 7, or 14 days in male CD-1, C57BL/6J, and C3H/HeNClrBR mice. Cyproconazole produced similar, dose-responsive effects in all three strains of mice, and the response was similar to that of phenobarbital. Subsequently, Car-null and wild-type male mice on a C3H/HeNClrBR background were administered 200 or 450 ppm cyproconazole, or 850 ppm phenobarbital for up to 7 days. In wild-type mice, 200 ppm cyproconazole caused liver hypertrophy, increased liver weight and cell proliferation, single-cell necrosis and fat vacuolation, effects generally similar to those caused by 850 ppm phenobarbital. Plasma cholesterol was decreased by both compounds, but cyproconazole had a greater effect. The higher dose (450 ppm) of cyproconazole caused similar changes, but greater evidence of liver damage was observed, including a large increase in plasma transaminases. Induction of CAR target genes Cyp2b10 and Gadd45beta was observed with both compounds, whereas the cell cycle regulatory gene Mdm2 was unaffected. In Car-null mice, the effects noted with either cyproconazole or phenobarbital were absent or greatly diminished. These experiments demonstrate that short-term liver effects of cyproconazole in mice are CAR-dependent and similar to those of phenobarbital, a known nongenotoxic rodent liver carcinogen.
authors.affiliation: Syngenta Crop Protection, Inc., Greensboro, North Carolina 27419, USA. richard.peffer@syngenta.com
authors.forename: Richard C
authors.initials: RC
authors.lastname: Peffer
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Moggs
authors.forename: Timothy
authors.initials: T
authors.lastname: Pastoor
authors.forename: Richard A
authors.initials: RA
authors.lastname: Currie
authors.forename: Jayne
authors.initials: J
authors.lastname: Wright
authors.forename: Gill
authors.initials: G
authors.lastname: Milburn
authors.forename: Felix
authors.initials: F
authors.lastname: Waechter
authors.forename: Ivan
authors.initials: I
authors.lastname: Rusyn
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000072467:Cytochrome P450 Family 2; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005659:Fungicides, Industrial / Q000633:toxicity*; D005786:Gene Expression Regulation; D020868:Gene Silencing; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006984:Hypertrophy; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000096:biosynthesis / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013045:Species Specificity; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D014230:Triazoles / Q000633:toxicity*; D014617:Vacuoles / Q000187:drug effects; D000097642:GADD45 Proteins
chemical_list: D000943:Antigens, Differentiation; D001189:Aryl Hydrocarbon Hydroxylases; D000072467:Cytochrome P450 Family 2; D005659:Fungicides, Industrial; D010634:Phenobarbital; D051736:Proto-Oncogene Proteins c-mdm2; D011944:Receptors, Androgen; D013250:Steroid Hydroxylases; D014230:Triazoles; C490125:Gadd45b protein, mouse; D000097642:GADD45 Proteins; C093628:cyproconazole; C101679:Cyp2b10 protein, mouse; C497207:Mdm2 protein, mouse