title: Gene expression profiling in the liver of CD-1 mice to characterize the hepatotoxicity of triazole fungicides.
abstract: Four triazole fungicides used in agricultural or pharmaceutical applications were examined for hepatotoxic effects in mouse liver. Besides organ weight, histopathology, and cytochrome P450 (CYP) enzyme induction, DNA microarrays were used to generate gene expression profiles and hypotheses on potential mechanisms of action for this class of chemicals. Adult male CD-1 mice were exposed daily for 14 days to fluconazole, myclobutanil, propiconazole, or triadimefon at three dose levels by oral gavage. Doses were based on previous studies that resulted in liver hypertrophy or hepatotoxicity. All four triazoles caused hepatocyte hypertrophy, and all except triadimefon increased relative liver/body weight ratios at the middle and high dose levels. CYP enzyme activities were also induced by all four triazoles at the middle and high doses as measured by the dealkylations of four alkoxyresorufins, although some differences in substrate specificity were observed. Consistent with this common histopathology and biochemistry, several CYP and xenobiotic metabolizing enzyme (XME) genes were differentially expressed in response to all four (Cyp2d26 and Cyp3a11), or three of the four (Cyp2c40, Cyp2c55, Ces2, Slco1a4) triazoles. Differential expression of numerous other CYP and XME genes discriminated between the various triazoles, consistent with differences in CYP enzyme activities, and indicative of possible differences in mechanisms of hepatotoxicity or dose response. Multiple isoforms of Cyp1a, 2b, 2c, 3a, and other CYP and XME genes regulated by the nuclear receptors constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were differentially expressed following triazole exposure. Based on these results, we expanded on our original hypothesis that triazole hepatotoxicity was mediated by CYP induction, to include additional XME genes, many of which are modulated by CAR and PXR.
authors.affiliation: Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA.
authors.forename: Amber K
authors.initials: AK
authors.lastname: Goetz
authors.forename: Wenjun
authors.initials: W
authors.lastname: Bao
authors.forename: Hongzu
authors.initials: H
authors.lastname: Ren
authors.forename: Judith E
authors.initials: JE
authors.lastname: Schmid
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Tully
authors.forename: Carmen
authors.initials: C
authors.lastname: Wood
authors.forename: John C
authors.initials: JC
authors.lastname: Rockett
authors.forename: Michael G
authors.initials: MG
authors.lastname: Narotsky
authors.forename: Guobin
authors.initials: G
authors.lastname: Sun
authors.forename: Guy R
authors.initials: GR
authors.lastname: Lambert
authors.forename: Sheau-Fung
authors.initials: SF
authors.lastname: Thai
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wolf
authors.forename: Stephen
authors.initials: S
authors.lastname: Nesnow
authors.forename: David J
authors.initials: DJ
authors.lastname: Dix
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005659:Fungicides, Industrial / Q000633:toxicity*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008862:Microsomes, Liver / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D014230:Triazoles / Q000633:toxicity*
chemical_list: D000935:Antifungal Agents; D005659:Fungicides, Industrial; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System