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.
abstract: Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA.
authors.affiliation: Syngenta Ltd., Jealott's Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK. Electronic address: richard.currie@syngenta.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Currie
authors.affiliation: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, United States. Electronic address: richard.peffer@syngenta.com.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Peffer
authors.affiliation: Syngenta Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300, United States. Electronic address: amber.goetz@syngenta.com.
authors.forename: Amber K
authors.initials: AK
authors.lastname: Goetz
authors.affiliation: Center for Molecular Toxicology and Carcinogenesis, Penn State University, University Park, PA 16802, United States. Electronic address: cjo10@psu.edu.
authors.forename: Curtis J
authors.initials: CJ
authors.lastname: Omiecinski
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, United States. Electronic address: goodman3@msu.edu.
authors.forename: Jay I
authors.initials: JI
authors.lastname: Goodman
mesh_terms: D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens; D049109:Cell Proliferation / Q000187:drug effects; D000090702:Constitutive Androstane Receptor; D005260:Female; D005659:Fungicides, Industrial / Q000633:toxicity*; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D022781:Hepatocytes / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000633:toxicity*; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000139:chemically induced; D009929:Organ Size / Q000187:drug effects; D010634:Phenobarbital / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D043922:Toxicogenetics; D014230:Triazoles / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D002273:Carcinogens; D000090702:Constitutive Androstane Receptor; D005659:Fungicides, Industrial; D006993:Hypnotics and Sedatives; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; C045950:propiconazole; D010634:Phenobarbital
keywords: Conazoles; Constitutive androstane receptor; Phenobarbital; Propiconazole; Toxicogenomics