title: Microarray analysis of hepatic gene expression in pyrazole-mediated hepatotoxicity: identification of potential stimuli of Cyp2a5 induction.
abstract: Cytochrome P450 2a5 (Cyp2a5) expression is induced during liver damage caused by hepatotoxins such as pyrazole, however, the mechanism underlying this overexpression is unclear. In order to identify pathophysiological and cellular responses to pyrazole that might alter Cyp2a5 expression, we examined the effect of pyrazole on mouse hepatic gene expression in C57BL/6 mice using Affymetrix 430 2.0 microarrays. Over 3000 differentially expressed genes were identified 24-h after pyrazole treatment that were associated with a variety of cellular pathways. Upregulated genes were primarily involved in the splicing and processing of RNA and the unfolded protein response pathway, while downregulated genes were associated with amino acid and lipid metabolism, and generation of precursor metabolites for energy production. We also examined the effects of pyrazole on cellular pathways linked to metabolic and histopathological changes observed with pyrazole toxicity. Increased mRNA levels were observed for genes involved in bilirubin production, whereas the major genes of the urea cycle were strongly decreased. Changes in genes involved in carbohydrate metabolism were also observed which could explain pyrazole-induced glycogen depletion and decreased serum glucose. In addition, over 100 genes involved in the cellular stress response were upregulated by pyrazole treatment, including genes involved in the unfolded protein response and redox status. Based on these results and previous evidence concerning the regulation of Cyp2a5, we have identified several pathophysiological changes including altered energy homeostasis, hyperbilirubinemia, ER stress, and altered redox status that are associated with CYP2A5 overexpression and may represent potential stimuli for the induction of Cyp2a5.
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada N1G 2W1.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Nichols
authors.forename: Gordon M
authors.initials: GM
authors.lastname: Kirby
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis*; D001663:Bilirubin / Q000097:blood; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D004721:Endoplasmic Reticulum / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009584:Nitrogen / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D011720:Pyrazoles / Q000633:toxicity*; D014508:Urea / Q000378:metabolism
chemical_list: D011720:Pyrazoles; C031280:pyrazole; D014508:Urea; D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585520:Cyp2a5 protein, mouse; D065637:Cytochrome P-450 CYP2A6; D000072467:Cytochrome P450 Family 2; D005947:Glucose; D009584:Nitrogen; D001663:Bilirubin