title: Identification of glutathione depletion-responsive genes using phorone-treated rat liver.
abstract: To identify candidate biomarker gene sets to evaluate the potential risk of chemical-induced glutathione depletion in livers, we conducted microarray analysis on rat livers administered with phorone (40, 120 and 400 mg/kg), a prototypical glutathione depletor. Hepatic glutathione content was measured and glutathione depletion-responsive gene probe sets (GSH probe sets) were identified using Affymetrix Rat Genome 230 2.0 GeneChip by the following procedure. First, probe sets, whose signal values were inversely correlated with hepatic glutathione content throughout the experimental period, were statistically identified. Next, probe sets, whose average signal values were greater than 1.5-fold compared to those of controls 3 hr after phorone treatment, were selected. Finally, probe sets without unique Entrez Gene ID were removed, ending up with 161 probe sets in total. The usefulness of the identified GSH probe sets was verified by a toxicogenomics database. It was shown that signal profiles of the GSH probe sets in rats treated with bromobenzene were strongly altered compared with other chemicals. Focusing on bromobenzene, time-course profiles of hepatic glutathione content and gene expression revealed that the change in gene expression profile was marked after the bromobenzene treatment, whereas hepatic glutathione content had recovered after initial acute depletion, suggesting that the gene expression profile did not reflect the hepatic glutathione content itself, but rather reflects a perturbation of glutathione homeostasis. The identified GSH probe sets would be useful for detecting glutathione-depleting risk of chemicals from microarray data.
authors.affiliation: Toxicogenomics Project, National Institute of Biomedical Innovation, Osaka, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Kiyosawa
authors.forename: Takeki
authors.initials: T
authors.lastname: Uehara
authors.forename: Weihua
authors.initials: W
authors.lastname: Gao
authors.forename: Ko
authors.initials: K
authors.lastname: Omura
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Hirode
authors.forename: Toshinobu
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Mizukawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ono
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Miyagishima
authors.forename: Taku
authors.initials: T
authors.lastname: Nagao
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Urushidani
mesh_terms: D000818:Animals; D001969:Bromobenzenes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005978:Glutathione / Q000172:deficiency / Q000378:metabolism*; D007659:Ketones / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D051381:Rats; D018570:Risk Assessment; D013997:Time Factors; D043922:Toxicogenetics / Q000379:methods
chemical_list: D001969:Bromobenzenes; D007659:Ketones; C018637:phorone; C032036:bromobenzene; D005978:Glutathione