title: Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray.
abstract: Electrophiles generated during metabolic activation of carcinogens and reactive oxygen species formed from endogenous and exogenous sources might play a significant role in carcinogenesis. Cancer chemoprevention by induction of phase II detoxifying enzymes to counteract the insults of these reactive intermediates is under intensive investigation. Nrf2, a bZIP transcription factor, plays a central role in the regulation of phase II genes by binding to the antioxidant response element (ARE) in their promoters. Identification of novel Nrf2-regulated genes is likely to provide insight into cellular defense systems against the toxicities of electrophiles and oxidants and may define effective targets for achieving cancer chemoprevention. Phenethyl isothiocyanate (PEITC) is a promising chemopreventive agent that exerts its effects by induction of phase II enzymes via activation of Nrf2. In the present study, a transcriptional profile of liver of the wild-type (Nrf2+/+) and knock-out (Nrf2-/-) mice after treatments with vehicle or PEITC at 3 h and at 12 h was generated using the Affymetrix Mouse Genome 430 2.0 Array. Comparative analysis of gene expression changes between different treatment groups of wild-type and Nrf2-deficient mice facilitated identification of numerous genes regulated by Nrf2. These Nrf2-dependent and PEITC-inducible genes include known detoxication enzymes, as well as novel xenobiotic-metabolizing genes regulated by Nrf2 such as CYP 2c55, CYP 2u1 and aldehyde oxidase. Unexpected clusters included genes for heat shock proteins, ubiquitin/26 S proteasome subunits, and lipid metabolism molecules. Collectively, the identification of these genes not only provides novel insight into the effect of PEITC on global gene expression and chemoprevention, but also reveals the role of Nrf2 in those processes, which would confer cancer chemopreventive future.
authors.affiliation: Graduate Program in Pharmaceutical Science, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Hu
authors.forename: Changjiang
authors.initials: C
authors.lastname: Xu
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Shen
authors.forename: Mohit R
authors.initials: MR
authors.lastname: Jain
authors.forename: Tin Oo
authors.initials: TO
authors.lastname: Khor
authors.forename: Avantika
authors.initials: A
authors.lastname: Gopalkrishnan
authors.forename: Wen
authors.initials: W
authors.lastname: Lin
authors.forename: Bandaru
authors.initials: B
authors.lastname: Reddy
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.forename: Ah-Ng Tony
authors.initials: AN
authors.lastname: Kong
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D018890:Chemoprevention; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D017879:Isothiocyanates / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D050217:Metabolic Detoxication, Phase II / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D016588:Anticarcinogenic Agents; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; C058305:phenethyl isothiocyanate