title: 1-Cyano-2,3-epithiopropane is a novel plant-derived chemopreventive agent which induces cytoprotective genes that afford resistance against the genotoxic alpha,beta-unsaturated aldehyde acrolein.
abstract: Epithionitriles represent a previously unrecognized class of cancer chemopreventive phytochemical generated from alkenyl glucosinolates in cruciferous vegetables. In rat liver RL-34 epithelial cells, 1-cyano-2,3-epithiopropane (CETP), 1-cyano-3,4-epithiobutane (CETB) and 1-cyano-4,5-epithiopentane (CETPent) were shown to induce cytoprotective enzymes including NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione (GSH) S-transferase A3 and the glutamate-cysteine ligase modifier subunit; CETP was more potent in this regard than were either CETB or CETPent, with 50 microM CETP eliciting a remarkable approximately 10-fold induction of NQO1. Furthermore, 50 microM CETP stimulated a 2.0-fold overproduction of GSH in RL-34 cells. Transfection experiments demonstrated that epithionitriles induced gene expression through an antioxidant response element (ARE) and that transactivation of an Nqo1-luciferase reporter plasmid was dependent on NF-E2 p45-related factor 2 (Nrf2), a cap'n'collar basic region leucine zipper transcription factor. Evidence is presented that CETP affected Nrf2-mediated induction of ARE-driven transcription by inhibiting Kelch-like ECH-associated protein 1 (Keap1), a ubiquitin ligase substrate adaptor that negatively regulates Nrf2. We found that Nqo1 was expressed constitutively at high levels in Keap1(-/-) mouse embryonic fibroblasts (MEFs) and it was not further induced by CETP. However, knock-in of mouse Keap1 or zebrafish Keap1a into Keap1(-/-) MEFs repressed Nqo1-luciferase reporter gene activity, but repression by the murine or zebrafish proteins was antagonized by CETP. Pre-treatment of Nrf2(+/+) MEFs, but not Nrf2(-/-) MEFs, with 15 microM CETP for 24 h conferred 2.4-fold resistance against subsequent exposure to the alpha,beta-unsaturated aldehyde acrolein, indicating that the phytochemical exerts chemopreventive properties against genotoxic xenobiotics.
authors.affiliation: Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Kelleher
authors.forename: Michael
authors.initials: M
authors.lastname: McMahon
authors.forename: Ian M
authors.initials: IM
authors.lastname: Eggleston
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dixon
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: John D
authors.initials: JD
authors.lastname: Hayes
mesh_terms: D000171:Acrolein / Q000037:antagonists & inhibitors*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D005961:Glucosinolates / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000502:physiology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology*; D011407:Propane / Q000031:analogs & derivatives* / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D013438:Sulfhydryl Compounds / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C544438:1-cyano-2,3-epithiopropane; D000975:Antioxidants; D005961:Glucosinolates; D009570:Nitriles; D010936:Plant Extracts; D012333:RNA, Messenger; D013438:Sulfhydryl Compounds; D000171:Acrolein; D008156:Luciferases; D005978:Glutathione; D011407:Propane