title: Select cyclopentenone prostaglandins trigger glutathione efflux and the role of ABCG2 transport.
abstract: Electrophilic cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)), initiate redox-based cell signaling responses including increased intracellular glutathione (GSH) synthesis. We investigated whether cyPGs facilitated GSH efflux and if members of the ATP-binding cassette (ABC) protein family mediated the efflux. Four human cell lines were treated with 1-6 microM cyPGs for 48 h. Media and cells were harvested for GSH measurements using HPLC-EC. CyPG treatment increased extracellular GSH levels two- to threefold over controls in HN4 and C38 cells and five- to sixfold in SAEC and MDA 1586 cells and was dependent on increased GSH synthesis. Our studies show that prostaglandin D(2) and its metabolites, prostaglandin J(2) and 15dPGJ(2), specifically induce GSH efflux compared to other eicosanoids. These higher extracellular GSH levels were associated with protection from tert-butylhydroperoxide. Superarray analysis of ABC transporters suggested only ABCG2 expression had a positive relationship in the four cell types compared with extracellular GSH increases after cyPG treatment. The ABCG2 substrate Hoechst 33342 inhibited extracellular GSH increase after 15dPGJ(2) treatment. We report for the first time that ABCG2 may play a role in GSH efflux in response to cyPG treatment and may link inflammatory signaling with antioxidant adaptive responses.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado at Denver Health Sciences Center, Denver, CO 80262, USA.
authors.forename: Heather M
authors.initials: HM
authors.lastname: Brechbuhl
authors.forename: Elysia
authors.initials: E
authors.lastname: Min
authors.forename: Chirag
authors.initials: C
authors.lastname: Kariya
authors.forename: Barbara
authors.initials: B
authors.lastname: Frederick
authors.forename: David
authors.initials: D
authors.lastname: Raben
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019610:Cytoprotection / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000096:biosynthesis* / Q000235:genetics; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013379:Substrate Specificity; D020122:tert-Butylhydroperoxide / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D020122:tert-Butylhydroperoxide; D005978:Glutathione; C017807:bisbenzimide ethoxide trihydrochloride; D015230:Prostaglandin D2