title: A fluorescent analogue of tauroursodeoxycholic acid reduces ER stress and is cytoprotective.
abstract: Tauroursodeoxycholic acid (TUDCA) is a cytoprotective ER stress inhibitor and chemical chaperone. It has therapeutic potential in a wide array of diseases but a specific macromolecular target or molecular mechanism of action remains obscure. This Letter describes an effective new synthetic approach to taurine conjugation of bile acids which we used to prepare 3α-dansyl TUDCA (4) as a probe for TUDCA actions. As a model of ER stress we used the hepatocarcinoma cell line HUH7 and stimulation with either deoxycholic acid (DCA, 200μM) or tunicamycin (5μg/ml) and measured levels of Bip/GRP78, ATF4, CHOP and XBP1s/XBP1u. Compound 4 was more effective than UDCA at inhibiting ER stress markers and had similar effects to TUDCA. In a model of cholestasis using the cytotoxic DCA to induce apoptosis, pretreatment with 4 prevented cell death similarly to TUDCA whereas the unconjugated clinically used UDCA had no effect. 3α-Dansyl TUDCA (4) appears to be a suitable reporter for TUDCA effects on ER stress and related cytoprotective activity.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Jason
authors.initials: J
authors.lastname: Gavin
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Fran
authors.initials: F
authors.lastname: Quilty
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Ferenc
authors.initials: F
authors.lastname: Majer
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Georgina
authors.initials: G
authors.lastname: Gilsenan
authors.affiliation: Institute for Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors.forename: Anne Marie
authors.initials: AM
authors.lastname: Byrne
authors.affiliation: Institute for Molecular Medicine, Trinity Centre for Health Sciences, St James's Hospital, Dublin 8, Ireland.
authors.forename: Aideen
authors.initials: A
authors.lastname: Long
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Gabor
authors.initials: G
authors.lastname: Radics
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address: gilmerjf@tcd.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000818:Animals; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D013655:Taurochenodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005456:Fluorescent Dyes; C000717247:HSPA5 protein, human; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine
keywords: Bile acid; Cytoprotection; ER stress; Fluorescent reporter; Liver; TUDCA