1. A fluorescent analogue of tauroursodeoxycholic acid reduces ER stress and is cytoprotective.
- Author
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Gavin J, Quilty F, Majer F, Gilsenan G, Byrne AM, Long A, Radics G, and Gilmer JF
- Subjects
- Animals, Endoplasmic Reticulum Chaperone BiP, Humans, Endoplasmic Reticulum Stress drug effects, Fluorescent Dyes chemistry, Taurochenodeoxycholic Acid pharmacology
- 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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