Document Detail

Transport via SLC5A8 (SMCT1) is obligatory for 2-oxothiazolidine-4-carboxylate to enhance glutathione production in retinal pigment epithelial cells.
MedLine Citation:
PMID:  21508099     Owner:  NLM     Status:  MEDLINE    
PURPOSE: To evaluate the role of SLC5A8 in the transport of 2-oxothiazolidine-4-carboxylate (OTC) and to determine whether OTC augments glutathione production in RPE cells, thereby providing protection against oxidative stress.
METHODS: SLC5A8-mediated transport of OTC was monitored in Xenopus laevis oocytes by electrophysiological means. Saturation kinetics, Na(+)-activation kinetics, and inhibition by ibuprofen were analyzed by monitoring OTC-induced currents as a measure of transport activity. Oxidative stress was induced in ARPE-19 cells and primary RPE cells isolated from wild type and Slc5a8(-/-) mouse retinas using H(2)O(2), and the effects of OTC on cell death and intracellular glutathione concentration were examined.
RESULTS: Heterologous expression of human SLC5A8 in X. laevis oocytes induced Na(+)-dependent inward currents in the presence of OTC under voltage-clamp conditions. The transport of OTC via SLC5A8 was saturable, with a K(t) of 104 ± 3 μM. The Na(+)-activation kinetics was sigmoidal with a Hill coefficient of 1.9 ± 0.1, suggesting involvement of two Na(+) in the activation process. Ibuprofen, a blocker of SLC5A8, inhibited SLC5A8-mediated OTC transport; the concentration necessary for half-maximal inhibition was 17 ± 1 μM. OTC increased glutathione levels and protected ARPE-19 and primary RPE cells isolated from wild type mouse retinas from H(2)O(2)-induced cell death. These effects were abolished in primary RPE isolated from Slc5a8(-/-) mouse retinas.
CONCLUSIONS: OTC is a transportable substrate for SLC5A8. OTC augments glutathione production in RPE cells, thereby protecting them from oxidative damage. Transport via SLC5A8 is obligatory for this process.
Ellappan Babu; Sudha Ananth; Rajalakshmi Veeranan-Karmegam; Veena Coothankandaswamy; Sylvia B Smith; Thomas Boettger; Vadivel Ganapathy; Pamela M Martin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-07-29
Journal Detail:
Title:  Investigative ophthalmology & visual science     Volume:  52     ISSN:  1552-5783     ISO Abbreviation:  Invest. Ophthalmol. Vis. Sci.     Publication Date:  2011 Jul 
Date Detail:
Created Date:  2011-08-01     Completed Date:  2011-09-30     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  7703701     Medline TA:  Invest Ophthalmol Vis Sci     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5749-57     Citation Subset:  IM    
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA.
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MeSH Terms
Biological Transport / physiology
Cation Transport Proteins / genetics,  metabolism*
Cell Survival / drug effects
Cyclooxygenase Inhibitors / pharmacology
Drug Interactions
Glutathione / metabolism*
Hydrogen Peroxide / toxicity
Ibuprofen / pharmacology
Mice, Mutant Strains
Oocytes / physiology
Oxidants / toxicity
Oxidative Stress / drug effects,  physiology
Pyrrolidonecarboxylic Acid / chemistry,  pharmacokinetics*
Retinal Pigment Epithelium / cytology,  drug effects*,  metabolism*
Thiazolidines / chemistry,  pharmacokinetics*
Xenopus laevis
Grant Support
K99/R00 EY018053/EY/NEI NIH HHS
Reg. No./Substance:
0/Cation Transport Proteins; 0/Cyclooxygenase Inhibitors; 0/Oxidants; 0/SLC5A8 protein, human; 0/Slc5a8 protein, mouse; 0/Thiazolidines; 15687-27-1/Ibuprofen; 19750-45-9/2-oxothiazolidine-4-carboxylic acid; 70-18-8/Glutathione; 7722-84-1/Hydrogen Peroxide; 98-79-3/Pyrrolidonecarboxylic Acid

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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