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Subcellular distribution of FTY720 and FTY720-phosphate in immune cells - another aspect of Fingolimod action relevant for therapeutic application
- Source :
- Schröder, Matthias; Arlt, Olga; Schmidt, Helmut; Huwiler, Andrea; Angioni, Carlo; Pfeilschifter, Josef M; Schwiebs, Anja; Radeke, Heinfried H (2015). Subcellular distribution of FTY720 and FTY720-phosphate in immune cells-another aspect of Fingolimod action relevant for therapeutic application. Biological chemistry, 396(6-7), pp. 795-802. De Gruyter 10.1515/hsz-2014-0287
- Publication Year :
- 2019
-
Abstract
- FTY720 (Fingolimod; Gilenya®) is an immune-modulatory prodrug which, after intracellular phosphorylation by sphingosine kinase 2 (SphK2) and export, mimics effects of the endogenous lipid mediator sphingosine-1-phosphate. Fingolimod has been introduced to treat relapsing-remitting multiple sclerosis. However, little has been published about the immune cell membrane penetration and subcellular distribution of FTY720 and FTY720-P. Thus, we applied a newly established LC-MS/MS method to analyze the subcellular distribution of FTY720 and FTY720-P in subcellular compartments of spleen cells of wild type, SphK1- and SphK2-deficient mice. These studies demonstrated that, when normalized to the original cell volume and calculated on molar basis, FTY720 and FTY720-P dramatically accumulated several hundredfold within immune cells reaching micromolar concentrations. The amount and distribution of FTY720 was differentially affected by SphK1- and SphK2-deficiency. On the background of recently described relevant intracellular FTY720 effects in the nanomolar range and the prolonged application in multiple sclerosis, this data showing a substantial intracellular accumulation of FTY720, has to be considered for benefit/risk ratio estimates.
- Subjects :
- Multiple Sclerosis
Clinical Biochemistry
Sphingosine kinase
610 Medicine & health
Biology
Pharmacology
Biochemistry
Cell membrane
Mice
chemistry.chemical_compound
Immune system
Sphingosine
Tandem Mass Spectrometry
hemic and lymphatic diseases
medicine
Animals
Sphingosine-1-phosphate
Phosphorylation
Molecular Biology
Cells, Cultured
Fingolimod Hydrochloride
Lipid signaling
Fingolimod
Organophosphates
Mice, Inbred C57BL
Phosphotransferases (Alcohol Group Acceptor)
SPHK2
medicine.anatomical_structure
chemistry
Female
Lysophospholipids
Spleen
Intracellular
medicine.drug
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Schröder, Matthias; Arlt, Olga; Schmidt, Helmut; Huwiler, Andrea; Angioni, Carlo; Pfeilschifter, Josef M; Schwiebs, Anja; Radeke, Heinfried H (2015). Subcellular distribution of FTY720 and FTY720-phosphate in immune cells-another aspect of Fingolimod action relevant for therapeutic application. Biological chemistry, 396(6-7), pp. 795-802. De Gruyter 10.1515/hsz-2014-0287 <http://dx.doi.org/10.1515/hsz-2014-0287>
- Accession number :
- edsair.doi.dedup.....06342b3cfad21689203705c1960c1fbf