6533b7ddfe1ef96bd1273e34

RESEARCH PRODUCT

Improved synthesis and in vitro evaluation of the cytotoxic profile of oxysterols oxidized at C4 (4α- and 4β-hydroxycholesterol) and C7 (7-ketocholesterol, 7α- and 7β-hydroxycholesterol) on cells of the central nervous system

Jean Marc RiedingerThomas NuryMohammad SamadiAmira ZarroukAmira ZarroukGérard Lizard

subject

Central Nervous SystemCell SurvivalCentral nervous systemMolecular ConformationCell LineStructure-Activity RelationshipDrug Discoverypolycyclic compoundsmedicineHumansCytotoxic T cellViability assayKetocholesterolsCell ProliferationPharmacologyDose-Response Relationship DrugChemistryCell growthOrganic ChemistryGeneral MedicineHydroxycholesterolsIn vitroSterolsOn cellsmedicine.anatomical_structureBiochemistryToxicitylipids (amino acids peptides and proteins)sense organs4β hydroxycholesterolOxidation-Reduction

description

Whereas the biological activities of oxysterols oxidized at C7 (7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), 7α-hydroxycholesterol (7α-OHC)) are well documented, those of oxysterols oxidized at C4 (4β-hydroxycholesterol (4β-OHC), 4α-hydroxycholesterol (4α-OHC)) are not well known, especially on the cells of the central nervous system. Therefore, an improved methodology has been validated for 4β-OHC and 4α-OHC synthesis, and the effects on cell viability and cell growth of these molecules were studied on immortalized, tumoral and normal brain cells (158N, C6 and SK-N-BE cells, and mixed primary cultures of astrocytes and oligodendrocytes). Whereas inhibition of cell growth with 7KC, 7β-OHC, and 7α-OHC is associated with a decrease of cell viability (cytotoxic activities), our data establish that 4β-OHC and 4α-OHC have no effect on cell viability, and no or minor effect on cell growth evocating cytostatic properties. Thus, comparatively to oxysterols oxidized at C7, the toxicity of oxysterols oxidized at C4 is in the following range of order: 7KC ≥ 7β-OHC > 7α-OHC > (4β-OHC ≥ 4α-OHC). Interestingly, to date, 4β-OHC and 4α-OHC are the only oxysterols identified with cytostatic properties suggesting that these molecules, whereas not cytotoxic, may have some interests to counteract cell proliferation.

https://doi.org/10.1016/j.ejmech.2013.09.028