title: 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.
abstract: 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.
authors.affiliation: Université de Bourgogne, Equipe 'Biochimie du peroxysome, inflammation et métabolisme lipidique' EA 7270, INSERM, Dijon, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nury
authors.forename: Mohammad
authors.initials: M
authors.lastname: Samadi
authors.forename: Amira
authors.initials: A
authors.lastname: Zarrouk
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Riedinger
authors.forename: Gérard
authors.initials: G
authors.lastname: Lizard
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002490:Central Nervous System / Q000166:cytology / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry*; D007653:Ketocholesterols / Q000737:chemistry*; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D013261:Sterols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D006888:Hydroxycholesterols; D007653:Ketocholesterols; D013261:Sterols
keywords: 158N murine oligodendrocytes; 4α-Hydroxycholesterol; 4β-Hydroxycholesterol; C6 rat glioma cells; Cell growth; Cell viability; Glial cells primary culture; SK-N-BE human neuroblastoma cells