Effect of 7 beta-hydroxycholesterol on astrocyte primary cultures and derived spontaneously transformed cell lines. Cytotoxicity and cholesterogenesis.
The correlation between the lethal effect of 7 beta-hydroxycholesterol (7 beta-OH-CH) on spontaneously transformed cell lines derived from rat astrocyte primary cultures (normal cells) and de novo cholesterogenesis was investigated. Both 7 beta-OH-CH and 7-keto-CH were not cytotoxic on normal cells but 7 beta-OH-CH affected markedly the viability of the transformed cells. The use of [14C]acetate or [14C]mevalonate indicated that 7-keto-CH inhibits de novo cholesterogenesis upstream of 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) in both cell types whereas 7 beta-OH-CH also inhibits downstream of HMGR. The accumulation of two radiolabelled products X1 and X2 between mevalonate and CH was found in unsaponifiable neutral lipids extracted from 7 beta-OH-CH treated transformed cells. HPLC and GC-MS revealed that X1 and X2 are not lanosterol and 24,25-epoxylanosterol, respectively. Incubation of the transformed cells with X1 and X2 did not affect their viability. Our data demonstrate that, under our experimental conditions, 7 beta-OH-CH cytotoxicity is not linked to the inhibition of de novo cholesterogenesis in cultured glial transformed cells.
Behr
P
P
Centre de Neurochimie du CNRS, Strasbourg, France.
Kupferberg
A
A
Leray
C
C
Urban
P F
PF
Mersel
M
M
D000085:Acetates / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000201:enzymology; D002461:Cell Line, Transformed; D002784:Cholesterol / Q000096:biosynthesis*; D006888:Hydroxycholesterols / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008798:Mevalonic Acid / Q000378:metabolism; D051381:Rats
D000085:Acetates; D006888:Hydroxycholesterols; C011724:cholest-5-en-3 beta,7 alpha-diol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D008798:Mevalonic Acid