Metabolism of 7 beta-hydroxycholesterol in astrocyte primary cultures and derived spontaneously transformed cell lines: correlation between the esterification on C-3 -OH by naturally occurring fatty acids and cytotoxicity.
The lethal effect of 7 beta-hydrocholesterol (7 beta-OHC) on spontaneously transformed cell lines, derived from neonatal rat astrocyte primary cultures and the extent of 7 beta-OHC esterification by naturally occurring fatty acids on C-3 -OH (metabolite) was investigated. The extent of cellular death and metabolite biosynthesis matched with the 7 beta-OHC concentrations. Incubation of the cells with 10 microM 7 beta-OHC in the presence of either lipoproteins depleted fetal calf serum or with increasing serum concentrations revealed proportionality between the degree of cellular cytotoxicity and metabolite levels. The use of tetracaine or progesterone as acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors indicated that ACAT was involved in metabolite production; the inhibition of metabolite biosynthesis slowed down 7 beta-OHC lethal effect. Incubation of the cells with 1 mM db-cAMP, prior 7 beta-OHC treatment, enhanced both metabolite production and cellular death. These findings support the view that the metabolite is directly implicated in the cytotoxic action.
Centre de Neurochimie du CNRS, Strasbourg, France.
A
A
Kupferberg
P
P
Behr
M
M
Mersel
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism* / Q000633:toxicity; D006888:Hydroxycholesterols / Q000378:metabolism* / Q000633:toxicity; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D013748:Tetracaine / Q000494:pharmacology
D002788:Cholesterol Esters; D006888:Hydroxycholesterols; D013748:Tetracaine; D011374:Progesterone; C011724:cholest-5-en-3 beta,7 alpha-diol; D002785:Sterol O-Acyltransferase