Effect of oxygenated sterols on 3-hydroxy-3-methylglutaryl coenzyme a reductase and DNA synthesis in phytohemagglutinin-stimulated human lymphocytes

Fifteen oxygenated sterols at the concentration of 25 μg/ml were tested on DNA synthesis of phytohemagglutinin stimulated human lymphocytes. In a cholesterol containing medium, the inhibitory effect was strictly dependent of the side chain structure of the sterol and only due to an hydroxylation at position 25. Three oxygenated sterols, which slightly inhibited DNA synthesis, strongly suppressed the peak of 3-hydroxy-3-methylglutaryl CoA reductase activity that normally precedes DNA synthesis. The 25-hydroxycholesterol suppressed the reductase activity even at 5 μg/ml, but was active on DNA synthesis only at 25 μg/ml; at this concentration, the later the 25-hydroxycholesterol was added, the weaker the inhibition of DNA synthesis was. Hence the sterol synthesis related to the early increase of 3-hydroxy-3-methylglutaryl CoA reductase activity is probably not essential to the cellular division. Several hypothesis on the mechanism of action of the 25-hydroxycholesterol are discussed.