R. B. Ramsey, M. Fredericks
Jun 15, 1977
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0
Influential Citations
9
Citations
Quality indicators
Journal
Biochemical pharmacology
Abstract
Abstract The hypocholesterolemic agent zuclomiphene was found to inhibit sterol formation from [2-14C]mevalonic acid in cell-free preparations of developing rat brain. This inhibition was found if zuclomiphene were added to an incubation of normal brain. If the animals were pretreated for several weeks with the drug, but the brain tissue then incubated without the drug being added, the same reduction in sterol biosynthesis was seen. Incubation of brain tissue from pretreated animals, with addition of drug to the incubation as well, had reduced sterol biosynthetic activity, but the total labeled neutral lipid fraction was greater than without drug addition to the incubation. Intracerebral injection of [2-14C]mevalonic acid into zuclomiphene-treated and control animals resulted in the isolation of much less labeled cholesterol from the drug-treated animal brains. Thin-layer Chromatographic and radioactivity-monitored gas—liquid Chromatographie analysis of the labeled free sterol fractions indicated more labeled lanosterol and zymosterol and less labeled desmosterol in the drug-treated brains. Approximately 20 per cent of the total free sterol radioactivity derived from the drug-treated brains had the mobility of CΔ5,727-CΔ8,1427 sterols on silver nitrate thin-layer chromatography plates. On radioactivity-monitored gas-liquid chromatography the radioactive material derived from this thin-layer region was found to be contained in only one sterol. It had a retention time greater than CΔ8,1429 but less than would be expected for CΔ8,14,2429. Intraperitoneal administration of [3-14C]-D-(−)-β-hydroxybutyrate to zuclomiphene and corresponding controls resulted in lower [14C]sterol content in brain, spinal cord and liver of the treated animals. Silver nitrate thin-layer chromatography of the [3-14C]-d-(−)-β-hydroxybutyrate labeled brain and spinal cord free sterol fractions again indicated increased radioactivity in the CΔ5,727−CΔ8,1427 sterol region. One of the short-term effects of zuclomiphene pretreatment in the central vervous system seems to be blockage of sterol biosynthesis shortly after lanosterol formation.