Abstract
When the hypocholesterolemic agent AY-9944 was examined in vitro and in vivo for its influence on developing brain sterol biosynthesis, multiple effects were exhibited. Addition of AY-9944 to incubations of cell-free preparations resulted in a decrease in [ 14C]sterol biosynthesis from [2- 14C]mevalonic acid. Pretreatment of animals with AY-9944 and subsequent incubation of their brain tissue in vitro resulted in greater labeled sterol synthesis than in control incubations. Pretreatment of animals with AY-9944 followed by intracerebral injection of [2- 14C]mevalonic acid resulted in comparable labeled sterol biosynthesis in control and drug-treated brains, but reduced [ 14C]cholesterol formation by the AY-9944-treated animals. Examination of the labeled free sterol fractions by thin-layer chromatography and radioactivity-monitored gas chromatography indicated several labeled sterols present in the AY-9944-treated brain tissue that were not seen in controls. These [ 14C]sterols were: 4,4-dimethyl-5α-cholesta-8,14,24-trien-3β-ol; 5α-cholesta-7,24-dien-3β-ol; 5α-cholesta-8,14,24-trien-3β-ol; cholesta-5,7,24-trien-3β-ol; cholesta-5.7-dien-3β-ol; and an unknown 4α-methyl sterol. Another set of developing rats was pretreated with a combination of AY-9944 and zuclomiphene. another hypocholesterolemic agent. Intracerebral administration of [2- 14C]mevalonic acid resulted in lower [ 14C]sterol and labeled cholesterol synthesis in the brain tissue of drug-treated animals than in controls. Thin-layer and radioactivity-monitored gas Chromatographie analysis again revealed [ 14C]sterols other than those present in controls. Two labeled Δ 7 sterols, 5α-cholesta-7,24-dien-3β-ol and cholesta-5.7,24-trien-3β-ol. a 4α-methyl sterol of unknown structure, previously seen in the AY-9944-treated brain tissue, and a 4,4-dimethyl sterol, also of unknown structure, were present in the brains of the drug-treated animals. The present findings indicate not only that both drugs block central nervous system sterol synthesis at several points, but also that use of these hypocholesterolemic agents in various combinations may further elucidate the pathway(s) and control of neural sterol biosynthesis.
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