Concentration-dependent effects of AY-9944 and U18666A on sterol synthesis in brain: Variable sensitivities of metabolic steps

Document Type

Article

Publication Title

Biochemical Pharmacology

Abstract

The possibility that the effects of inhibitors of sterol biosynthesis in brain are concentration dependent was examined. The drugs 3β-(2-diethylaminoethoxy) androst-5-en-17-one-HCl (U18666A) and trans-1,4-bis (2-chlorobenzylaminomethyl) cyclohexane-2HCl (AY-9944) were evaluated, because both substances markedly affect brain sterol metabolism and have been reported to alter the structure and/or function of developing brain. Incorporation of [2-14C]-DL-mevalonate by cell-free homogenates of rat brain into squalene and individual sterol fractions was measured in the absence and presence of a wide range of inhibitor concentrations. The qualitative and quantitative effects of U18666A and, to a lesser extent of AY-9944 on the formation of radiolabeled brain sterols were highly dependent on inhibitor concentration. The results indicate that there are two categories of metabolic steps in the pathways for sterol synthesis that were sensitive to inhibition by U18666A and AY-9944. The first category comprises steps that are located before lanosterol formation and were suppressed only by relatively high concentrations of inhibitors. At these higher inhibitor concentrations essentially all sterol synthesis was eliminated and drug effects at sites after lanosterol were therefore obscured. U18666A was over 6000 times more active than AY-9944 in inhibiting at category one sites. The second category of steps comprises those that are located late in cholesterol biosynthesis and were very sensitive to inhibition. Inhibitor effects at these late steps appeared to be drug-specific. © 1980, All rights reserved.

First Page

2751

Last Page

2754

DOI

10.1016/0006-2952(80)90006-4

Publication Date

1-1-1980

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