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Abstract
Lanosterol 14 alpha-demethylase (P45014DM) is the cytochrome P450 enzyme complex responsible for an early step in cholesterol biosynthesis, namely the 14 alpha-demethylation of lanosterol. We have synthesized a novel series of steroidal substrate analogues, designed to be specific and potent inhibitors of P45014DM. We describe here the effects of these compounds on sterol biosynthesis downstream from lanosterol, focusing ultimately on their efficacy as inhibitors of cholesterol biosynthesis. Results using a radio-high performance liquid chromatography (HPLC) assay show that in rat liver microsomal preparations, with [24,25-3H]dihydrolanosterol as substrate, the compounds do indeed inhibit the biosynthesis of sterols downstream from lanosterol. A range of inhibitory potencies was observed, and the key enzyme being inhibited was believed to be P45014DM. Inhibitor efficacy was readily correlated with non-metabolized [24,25-3H]dihydrolanosterol, formation of 4,4-dimethyl-cholest-8-en-3 beta-ol, and formation of lathosterol, a sterol believed to be an excellent indicator of whole body cholesterol biosynthesis in humans.
Highlights
Lanosterol 14a-demethylase (P45014DM) is the cytochrome P450 enzyme complex responsible for an early step in cholesterol biosynthesis, namely the l4a-demethylation of lanosterol
We established incubation times and substrate concentrations that would permit the use of the radioHPLC assay for examining the effects of our inhibitors on sterol biosynthesis from [24,25-3H]dihydrolanosterol ([24,25-3H]DHL) in the microsomal fraction of rat liver homogenate
We have studied the effects of a series of sterols, designed as inhibitors of P45014DM, on cholesterol biosynthesis in rat liver microsomes
Summary
Lanosterol 14a-demethylase (P45014DM) is the cytochrome P450 enzyme complex responsible for an early step in cholesterol biosynthesis, namely the l4a-demethylation of lanosterol. A range of inhibitory potencies was observed, and the key enzyme being inhibited was believed to be P 4 5 0 1 4 ~ ~In.hibitor efficacy was readily correlated with non-metabobized [24,25-3H]dihydrolanosterol,formation of 4,4-dimethyl-cholest8-en-3/3-01, and formation of lathosterol, a sterol believed to be an excellent indicator of whole body cholesterol biosynthesis in humans. Lanosterol 14a-demethylase (P45014DM) is the cytochrome P450 enzyme complex responsible for an early step in cholesterol biosynthesis, namely the 14a-demethylation of lanosterol 2 [1] (Scheme 1). A range of inhibitory potencies was observed, and the key enzyme being inhibited was believed to be P 4 5 0 1 2 ~ ~In.hibitor efficacy was readily correlated with non-metabolized [24,25-3H]dihydrolanosterol,formahn of 4,4-dimethyl-cholest-8(9)-en-3fl-4o1, and formation of lathosterol 5, a sterol believed to be an excellent indicator of whole body cholesterol biosynthesis in humans [3]
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