Faculty Research 1980 - 1989

Inhibition of sterol biosynthesis in animal cells by 14 alpha-hydroxymethyl sterols.

Document Type

Article

Publication Date

1980

Keywords

Cells-Cultured, Fetus, Hydroxymethylglutaryl-CoA-Reductases, Kinetics, L-Cells, Liver: en, Mice, Sterols, Structure-Activity-Relationship

First Page

571

Last Page

584

JAX Source

J-Lipid-Res. 1980 Jul; 21(5):571-84.

Abstract

The chemical syntheses of a number of 14 alpha-hydroxymethyl sterols and 14 alpha -hydroxymethyl-15 alpha-hydroxysterols and their derivatives have been pursued to permit evaluation of their activity in the inhibition of sterol biosynthesis in animal cells in culture. Described herein are chemical syntheses of 7 alpha,8 slpha-epoxy-14 alpha-methyl-5 alpha-cholestan-3 beta,15 alpha-diol, 14 alpha-methyl-5 alpha-cholestan-3 beta,7 alpha,15 alpha-triol, 3 beta,15 alpha-diacetoxy-14 alpha-methyl-5 alpha-cholestan-7 alpha-ol, 3 beta,15 alpha-diacetoxy-7 alpha,32-epoxy-14 alpha-methyl-5 alpha-cholestane, 14 alpha-hydroxymethyl-5 alpha-cholest-6-en-3 beta,15 alpha-diol, 14 alpha-hydroxymethyl-5 alpha-cholest-7-en-3 beta,15 alpha-diol, 7 alpha,32-epoxy-14 alpha-methyl-5 alpha-cholestan-3 beta,15 alpha-diol, 14 alpha-hydroxymethyl-5 alpha-cholest-6-en-3-one, 14 alpha-hydroxymethyl-5 alpha-cholest-7-en-3-one, and 14 alpha-hydroxymethyl-5 alpha-cholets-7-en-15 alpha-ol-3-one. The effects of eight of the above compounds and of 14 alpha-hydroxymethyl-5 alpha-cholest-8-en-3 beta-ol, 14 alpha-hydroxymethyl-5 alpha-cholest-7-en-3 beta-ol, 14 alpha-hydroxymethyl-5 alpha-cholest-6-en-3 beta-ol, and 7 alpha,32-epoxy-14 alpha-methyl-5 alpha-cholestan-3 beta-ol on the synthesis of digitonin-precipitalbe sterols and on levels of HMG-CoA reductase activity in L cells and in primary cultures of fetal mouse liver cells have been investigated. All of the 14 alpha-hydroxymethyl sterols and 14 alpha-hydroxymethyl-15 alpha-hydroxysterols were found to be potent inhibitors of sterol synthesis and to reduce the levels of HMG-CoA reductase activity in these cells. Since hydroxylation of the 14 alpha-methyl group of 14 alpha-methyl sterol precursors of cholesterol can be considered as an obligatory step in the biosynthesis of cholesterol, the finding that 14 alpha-hydroxymethyl sterols are potent inhibitors of cholesterol biosynthesis and cause a reduction in the levels of HMG-CoA reductase activity raises the possibility that oxygenated sterol precursors of cholesterol, such as 14 alpha-hydroxymethyl sterols, may play an important role in the regulation of cholesterol synthesis and in the regulation of processes dependent upon mevalonate and sterol formation.

Link to Full Text

Share

COinS