Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol biosynthesis by oxylanosterols

Journal Article · Sat Nov 01 04:00:00 EST 1986 · J. Lipid Res.; (United States)

OSTI ID:6792682

Panini, S R; Sexton, R C; Gupta, A K; Parish, E J; Chitrakorn, S; Rudney, H

Treatment of rat intestinal epithelial cell cultures with the oxidosqualene cyclase inhibitor, 3 beta-(2-(diethylamino)-ethoxy)androst-5-en-17-one (U18666A), resulted in an accumulation of squalene 2,3:22,23-dioxide (SDO). When U18666A was withdrawn and the cells were treated with the sterol 14 alpha-demethylase inhibitor, ketoconazole, SDO was metabolized to a product identified as 24(S),25-epoxylanosterol. To test the biological effects and cellular metabolism of this compound, we prepared 24(RS),25-epoxylanosterol by chemical synthesis. The epimeric mixture of 24,25-epoxylanosterols could be resolved by high performance liquid chromatography on a wide-pore, non-endcapped, reverse phase column. Both epimers were effective suppressors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity of IEC-6 cells. The suppressive action of the natural epimer, 24(S),25-epoxylanosterol, but not that of 24(R),25-epoxylanosterol could be completely prevented by ketoconazole. IEC-6 cells could efficiently metabolize biosynthetic 24(S),25-epoxy(/sup 3/H)anosterol mainly to the known reductase-suppressor 24(S),25-epoxycholesterol. This metabolism was substantially reduced by ketoconazole. These data support the conclusion that 24(S),25-epoxylanosterol per se is not a suppressor of HMG-CoA reductase activity but is a precursor to a regulatory oxysterol(s). It has recently been reported that 25-hydroxycholesterol can occur naturally in cultured cells in amounts sufficient to effect regulation of HMG-CoA reductase. In order to investigate the biological effects of possible precursors of 25-hydroxycholesterol, we chemically synthesized 25-hydroxylanosterol and 25-hydroxylanostene-3-one. Both oxylanosterol derivatives suppressed cellular sterol synthesis at the level of HMG-CoA reductase. (Abstract Truncated)

• Research Organization: Univ. of Cincinnati Medical Center, OH
• OSTI ID: 6792682
• Journal Information: J. Lipid Res.; (United States), Journal Name: J. Lipid Res.; (United States) Vol. 11; ISSN JLPRA
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL TISSUES
ANIMALS
BIOSYNTHESIS
BODY
CELL CULTURES
CHOLESTEROL
DIGESTIVE SYSTEM
ENZYME ACTIVITY
ENZYME INHIBITORS
ENZYMES
EPITHELIUM
GASTROINTESTINAL TRACT
HYDROXY COMPOUNDS
INTESTINES
KINETICS
LABELLED COMPOUNDS
MAMMALS
METABOLISM
ORGANIC COMPOUNDS
ORGANS
OXIDOREDUCTASES
RATS
RODENTS
STEROIDS
STEROLS
STRUCTURE-ACTIVITY RELATIONSHIPS
SYNTHESIS
TISSUES
TRITIUM COMPOUNDS
VERTEBRATES