Abstract

Research initiated by the discovery that 4, 4, 10Beta-trimethyl-transdecal-3Beta-ol (TMD) is an effective inhibitor of cholesterol biosynthesis at the oxidosqualene cyclase stage will be continued. This finding has enabled an ongoing investigation of the biochemistry of squalene 2,3(Sapproximately);22(Sapproximately),23-dioxide and related dioxygenated triterpenoids and steroids. Of particular potential significance is the finding that 24(Sapproximately),25-epoxycholesterol is formed in the normal course of sterol biosynthesis by the enzymes in rat liver homogenate. It will be determined whether this epoxide occurs in intact tissue and, if so, what its biochemical properties and metabolic fate are. Greater understanding of the natural mechanisms of cholesterol formation and regulation may result from this research, and such understanding will eventually be important in achieving control of atherosclerosis. The inhibition of cholesterol biosynthesis by TMD has also proved to be valuable in collaborative studies of cell replication, and these investigations will continue. The effect of substances structurally related to TMD on cholesterol biosynthesis will be studied in order to elucidate the structural requirements for inhibition and to develop additional inhibitors which will be useful as research tools. TMD and related inhibitors of oxidosqualene cyclase will also be used to try to gain insight into the structure and mechanism of this important enzyme through efforts at purification by affinity chromatography and at affinity labelling of the active side.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL023083-06
Application #
3337141
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1979-08-01
Project End
1986-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
6
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Dartmouth College
Department
Type
Schools of Arts and Sciences
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code

  Publications

Spencer, T A; Clark, D S; Johnson, G A et al. (1997) Feasibility of an immunoassay for mevalonolactone. Bioorg Med Chem 5:873-82
Saucier, S E; Kandutsch, A A; Clark, D S et al. (1993) Hepatic uptake and metabolism of ingested 24-hydroxycholesterol and 24(S),25-epoxycholesterol. Biochim Biophys Acta 1166:115-23
Panini, S R; Everson, G T; Spencer, T A (1991) Effects of specific inhibition of sterol biosynthesis on the uptake and utilization of low density lipoprotein cholesterol by HepG2 cells. J Lipid Res 32:1657-65
Saucier, S E; Kandutsch, A A; Gayen, A K et al. (1990) Oxygenation of desmosterol and cholesterol in cell cultures. J Lipid Res 31:2179-85
Saucier, S E; Kandutsch, A A; Gayen, A K et al. (1989) Oxysterol regulators of 3-hydroxy-3-methylglutaryl-CoA reductase in liver. Effect of dietary cholesterol. J Biol Chem 264:6863-9
Taylor, F R; Kandutsch, A A; Anzalone, L et al. (1988) Photoaffinity labeling of the oxysterol receptor. J Biol Chem 263:2264-9
Saucier, S E; Kandutsch, A A; Phirwa, S et al. (1987) Accumulation of regulatory oxysterols, 32-oxolanosterol and 32-hydroxylanosterol in mevalonate-treated cell cultures. J Biol Chem 262:14056-62
Taylor, F R; Kandutsch, A A; Gayen, A K et al. (1986) 24,25-Epoxysterol metabolism in cultured mammalian cells and repression of 3-hydroxy-3-methylglutaryl-CoA reductase. J Biol Chem 261:15039-44
Saucier, S E; Kandutsch, A A; Taylor, F R et al. (1985) Identification of regulatory oxysterols, 24(S),25-epoxycholesterol and 25-hydroxycholesterol, in cultured fibroblasts. J Biol Chem 260:14571-9
Spencer, T A; Gayen, A K; Phirwa, S et al. (1985) 24(S),25-Epoxycholesterol. Evidence consistent with a role in the regulation of hepatic cholesterogenesis. J Biol Chem 260:13391-4