The hypocholesteremic effect of 3β-(β-dimethylaminoethoxy)-androst-5-en-17-one and its mechanism of action

Gordon, Samuel; Cantrall, Edward W.; Cekleniak, Walter P.; Albers, H.; Littell, Ruddy; Bernstein, Seymour

doi:10.1016/0006-291x(61)90145-0

Cited by 18 publications

(2 citation statements)

References 3 publications

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“…Several 3-dialkylaminoethoxy compounds were tested in the early 1960s for hypocholesterolemic activity. Most, including U18666A, caused the substitution of desmosterol for cholesterol [4][5][6]. One, {1-[p-(b-diethylaminoethoxy)-phenyl]-1-(p-tolyl)-2-(p-chlorophenyl)ethanol)}, known as Mer 29 or triparanol, was introduced into humans and then promptly withdrawn from clinical use because of drugrelated cataract formation [7,8].…”

Section: U18666a and Sterol Synthesismentioning

confidence: 99%

Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes

Cenedella

2009

Lipids

200

187

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The multiple actions of U18666A have enabled major discoveries in lipid research and contributed to understanding the pathophysiology of multiple diseases. This review describes these advances and the utility of U18666A as a tool in lipid research. Harry Rudney's recognition that U18666A inhibited oxidosqualene cyclase led him to discover a pathway for formation of polar sterols that he proved to be important regulators of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase. Laura Liscum's recognition that U18666A inhibited the egress of cholesterol from late endosomes and lysosomes led to greatly improved perspective on the major pathways of intracellular cholesterol trafficking. The inhibition of cholesterol trafficking by U18666A mimicked the loss of functional Niemann-Pick type C protein responsible for NPC disease and thus provided a model for this disorder. U18666A subsequently became a tool for assessing the importance of molecular trafficking through the lysosomal pathway in other conditions such as atherosclerosis, Alzheimer's disease, and prion infections. U18666A also provided animal models for two important disorders: petite mal (absence) epilepsy and cataracts. This was the first chronic model of absence epilepsy. U18666A is also being used to address the role of oxidative stress in apoptosis. How can one molecule have so many effects? Perhaps because of its structure as an amphipathic cationic amine it can interact and inhibit diverse proteins. Restricting the availability of cholesterol for membrane formation through inhibition of cholesterol synthesis and intracellular trafficking could also be a mechanism for broadly affecting many processes. Another possibility is that through intercalation into membrane U18666A can alter membrane order and therefore the function of resident proteins. The similarity of the effects of natural and enantiomeric U18666A on cells and the capacity of intercalated U18666A to increase membrane order are arguments in favor of this possibility.

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Section: U18666a and Sterol Synthesismentioning

confidence: 99%

Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes

Cenedella

2009

Lipids

200

187

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“…(Furman et al, 1957;Hennes et al, 1960;Gordon et al, 1961)or the accelerated excretion of sterols and bile salts to the bile (West et al, 1961;Kumagai et al, 1966). But it has not yet been fully defined.…”

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confidence: 99%

Alteration of Cholesterol Metabolism Induced by Anabolic Steroid, Oxandrolone, Administration to Rats

et al. 1970

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SynopsisRemarkable lowering of plasma cholesterol by oxandrolone administration was observed in the hypercholesteremic rats fed the high cholesterol diet but not in the rats fed the low cholesterol diet during the short experimental period. Tween 80 induced hypercholesteremia or diabetic hypercholesteremia was not prevented by oxandrolone.Although the bile amount of the rats with bile fistulae was not influenced by the hormone administration, the biliary excretion of cholic acid and cholesterol was increased in the hormone treated group. Excretion of the radioactivity into the bile after labeled cholesterol injection was accelerated by oxandrolone. When 26-14C cholestereol was injected into the animals, more radioactivity was found in expiratory CO2 of the oxandrolone treated rats than that of the controls. Influx of administered cholesterol from plasma to the liver was accelerated in the oxandrolone fed rats with bile duct obstruction, and outflux of endogenous cholesterol from the liver to plasma was also increased.Cholesterol was accumulated in the liver by oxandrolone treatment when cholesterol was given simultaneously with the hormone, but the decrease of the hepatic cholesterol contents after the interruption of cholesterol feeding was promoted by the hormone administration.Therefore, the main mechanism of the hypocholesteremic effect of anabolic steroids is assumed to be both the acceleration of the shift of cholesterol from plasma to liver and secondary stimulation of cholesterol catabolism to bile acid.

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The biosynthesis of cholesterol

Olson

1965

Ergebnisse der Physiologie und exper. Pharmakologie

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The hypocholesteremic effect of 3β-(β-dimethylaminoethoxy)-androst-5-en-17-one and its mechanism of action

Cited by 18 publications

References 3 publications

Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes

Cholesterol Synthesis Inhibitor U18666A and the Role of Sterol Metabolism and Trafficking in Numerous Pathophysiological Processes

Alteration of Cholesterol Metabolism Induced by Anabolic Steroid, Oxandrolone, Administration to Rats

The biosynthesis of cholesterol

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