Inhibition of Cholesterol Biosynthesis in the Rat by 3 -(2-diethylaminoethoxy)androst-5-en-17-one, hydrochloride

Phillips, William A.; Avigan, Joel

doi:10.3181/00379727-112-28003

Cited by 40 publications

(18 citation statements)

References 2 publications

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“…At 3 months of age, sterol analysis of plasma and liver tissue showed that desmosterol accounted for 99% of total sterols. The lack of malformations in the genetic mouse model, in comparison to both human patients and pharmacological models of desmosterolosis ( 202 ), is likely due to availability of maternal cholesterol during embryogenesis in the mouse. The viability of Dhcr24 mutant mice is variable.…”

Section: Hydrops-ectopic Calcifi Cation-moth-eaten Skeletal Dysplasiamentioning

confidence: 99%

Malformation syndromes caused by disorders of cholesterol synthesis

Porter

Herman

2011

Journal of Lipid Research

407

440

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Section: Hydrops-ectopic Calcifi Cation-moth-eaten Skeletal Dysplasiamentioning

confidence: 99%

Malformation syndromes caused by disorders of cholesterol synthesis

Porter

Herman

2011

Journal of Lipid Research

407

440

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“…Treatment of neonatal rats systemically by subcutaneous or intraperitoneal injection with U18666A [3-␤ (2-diethylaminoethoxy)androst-5-en-17-one hydrochloride], an inhibitor of 3 ␤ -hydroxysterol-⌬ 24 -reductase (desmosterol reductase) ( 120 ), results in accumulation of desmosterol (cholesta-5,24-dien-3 ␤ -ol) and depletion of cholesterol in all bodily tissues, but, unlike AY9944, it also causes cataract formation ( 121 ). This has been used as an animal model of desmosterolosis, another rare hereditary human disease in the constellation of postsqualene defects in the cholesterol biosynthetic pathway ( 122,123 ).…”

Section: Does the Retina Require Cholesterol To Achieve Normal Structmentioning

confidence: 99%

The ins and outs of cholesterol in the vertebrate retina

Fliesler

Brétillon

2010

Journal of Lipid Research

133

138

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Journal of Lipid Research Volume 51, 2010 3399 plus glial cells (Müller cells, astrocytes, and microglia).[For an excellent overview of retinal structure and cytoarchitecture, see ( 1 ) and http://webvision.med.utah. edu/]. The neuronal cells are distributed into discrete histological layers in the fully differentiated retina ( Fig. 1 ), with the ganglion cell layer arranged proximal to the vitreous and the photoreceptor cells (rods and cones) residing at the opposite side of the neural retina, just underneath the retinal pigment epithelium (RPE) layer. The RPE is a monolayer of polarized epithelial cells that serves as the interface between the neural retina and the choroid, the blood supply to the outer cell layers of the retina. The apical tips of the photoreceptor outer segments (OS) are adjacent to and invaginate into the apical face of the RPE (one of the few examples of apical-apical cellular contact in the body) ( Fig. 1C ). Bruch's membrane (BrM; Fig. 1B, C ) is not a membrane, per se, but rather a pentalaminar structure that consists of the basement membranes of the RPE cells and the endothelial cells of the choriocapillaris ( Fig. 1C ), plus the extracellular matrix that fi lls the space between these two membranes [reviewed in ( 2, 3 )].The relatively modest compendium of cell types mentioned above, however, belies the amazing, higher order complexity of this sensory tissue. It has been estimated that there are actually about 55 anatomically distinct neuronal cell types in the adult mammalian retina, of which about 22 have been thoroughly characterized with regard to their fi ne structure and functional repertoire [reviewed in ( 4 )]. For example, photoreceptors consist of both rods and cones, with cones being subdivided into two (three in Abstract The vertebrate retina has multiple demands for utilization of cholesterol and must meet those demands either by synthesizing its own supply of cholesterol or by importing cholesterol from extraretinal sources, or both. Unlike the blood-brain barrier, the blood-retina barrier allows uptake of cholesterol from the circulation via a lipoprotein-based/receptor-mediated mechanism. Under normal conditions, cholesterol homeostasis is tightly regulated; also, cholesterol exists in the neural retina overwhelmingly in unesterifi ed form, and sterol intermediates are present in minimal to negligible quantities. However, under certain pathological conditions, either due to an inborn error in cholesterol biosynthesis or as a consequence of exposure to selective inhibitors of enzymes in the cholesterol pathway, the ratio of sterol intermediates to cholesterol in the retina can rise dramatically and persist, in some cases resulting in progressive degeneration that signifi cantly compromises the structure and function of the retina. The mature vertebrate retina is a highly stratifi ed, multicellular tissue classically described as consisting of six fundamental neuronal cell types (photoreceptor, bipolar, ganglion, horizontal, amacrine, and interplexiform cells) the normal...

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“…Previous studies (33) and the results of the current study show that the development of cataracts in young U18666A-treated rats was accompanied by an ‫%52ف‬ decrease in the molar ratio of cholesterol to phospholipid in lens. Although it is well established that U18666A can decrease cholesterol availability by inhibiting OSC (41) and desmosterol reductase (12), more recent reports indicate that U18666A also inhibits synthesis at sterol ⌬8,⌬7-isomerase (42) and the ⌬24-isomerase of several intermediates (43). In addition to inhibiting cholesterol synthesis, U18666A is now known to impair intracellular cholesterol trafficking, at minimum, by interfering with the movement of lysosomal cholesterol (derived from extracellular lipoproteins) to the plasma membrane (36) and the movement of cholesterol from the plasma membrane to the endoplasmic reticulum (38).…”

Section: Discussionmentioning

confidence: 99%

“…OSC inhibitors can rapidly induce cataracts in rodents, suggesting that the procataractogenic effects of these drugs may be attributable to mechanisms unrelated to the inhibition of cholesterol biosynthesis. OSC inhibitors constitute a class of amphiphilic, cationic-tertiary amines that include U18666A from Upjohn (now Pharmacia-Upjohn) (12), BIBX79 and BIBB 515 from Boehringer Ingelheim (13,14), Ro48-8071 from HoffmannLa Roche (15), and ZD9720 and ZD7851 from AstraZeneca (8). U18666A (7), ZD9720 (8), ZD7851 (8), Ro48-8071, and Ro61-0842 can induce cataracts in rats, mice, and dogs after only 10-20 days of treatment.…”

mentioning

confidence: 99%

“…Pharmaceutical companies have been exploring the development of a new generation of hypocholesterolemic drugs that inhibit the OSC-catalyzed step in the cholesterol biosynthetic pathway (8,(12)(13)(14)(15). The potential advantages over the statins, collectively the most prescribed drugs in the United States, include less secondary increase of HMG-CoA reductase and uninhibited formation of isoprenes, intermediates that are formed in the cholesterol pathway between mevalonic acid and squalene and that are essential for cell function ( Fig.…”

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confidence: 99%

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Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor

Cenedella

Jacob²,

Borchman

et al. 2004

Journal of Lipid Research

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Induction of cataracts in experimental animals is a common toxic feature of oxidosqualene cyclase (OSC) inhibitors. U18666A has been shown to produce irreversible lens damage within a few weeks of treatment. Drug actions, besides reducing the availability of cholesterol, could contribute to cataract formation. Cholesterol added to cultures of lens epithelial cells could only partially overcome the growth-inhibiting effects of U18666A. In view of this finding and the fact that U18666A and other OSC inhibitors are highly lipophilic cationic tertiary amines, we tested the hypothesis that the cataractogenic effect of U18666A is related to direct perturbation of lens membrane structure and function. Based on changes in the anisotropy of fluorescent probes, U18666A incorporated into bovine lens lipid model membranes increased membrane structural order and, using small-angle x-ray diffraction, U18666A was shown to intercalate into the lens lipid model membranes and produce a broad condensing effect on membrane structure. Also, exposure of cultured lens epithelial cells and intact rat lenses to U18666A induced apoptosis. Induction of apoptosis may begin by intercalation of U18666A into cell membranes. By increasing membrane structural order, U18666A may also increase light scatter, thus directly contributing to lens opacification. -Cenedella, R.

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Inhibition of Cholesterol Biosynthesis in the Rat by 3 -(2-diethylaminoethoxy)androst-5-en-17-one, hydrochloride

Cited by 40 publications

References 2 publications

Malformation syndromes caused by disorders of cholesterol synthesis

Malformation syndromes caused by disorders of cholesterol synthesis

The ins and outs of cholesterol in the vertebrate retina

Direct perturbation of lens membrane structure may contribute to cataracts caused by U18666A, an oxidosqualene cyclase inhibitor

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