An Inhibitor of Cholesterol Biosynthesis

Chappel, C.I.; Dubuc, Jean-Émile; Dvornik, D.; Givner, Morris L.; Humber, Leslie G.; Kraml, M.; Voith, K; Gaudry, Roger

doi:10.1038/201497a0

Cited by 32 publications

(15 citation statements)

References 4 publications

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“…AY9944 [trans-1,4-bis (2-chlorobenzylaminomethyl) cyclohexane dihydrochloride] is a selective inhibitor of DHCR7, the same enzyme that is affected in SLOS ( 33,34 ). Kolf-Clauw et al (35)(36)(37)(38) and Xu et al ( 39 ) generated animal models of SLOS by treating rats with AY9944 or with a related DHCR7 inhibitor, BM15766; however, postnatal viability was limited.…”

Section: Isolation Of Oxysterols From Brain Tissues Of Ay9944-treatedmentioning

confidence: 99%

Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome

Liu

Sheflin

et al. 2011

Journal of Lipid Research

110

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Section: Isolation Of Oxysterols From Brain Tissues Of Ay9944-treatedmentioning

confidence: 99%

Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome

Liu

Sheflin

et al. 2011

Journal of Lipid Research

110

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“…Work on mammalian tissue has shown that SKF 525-A and SKF 3301-A act before the formation of squalene (Holmes & Bentz, 1960;Holmes & Di Tullio, 1962 Hypocholesteremic compounds and fungi 333 7732-A, and SKF 7997-A3 principally inhibit the conversion of lanosterol to zymosterol (Holmes & Di Tullio, 1962). AY 9944 inhibits the saturation of the double bond at position 7 ; 7-dehydrocholesterol cannot be converted to cholesterol (Chappel et al 1964;Horlick, 1966). It has also been shown that SKF 7997-A3 inhibits sterol synthesis in the flowering plant Xanthium pensylvanicum (Bonner, Heftmann & Zeevaart, 1963).…”

Section: Introductionmentioning

confidence: 99%

Effects of Inhibitors of Sterol Synthesis on Growth of Sordaria and Phytophthora

Elliott

1969

Journal of General Microbiology

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SUMMARYFour hypocholesteremic compounds, SKF 330I-A, SKF 525-A, SKF 16467-A and AY 9944, inhibited the growth of SordariaJimicola; SKF 2314, SKF 7732-A3 and SKF 7997-A3 did not. All seven compounds inhibited the growth of Phytophthora cactorum. The inhibition of growth of S. Jimicola by SKF 3301-A and AY 9944 was annulled by certain unsaturated fatty acids but not by sterols; with P. cactorum the inhibition was annulled by oleic acid + cholesterol.With Sordaria Jimicola sub-inhibitory concentrations of SKF 3301-A caused growth which showed two phases, distinguished by an abrupt change in growth rate. At the position of the hyphal front when growth rate changed a ring of perithecia was formed. During the second period, when growth was slower, perithecia were formed in rings: The number of perithecia formed could be at least twice that in the drug-free controls. With AY 9944 no perithecia were produced at concentrations sub-inhibitory to vegetative growth. On media with SKF 3301-A or AY 9944 and oleic acid, few perithecia were formed despite good vegetative growth; with SKF ~~o I -A , but not AY 9944, the addition of cholesterol as well increased perithecial production.

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“…A single oral dose of AY 9944 has been shown to depress hepatic cholesterol synthesis in rats by 92 % after 2 h and 55 % after 48 h [2]. In our experiments when rats were given a single oral dose of the drug bile salt synthesis was strongly inhibited (70 -80 "/,) in hepatocytes prepared 2 h later (Fig.…”

Section: Discussionmentioning

confidence: 61%

The Effect of the Hypocholesteremic Drug, AY 9944 on the Synthesis of Bile Salts in Rat Liver

Botham¹,

Boyd²

1981

Eur J Biochem

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I. The compound trans-2,4 bis-(2-dichlorobenzylaminomethyljcyclohexane dihydrochloride (AY 9944) blocks cholesterol synthesis at a late stage. This leads to a decrease in cholesterol and accumulation of cholesta-5,7-diene-3 , ! $ 01 (7-dehydrocholesterol) in tissues and plasma.2. The effect of AY9944 on bile salt synthesis in rat liver was studied. The synthesis of conjugated cholic and chenodeoxycholic acids was measured in hepatocytes isolated from rats 2 h, 24 h and 48 h after administration of a single oral dose of AY 9944. Production of the two bile salts was inhibited by 70 -80 % in hepatocytes from AY 9944-treated as compared to untreated animals.3. When AY9944 was added to the incubation medium in vitro of hepatocytes prepared from untreated rats the synthesis of conjugated cholic and chenodeoxycholic acids was not inhibited during the first hour of incubation, probably because of the presence of endogenous cholesterol. However when hepatocytes from untreated rats were incubated with AY 9944 for periods of 2 h or longer, bile salt production was decreased markedly.4. Bile salt synthesis is stimulated when rats are subjected to total biliary drainage for 24 h. The effect of AY 9944 on this stimulation was studied. The content of conjugated cholic and chenodeoxycholic acid in the bile was measured as an indicator of bile salt synthesis.5. In control animals the rate of secretion of biliary bile salts began to increase after about 24 h of total biliary drainage and reached a maximum after approximately 36 h. A single oral dose of AY 9944 given 2 h after the start of total biliary drainage delayed and reduced this response.6. The results show that inhibition of cholesterol synthesis by AY 9944 resulting in the replacement of cholesterol by 7-dehydrocholesterol decreases but does not completely prevent bile salt synthesis.The drug AY 9944 [trans-1,4 bis-(2-dichlorobenzylaminomethy1)cyclohexane dihydrochloride] specifically inhibits the final step in the biosynthesis of cholesterol and leads to the accumulation of its immediate precursor, 7-dehydrocholesterol, in plasma and tissues [I -41. The first and ratelimiting step in the conversion of cholesterol to bile salts is the 7a-hydroxylation of cholesterol [5 -71. As 7-dehydrocholesterol cannot be hydroxylated in the 7a position without first being converted to cholesterol it is possible that AY 9944 might inhibit bile salt synthesis (see Fig. 1).Experiments in our laboratory and others have shown that isolated hepatocytes are able to synthesis bile salts in vitro [7 -I?]. We have tested the effect of AY9944 in vivo and in vitro on bile salt synthesis in isolated hepatocytes by administration of the drug in vivo prior to killing the animal and by incubation of liver cells in the presence of AY 9944 in vitro.When rats are biliary drained a large increase in bile salt synthesis occurs after about 24-36 h [lo, 111. This results in increased secretion of bile salts into the bile. If hepatic bile salt synthesis were inhibited by AY 9944 the biliary content of bile s...

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An Inhibitor of Cholesterol Biosynthesis

Cited by 32 publications

References 4 publications

Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome

Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome

Effects of Inhibitors of Sterol Synthesis on Growth of Sordaria and Phytophthora

The Effect of the Hypocholesteremic Drug, AY 9944 on the Synthesis of Bile Salts in Rat Liver

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