Potent inhibition of cholesterol biosynthesis in 3T3 fibroblasts by N-[(1,5,9)-trimethyldecyl]-4α, 10-dimethyl-8-AZA-trans-decal-3β-OL, a new 2,3-oxidosqualene cyclase inhibitor

Gerst, Nicolas; Duriatti, Albert; Schuber, Francis; Taton, Maryse; Benveniste, Pierre; Rahier, Alain

doi:10.1016/0006-2952(88)90542-4

Cited by 30 publications

(12 citation statements)

References 25 publications

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“…From our cellular data it does not seem that fenpropimorph is a good inhibitor of the mammalian cyclase. In contrast with results obtained recently with specific cyclase inhibitors in the same cellular system (Gerst et al, 1986(Gerst et al, , 1988), the levels of 2,3-oxidosqualene and 2,3:22,23-dioxidosqualene in the fenpropimorphtreated cells represent only minor amounts of the total non-saponifiable fraction. Moreover, when tested in vitro on a pig liver microsomal 2,3-oxidosqualene:lanosterol cyclase, this fungicide was found to be a poor inhibitor, i.e.…”

contrasting

confidence: 97%

“…were performed according to published procedures (Gerst et al, 1986;Costet et al, 1987). Analysis of the C27-sterol fractions by thin-layer argentation chromatography has been described elsewhere (Gerst et al, 1988). Separation of the polar sterols was performed by t.l.c.…”

Section: Cell Cultures and Sterol Synthesismentioning

confidence: 99%

“…The HMG-CoA reductase activity of cell extracts was measured as described previously (Gerst et al, 1988); the effect of fenpropimorph on the 2,3-oxidosqualene: lanosterol cyclase activity, associated to pig liver microsomes (microsomal fractions), was determined as described previously (Duriatti et al, 1985).…”

Section: Enzyme Activitiesmentioning

confidence: 99%

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Inhibition by the fungicide fenpropimorph of cholesterol biosynthesis in 3T3 fibroblasts

Corio-Costet¹,

Gerst²,

Benveniste³

et al. 1988

Biochemical Journal

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Fenpropimorph (N-[3-(p-t-butylphenyl)-2-methylpropyl]-cis-2,6-dimethylmorpholine), a morpholine fungicide known to be an inhibitor of sterol biosynthesis in fungi and in higher plants, was demonstrated to be an efficient inhibitor of cholesterol biosynthesis in cultured Swiss 3T3 fibroblasts. Treatment of the mammalian cells with fenpropimorph resulted in a dose-dependent inhibition of [14C]acetate incorporation into the C27 sterols [IC50 (concentration causing half-maximal inhibition) = 0.5 microM], which was accompanied by an accumulation of polar sterols and a decrease in cellular hydroxymethylglutaryl-CoA reductase activity. Exposure of the cells to the drug affected cell growth. Analysis of the sterols in the growth-arrested and in the pulse-labelled cells indicate that fenpropimorph has, in the sterol-biosynthetic pathway, target enzymes in mammalian cells different from those in the other phyla. Whereas in plants and fungi fenpropimorph mainly affects sterol isomerases and reductases, in the fibroblasts its main target seems to be the demethylation of lanosterol.

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confidence: 97%

Section: Cell Cultures and Sterol Synthesismentioning

confidence: 99%

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Inhibition by the fungicide fenpropimorph of cholesterol biosynthesis in 3T3 fibroblasts

Corio-Costet¹,

Gerst²,

Benveniste³

et al. 1988

Biochemical Journal

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“…MDL28,815, a rationally designed inhibitor of sterol biosynthesis, resembles cholesterol and mimics the high energy reaction intermediates of several of the late steps of sterol modification (Gerst et al , 1988). Despite a chemical structure different from that of morpholines its affinity for the (+)‐[ 3 H]‐pentazocine labelled sigma 1 ‐site of guinea‐pig brain microsomes was close ( K i 0.16 ± 0.04 n m ( n = 3)) to that of tridemorph (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…The ultrahigh affinity of fenpropimorph for the brain α 1 ‐site ( K i 5 p m ) suggests that this morpholine might be a valuable tool for studies on sigma 1 ‐mediated effects. The haloperidol congener trifluperidol ( K i 1.3 n m ) inhibits the sterol C 8 –C 7 isomerase of yeast (Sobus et al , 1977) whereas the azadecalin MDL28,815 ( K i 0.16 n m ) inhibits the mammalian sterol C 8 –C 7 isomerase in 3T3 mouse fibroblasts (Gerst et al , 1988) as well as in the human hepatoma cell line HepG2 (van Sickle et al , 1993). The anti‐hypercholesteraemic drug AY‐9944 ( K i 0.46 n m ) reduces sterol C 8 –C 7 isomerization in yeast (Pereira et al , 1983) and rat adrenal gland (Givner et al , 1967).…”

Section: Discussionmentioning

confidence: 99%

High affinity of sigma₁‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C₈–C₇ isomerase

Moebius

Reiter

Hanner

et al. 1997

British J Pharmacology

102

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1 The sigma-drug binding site of guinea-pig liver is carried by a protein which shares signi®cant amino acid sequence similarities with the yeast sterol C 8 ± C 7 isomerase (ERG2 protein). Pharmacologicallybut not structurally -the sigma 1 -site is also related to the emopamil binding protein, the mammalian sterol C 8 ± C 7 isomerase. We therefore investigated if sterol C 8 ± C 7 isomerase inhibitors are high anity ligands for the (+)-[3 H]-pentazocine labelled sigma 1 -binding site. 2 Among the compounds which bound with high anity to native hepatic and cerebral as well as to yeast expressed sigma 1 -binding sites were the agricultural fungicide fenpropimorph (K i 0.005 nM), the antihypocholesterinaemic drugs triparanol (K i 7.0 nM), AY-9944 (K i 0.46 nM) and MDL28,815 (K i 0.16 nM), the enantiomers of the ovulation inducer clomiphene (K i 5.5 and 12 nM, respectively) and the antioestrogene tamoxifen (K i 26 nM). 3 Except for tamoxifen these anities are essentially identical with those for the [ 3 H]-ifenprodil labelled sterol C 8 ± C 7 isomerase of S. cerevisiae. This demonstrates that sigma 1 -binding protein and yeast isomerase are not only structurally but also pharmacologically related. Because of its aliations with yeast and mammalian sterol isomerases we propose that the sigma 1 -binding site is localized on a sterol isomerase related protein, involved in postsqualene sterol biosynthesis.

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Rationally Designed Inhibitors of Sterol Biosynthesis

Oehlschlager¹,

Czyzewska²

1992

Emerging Targets in Antibacterial and Antifungal Chemotherapy

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Potent inhibition of cholesterol biosynthesis in 3T3 fibroblasts by N-[(1,5,9)-trimethyldecyl]-4α, 10-dimethyl-8-AZA-trans-decal-3β-OL, a new 2,3-oxidosqualene cyclase inhibitor

Cited by 30 publications

References 25 publications

Inhibition by the fungicide fenpropimorph of cholesterol biosynthesis in 3T3 fibroblasts

Inhibition by the fungicide fenpropimorph of cholesterol biosynthesis in 3T3 fibroblasts

High affinity of sigma₁‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C₈–C₇ isomerase

Rationally Designed Inhibitors of Sterol Biosynthesis

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Potent inhibition of cholesterol biosynthesis in 3T3 fibroblasts by N-[(1,5,9)-trimethyldecyl]-4α, 10-dimethyl-8-AZA-trans-decal-3β-OL, a new 2,3-oxidosqualene cyclase inhibitor

Cited by 30 publications

References 25 publications

Inhibition by the fungicide fenpropimorph of cholesterol biosynthesis in 3T3 fibroblasts

Inhibition by the fungicide fenpropimorph of cholesterol biosynthesis in 3T3 fibroblasts

High affinity of sigma1‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C8–C7 isomerase

Rationally Designed Inhibitors of Sterol Biosynthesis

Contact Info

Product

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High affinity of sigma₁‐binding sites for sterol isomerization inhibitors: evidence for a pharmacological relationship with the yeast sterol C₈–C₇ isomerase