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Titolo:
Lack of toxic effects of F 12511, a novel potent inhibitor of acylcoenzymeA: cholesterol O-acyltransferase, on human adrenocortical cells in culture
Autore:
Junquero, D; Pilon, A; Carilla-Durand, E; Patoiseau, JF; Tarayre, JP; Torpier, G; Staels, B; Fruchart, JC; Colpaert, FC; Clavey, V; Delhon, A;
Indirizzi:
Ctr Rech Pierre Fabre, F-81106 Castres, France Ctr Rech Pierre Fabre Castres France F-81106 re, F-81106 Castres, France Univ Lille 2, INSERM U325, Inst Pasteur Lille, F-59019 Lille, France Univ Lille 2 Lille France F-59019 t Pasteur Lille, F-59019 Lille, France
Titolo Testata:
BIOCHEMICAL PHARMACOLOGY
fascicolo: 4, volume: 61, anno: 2001,
pagine: 387 - 398
SICI:
0006-2952(20010215)61:4<387:LOTEOF>2.0.ZU;2-V
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACYL-COENZYME-A; RECEPTOR CLASS-B; SR-BI; ADRENAL-HYPERPLASIA; ACAT-1 PROTEIN; GENE; COA; METABOLISM; EXPRESSION; ESTER;
Keywords:
ACAT; adrenal cells; F 12511; steroidogenesis; lipid metabolism; adrenal ultrastructure;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Junquero, D Ctr Rech Pierre Fabre, 17 Ave Jean Moulin, F-81106 Castres, France Ctr Rech Pierre Fabre 17 Ave Jean Moulin Castres France F-81106
Citazione:
D. Junquero et al., "Lack of toxic effects of F 12511, a novel potent inhibitor of acylcoenzymeA: cholesterol O-acyltransferase, on human adrenocortical cells in culture", BIOCH PHARM, 61(4), 2001, pp. 387-398

Abstract

Inhibition of acyl-coenzyme A: cholesterol O-acyltransferase (EC 2.3.1.26;ACAT) reduces intracellular cholesteryl esters that are substrates for steroidogenesis in adrenal cells. The adrenal side effects of ACAT inhibitors remain a key point for their development as antiatherosclerotic agents. Theaim of this study was to characterize the effects of a novel and powerful ACAT inhibitor, F 12511 (S)-2',3',5 '-trimethyl-4' -hydroxy-alpha -dodecylthio-phenylacetanilide, on the NCI-H295R cell line, which has functional properties comparable to those of normal human adrenal cells. F 12511 incubated with cultured cells for 4-72 hr strongly inhibited cholesteryl oleate formation. The concentrations required to produce 50% inhibition (IC50 values)ranged from 20 to 50 nM; in the presence of low-density lipoproteins (LDL), this effect was paralleled by a decrease in cholesteryl ester mass and anincrease in intracellular free cholesterol. At concentrations 100-fold larger than the IC50 value for up to 48 hr, F 12511 reduced neither the basal release of cortisol and aldosterone nor the production of cortisol stimulated by forskolin. F 12511 did not modify the mRNA levels of the steroidogenic enzyme genes cytochrome P450 cholesterol side-chain cleavage (P450scc), cytochrome P450 17 alpha -hydroxylase (P450c17), or cytochrome P450 21-hydroxylase (P450c21) or those of the LDL receptor and high-density lipoprotein scavenger receptor class B, type I (SR-BI) genes, either in the presence orabsence of adenosine 3',5'-cyclic monophosphate stimulation for 24 hr. Exposure to F 12511 at up to 3 mum for 24 or 48 hr did not result in significant change in morphological and ultrastructural characteristics; the cytoplasm contained large numbers of mitochondria with intact crystae, and the same typical features of secretory activity were observed in NCI-H295R controlcells. Exposure to 3 muM of F 12511 for 96 hr also did not affect cell viability. These data demonstrate that reduction of the substrate for steroidogenesis by the ACAT inhibitor F 12511 impairs neither steroid production nor transcription of genes involved in steroidogenesis and lipoprotein uptakein the pluripotent human adrenal cell line NCI-H295R. (C) 2001 Elsevier Science Inc. All rights reserved.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 11/07/20 alle ore 17:33:02