VASTATINS HAVE A DISTINCT EFFECT ON STEROL SYNTHESIS AND PROGESTERONESECRETION IN HUMAN GRANULOSA-CELLS IN-VITRO

Citation
Ak. Vanvliet et al., VASTATINS HAVE A DISTINCT EFFECT ON STEROL SYNTHESIS AND PROGESTERONESECRETION IN HUMAN GRANULOSA-CELLS IN-VITRO, Biochimica et biophysica acta, L. Lipids and lipid metabolism, 1301(3), 1996, pp. 237-241
Citations number
24
Categorie Soggetti
Biology,Biophysics
ISSN journal
00052760
Volume
1301
Issue
3
Year of publication
1996
Pages
237 - 241
Database
ISI
SICI code
0005-2760(1996)1301:3<237:VHADEO>2.0.ZU;2-F
Abstract
Lovastatin and simvastatin are strong inhibitors of cholesterol synthe sis in cultured human granulosa cells, as measured within 6 days after isolation, with IC50-values of respectively 27.0 and 18.2 nM obtained after 3.5 hours of incubation with the drugs. Pravastatin is a much w eaker inhibitor of cholesterol synthesis (IC50-value of 977.8 nM) in t hese cells. Under these conditions inhibition of cholesterol synthesis had no influence on progesterone secretion into the medium which was probably due to the presence of large cholesterol pools in the cells. To deplete these pools, granulosa cells were cultured for 7 days after which the culture medium was changed into medium supplemented with 20 % lipoprotein-depleted serum to deprive the cells of exogenous cholest erol. Additionally, 30 mIU of follicle-stimulating hormone and luteini zing hormone per ml were added to stimulate the progesterone productio n and secretion, thereby decreasing the cholesteryl ester pools. After 48 h of incubation, culture was continued without hormones for anothe r two days. Thereafter, the cells were preincubated for 24 h without o r with 1 mu M of lovastatin, simvastatin or pravastatin in medium cont aining lipoprotein-deficient serum and the above-mentioned hormones. T his period is followed by incubation for another 24 h in the presence of [C-14]acetate after which cells and media were collected for determ ination of C-14-labelled sterols synthesized and progesterone secreted into the media. Now, lovastatin and simvastatin, which strongly inhib ited sterol synthesis, significantly attenuated the secretion of proge sterone. One mu M of pravastatin had no significant effect on sterol s ynthesis nor on progesterone secretion. When the latter experiment was performed under conditions in which exogenous cholesterol was provide d in the form of human low density lipoproteins, no influence of the v astatins on progesterone secretion was observed, So under conditions i n which the cholesterol pools were decreased, lovastatin and simvastat in attenuated the progesterone secretion, whereas pravastatin did not. When pools were filled by exogenous cholesterol, no effect on progest erone secretion by either of the drugs was observed.