Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells.
Ovarian granulosa cells synthesize estrogens from androgens, which are catalyzed by aromatase cytochrome P450 (P450arom). Troglitazone (Tro), one of the insulin-sensitizing compounds, thiazolidinediones (TZDs), is a ligand for peroxisome proliferator activated receptor gamma (PPARgamma) and is effective in the treatment of both non-insulin-dependent diabetes mellitus (NIDDM) as well as polycystic ovary syndrome (PCOS). PPARgamma exerts a transcriptional activity as a PPARgamma:RXR heterodimer. In this study, we investigated the effects of Tro and/or RXR ligand, LG100268 (LG) on the aromatase activity in cultured human ovarian granulosa cells obtained from patients who underwent in vitro fertilization. Human ovarian granulosa cells expressed PPARgamma mRNA assessed by RT-PCR. The treatment of the granulosa cells with Tro for 24 h resulted in a dramatic inhibition of the aromatase activity in a dose-dependent manner. While the treatment with LG alone also inhibited the aromatase activity, the combined treatment with both Tro and LG caused a much more reduction in the aromatase activity. The changes in the aromatase activity by Tro and/or LG were associated with comparable changes in P450arom mRNA assessed by RT-PCR. These results suggest that Tro directly inhibit the aromatase activity in human granulosa cells probably via nuclear receptor system PPARgamma:RXR heterodimer. The findings may provide a biochemical basis for the decrease in the blood concentrations of estrogens which is observed after the in vivo administration of Tro and may also possibly be useful as a novel therapy for estrogen-dependent diseases.
Mu
Y M
YM
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
Yanase
T
T
Nishi
Y
Y
Waseda
N
N
Oda
T
T
Tanaka
A
A
Takayanagi
R
R
Nawata
H
H
D000328:Adult; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D047072:Aromatase Inhibitors; D002839:Chromans / Q000494:pharmacology*; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000097:blood; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D009539:Nicotinic Acids; D010053:Ovary / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013764:Tetrahydronaphthalenes; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000077288:Troglitazone
D047072:Aromatase Inhibitors; D002839:Chromans; D004791:Enzyme Inhibitors; D004967:Estrogens; D009539:Nicotinic Acids; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D001141:Aromatase; D000077288:Troglitazone; C095104:LG 100268