Diethylstilbestrol stimulates persistent phosphatidylinositol lipid turnover by an estrogen receptor-mediated mechanism in immature mouse uterus.
The effect of estrogen on phosphoinositide (PI) metabolism was evaluated in the immature mouse uterus, a tissue which undergoes estrogen-induced proliferation. Uteri isolated from untreated mice or from mice injected ip with diethylstilbestrol (DES) were incubated with [3H]myo-inositol and assessed for incorporation of label into PI lipids or inositol phosphate generation. DES administration elicited a rapid increase in [3H]myo-inositol incorporation, which persisted until at least 18 h post treatment. This effect could not be duplicated by incubation of uteri with DES in vitro, although [3H]myo-inositol incorporation in uteri removed from DES-treated mice remained elevated for 3 h of in vitro incubation. Stimulation of PI lipid metabolism by DES was blocked by ICI 164,384, a specific estrogen receptor antagonist. The effect of DES on PI metabolism consisted of a time-dependent increase in the specific activity of both phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate and a significant increase of inositol (1,4,5)-trisphosphate mass by 12 h post treatment. These changes occur before the onset of estrogen-induced DNA synthesis. The results indicate that estrogens rapidly modulate PI lipid turnover through an estrogen receptor-mediated mechanism. Since the metabolic products of PI lipids are important for signal transduction and cellular proliferation, altered metabolism of these lipids may play an integral role in estrogen-induced mitogenesis.
Laboratory of Reproductive and Developmental Toxicology, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709.
D M
DM
Ignar-Trowbridge
A R
AR
Hughes
J W
JW
Putney
J A
JA
McLachlan
K S
KS
Korach
D000818:Animals; D004028:Dienestrol / Q000494:pharmacology; D004054:Diethylstilbestrol / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D007294:Inositol / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000032:analysis; D050356:Lipid Metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D010716:Phosphatidylinositols / Q000378:metabolism*; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen / Q000502:physiology*; D014599:Uterus / Q000378:metabolism*
D004965:Estrogen Antagonists; D010716:Phosphatidylinositols; D053284:Polyunsaturated Alkamides; D011960:Receptors, Estrogen; D007294:Inositol; D004958:Estradiol; D004054:Diethylstilbestrol; C051781:ICI 164384; D015544:Inositol 1,4,5-Trisphosphate; D004028:Dienestrol