Naringenin: a weakly estrogenic bioflavonoid that exhibits antiestrogenic activity.
Treatment of immature 21-day-old female Sprague-Dawley rats with 17 beta-estradiol (E2) (0.5 microgram/rat) caused a significant increase in uterine wet weight, DNA synthesis, progesterone receptor (PR) binding, and peroxidase activity. At doses as high as 40 mg/rat, the bioflavonoid naringenin did not cause a significant increase in any of these E2-induced responses. However, in rats cotreated with E2 (0.5 microgram/rat) plus naringenin (30 mg/rat); there was a significant decrease in E2-induced uterine wet weight, DNA synthesis, PR binding, and peroxidase activity, indicating that naringenin exhibits antiestrogenic activity in the immature rodent uterus. The binding of uterine nuclear extracts to a 32P-labeled estrogen responsive element (ERE) or progesterone responsive element (PRE) was determined using gel electrophoretic band shift assays. Incubation of [32P]ERE with uterine nuclear extracts from rats treated with naringenin or E2 resulted in the formation of estrogen receptor (ER):ERE complexes; a higher mobility complex was prominent in the extracts from E2-treated rats, whereas a lower mobility complex was observed using nuclear extracts from naringenin-treated animals. There was a significant decrease in the intensity of the E2-induced complex using nuclear extracts from rats treated with E2 plus naringenin. In contrast, transformed cytosol from control rats gave an intense ER:ERE complex, whereas the intensity of the band was decreased markedly using transformed uterine cytosol from treated rats. Formation of a PR:PRE complex was also determined using transformed uterine cytosol. Cytosol from E2-treated rats gave an intense retarded band, whereas only weak bands were observed using cytosols from DMSO- (solvent), naringenin-, or naringenin plus E2-treated cells. The results of in vitro studies showed that 1 nM E2 increased (3- to 4-fold) the growth of MCF-7 human breast cancer cells, whereas 1-1000 nM naringenin had no effect on cell proliferation. In cells cotreated with 1 nM E2 plus 1000 nM naringenin, there was a significant decrease in E2-induced cell growth. In MCF-7 cells transiently transfected with a pS2 promoter-regulated luciferase reporter gene, naringenin exhibited weak estrogenic activity. In cells cotreated with 0.1 or 1.0 microM naringenin plus 1 nM E2, naringenin inhibited E2-induced luciferase activity. The results of these studies confirmed that naringenin is a weak estrogen that also exhibits partial antiestrogenic activity in the female rat uterus and MCF-7 human breast cancer cells.
Ruh
M F
MF
Department of Pharmacological and Physiological Science, Saint Louis University, School of Medicine, MO 63104, USA.
Zacharewski
T
T
Connor
K
K
Howell
J
J
Chen
I
I
Safe
S
S
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000648:ultrastructure; D003600:Cytosol / Q000378:metabolism; D004586:Electrophoresis / Q000379:methods; D004958:Estradiol / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology*; D005260:Female; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism / Q000648:ultrastructure; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists / Q000378:metabolism; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism
D004965:Estrogen Antagonists; D044950:Flavanones; D005419:Flavonoids; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D004958:Estradiol; C005273:naringenin