Kinetics of genistein and its conjugated metabolites in pregnant Sprague-Dawley rats following single and repeated genistein administration.
Diets high in soy-based products are well known for their estrogenic activity. Genistein, the predominant phytoestrogen present in soy, is known to interact with estrogen receptors (ER) alpha and beta and elicits reproductive effects in developing rodents. In the rat, genistein is metabolized predominantly to glucuronide and sulfate conjugates, neither of which is capable of activating ER. Therefore, it is critical to understand the delivery of free and conjugated genistein across the placenta to the fetus following maternal genistein exposure such that the potential fetal exposure to free genistein can be assessed. Genistein (4 or 40 mg/kg) was administered to pregnant Sprague-Dawley rats by oral gavage daily from gestation day (GD) 5 through 19 or on GD 19 alone. Maternal and GD 19 fetal tissues were collected 0.5, 1, 2, 4, 6, 8, 12, and 24 h following administration of the final dose on GD 19. Concentrations of genistein, genistein glucuronide, and genistein sulfate were quantitated by LC-MS/MS. In maternal plasma, genistein glucuronide was the predominant metabolite. In the fetal plasma, genistein glucuronide and genistein sulfate were the primary metabolites. Genistein levels in maternal and fetal plasma were much lower than its conjugates. The concentration of genistein in placental tissue was higher than either conjugate. Fetal concentrations of unconjugated genistein following administration of 40 mg/kg were above the EC50 for ERbeta activation. Repeated administration of 40 mg/kg genistein resulted in minor changes in genistein kinetics in the pregnant rat compared to single administration of the same dose. These data suggest that conjugated forms of genistein are not transported across the placenta. High placental concentrations of genistein indicate the placenta is a potential target organ for genistein action during gestation.
Soucy
Nicole V
NV
CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709, USA. nsoucy@ciit.org
Parkinson
Horace D
HD
Sochaski
Mark A
MA
Borghoff
Susan J
SJ
D000284:Administration, Oral; D000653:Amniotic Fluid / Q000737:chemistry; D000818:Animals; D016588:Anticarcinogenic Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005333:Fetus / Q000187:drug effects / Q000378:metabolism; D019833:Genistein / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization
D016588:Anticarcinogenic Agents; D019833:Genistein