Effect of dietary genistein on cell replication indices in C57BL6 mice.
The phytoestrogen and isoflavone, genistein, inhibited the activity of the DNA synthesis-related enzyme, topoisomerase-II (topo-II), altered cell-cycle traverse and produced cell death in cell culture models. In order to examine the potential effects of genistein on cell replication and cell death in an animal model, 8-week-old C57BL6 mice were fed either a control diet or one containing one of five doses (100-2000 ppm) of genistein for 28 days. At the end of the feeding period, both male and female mice were sacrificed and the serum isoflavone and aglycone levels determined by liquid chromatography with electrospray tandem mass spectrometry (LC-ES/MS/MS). Immunohistochemistry was utilized to measure the cell replication and cell death rates in the small intestine. Total isoflavone concentration increased from below the limits of detection (0.001 microM) in control animals to 0.28 microM in male and 0.54 microM in female mice fed the 2000 ppm diet. A decrease in the percentage of cells in G(0) and an increase in the percentage of cells in S-phase, consistent with topo-II-induced S-phase arrest, was found in the duodenum and jejunum of the small intestine. Thus, genistein appears to accumulate to a sufficient level to affect topo-II activity in the small intestine.
Morris
S M
SM
Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, HFT-120/DGRT/NCTR, 3900 NCTR Road, Jefferson, AR 72079, USA. smorris@nctr.fda.gov
Akerman
G S
GS
Warbritton
A R
AR
Patton
R E
RE
Doerge
D R
DR
Ding
Xuhong
X
Chen
J J
JJ
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000502:physiology; D004032:Diet; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D019833:Genistein / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects; D007529:Isoflavones / Q000097:blood; D007583:Jejunum / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D016196:S Phase / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D007529:Isoflavones; D018809:Proliferating Cell Nuclear Antigen; D059005:Topoisomerase II Inhibitors; D019833:Genistein; D004250:DNA Topoisomerases, Type II