title: Genistein stimulates jejunal chloride secretion via sex-dependent, estrogen receptor or adenylate cyclase mechanisms.
abstract: OBJECTIVE
  Daily subcutaneous injections with the phytoestrogen genistein, 600 mg/ kg genistein/day (600G) significantly increased intestinal chloride (Cl(-)) secretion (I(sc), µA/cm(2)) in C57BL/6J female and male murine jejunum after 1-2-weeks treatment.
  
  
  RESULTS
  In 600G females, basolateral application of the adenylate cyclase inhibitor MDL-12330A (10 µM) significantly reduced basal and total I(sc) in the presence of forskolin (27 and 40% respectively, P < 0.05), with no effect in 600G males, suggesting that 600G-mediated increases in I(sc) in females are due to an adenylate cyclase-dependent mechanism. Concomitant injections with the non-selective estrogen receptor (ER) antagonist ICI-182780 (25 mg/kg/day) resulted in a significant inhibition of basal I(sc) in males (38%, P < 0.05), but was without effect in females (further reinforcing an ER-independent mechanism of action). The ERα-selective antagonist (MPP, 25 mg/kg/day) similarly significantly inhibited the basal I(sc) (37%, P < 0.05) in males, whereas the ERβ-selective antagonist (PHTPP, 25 mg/kg/day) was without effect, suggesting that 600G-mediated increases in I (sc) in male mice are due to an ERα-dependent mechanism. Jejunum ERα/actin expression was significantly increased by 600G in males. Compared to intact mice, orchiectomy has differing effects on 600G-mediated basal Isc; castration (CAST) abolished the 600G-mediated increases in I(sc), and ovariectomy (OVX) had no effect on the 600G-stimulated increases in I(sc). Daily estradiol injections (10-20 mg/kg body weight estradiol (10E2 or 20E2) had no effect in intact females, whereas 10E2 significantly increased basal I(sc) in OVX females.
  
  
  CONCLUSIONS
  These data suggest that daily estradiol and genistein injections have differential sex-dependent mechanisms of action on murine intestinal Cl(-) secretion.
authors: Department of Physiology, Midwestern University, Glendale, AZ 85308, USA. lalnak@midwestern.edu
authors: Layla
authors: L
authors: Al-Nakkash
mesh_terms: D000199:Actins / Q000378:metabolism; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D020536:Enzyme Activators / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D000077267:Fulvestrant; D019833:Genistein / Q000494:pharmacology*; D007097:Imines / Q000494:pharmacology; D007419:Intestinal Secretions / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009919:Orchiectomy; D048789:Phytoestrogens / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D012727:Sex Characteristics; D015398:Signal Transduction
chemical_list: C524478:1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-(2-piperidinylethoxy)phenol)-1H-pyrazole; D000199:Actins; D000067956:Adenylyl Cyclase Inhibitors; D002712:Chlorides; D020536:Enzyme Activators; D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007097:Imines; D048789:Phytoestrogens; D010880:Piperidines; D011720:Pyrazoles; D005576:Colforsin; D000077267:Fulvestrant; D004958:Estradiol; C014925:RMI 12330A; D019833:Genistein; D000262:Adenylyl Cyclases