Stimulatory effects of the soy phytoestrogen genistein on noradrenaline transporter and serotonin transporter activity.
We examined the effects of genistein, one of the major soy phytoestrogens, on the activity of noradrenaline transporter (NAT) and serotonin transporter. Treatment with genistein (10 nM-10 microM) for 20 min stimulated [(3)H]noradrenaline (NA) uptake by SK-N-SH cells. Genistein also stimulated [(3)H]NA uptake and [(3)H]serotonin uptake by NAT and serotonin transporter transiently transfected COS-7 cells, respectively. Kinetics analysis of the effect of genistein on NAT activity in NAT-transfected COS-7 cells revealed that genistein significantly increased the maximal velocity of NA transport with little or no change in the affinity. Scatchard analysis of [(3)H]nisoxetine binding to NAT-transfected COS-7 cells showed that genistein increased the maximal binding without altering the dissociation constant. Although genistein is also known to be an inhibitor of tyrosine kinases, daidzein, another soy phytoestrogen and an inactive genistein analogue against tyrosine kinases, had little effect on [(3)H]NA uptake by SK-N-SH cells. The stimulatory effects on NAT activity were observed by treatment of tyrphostin 25, an inhibitor of epidermal growth factor receptor tyrosine kinase, whereas orthovanadate, a protein tyrosine phosphatase inhibitor, suppressed [(3)H]NA uptake by NAT-transfected COS-7 cells. These findings suggest that genistein up-regulates the activity of neuronal monoamine transporters probably through processes involving protein tyrosine phosphorylation.
Toyohira
Yumiko
Y
Department of Pharmacology, School of Medicine, University of Occupational and Environmental Health, Yahatanishiku, Kitakyushu, Japan. toyohira@med.uoeh-u.ac.jp
Ueno
Susumu
S
Tsutsui
Masato
M
Itoh
Hideaki
H
Sakai
Norio
N
Saito
Naoaki
N
Takahashi
Kojiro
K
Yanagihara
Nobuyuki
N
D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000378:metabolism; D000077267:Fulvestrant; D019833:Genistein / Q000494:pharmacology*; D006801:Humans; D009447:Neuroblastoma; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D048789:Phytoestrogens / Q000494:pharmacology*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D013025:Glycine max / Q000737:chemistry*; D014162:Transfection; D014316:Tritium; D014638:Vanadates / Q000494:pharmacology
D004791:Enzyme Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D048789:Phytoestrogens; D011960:Receptors, Estrogen; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D014316:Tritium; C011386:nisoxetine; D000077267:Fulvestrant; D012701:Serotonin; D014638:Vanadates; D004958:Estradiol; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; D009638:Norepinephrine