Effect of sulphation on the oestrogen agonist activity of the phytoestrogens genistein and daidzein in MCF-7 human breast cancer cells.
The phytoestrogens genistein, daidzein and the daidzein metabolite equol have been shown previously to possess oestrogen agonist activity. However, following consumption of soya diets, they are found in the body not only as aglycones but also as metabolites conjugated at their 4'- and 7-hydroxyl groups with sulphate. This paper describes the effects of monosulphation on the oestrogen agonist properties of these three phytoestrogens in MCF-7 human breast cancer cells in terms of their relative ability to compete with [(3)H]oestradiol for binding to oestrogen receptor (ER), to induce a stably transfected oestrogen-responsive reporter gene (ERE-CAT) and to stimulate cell growth. In no case did sulphation abolish activity. The 4'-sulphation of genistein reduced oestrogen agonist activity to a small extent in whole-cell assays but increased the relative binding affinity to ER. The 7-sulphation of genistein, and also of equol, reduced oestrogen agonist activity substantially in all assays. By contrast, the position of monosulphation of daidzein acted in an opposing manner on oestrogen agonist activity. Sulphation at the 4'-position of daidzein resulted in a modest reduction in oestrogen agonist activity but sulphation of daidzein at the 7-position resulted in an increase in oestrogen agonist activity. Molecular modelling and docking studies suggested that the inverse effects of sulphation could be explained by the binding of daidzein into the ligand-binding domain of the ER in the opposite orientation compared with genistein and equol. This is the first report of sulphation enhancing activity of an isoflavone and inverse effects of sulphation between individual phytoestrogens.
Pugazhendhi
D
D
School of Biological Sciences, The University of Reading, Reading RG6 6AJ, UK.
Watson
K A
KA
Mills
S
S
Botting
N
N
Pope
G S
GS
Darbre
P D
PD
D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060754:Equol; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000378:metabolism / Q000494:pharmacology*; D048789:Phytoestrogens / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000378:metabolism
C007610:4',7-dihydroxy-3,4-dihydroisoflavone; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D007529:Isoflavones; D048789:Phytoestrogens; D011994:Recombinant Proteins; D013431:Sulfates; D004958:Estradiol; D060754:Equol; C004742:daidzein; D019833:Genistein