title: Inhibition of oestrone sulphatase activity by tibolone and its metabolites.
abstract: Tibolone is a 19-nortestosterone derivative commonly used in hormone replacement therapy. Although tibolone and its 3alpha/beta-hydroxy metabolites exert oestrogenic effects on bone and the vasomotor system, they do not appear to stimulate breast tissue proliferation. It has been proposed that the lack of an oestrogenic effect on breast tissues may result from the inhibition of oestrone sulphatase (E1-STS) in this tissue by tibolone and its metabolites. In this study we have examined the ability of tibolone and its metabolites to inhibit E1-STS activity in intact breast cancer cells, its effect on E1-STS activity in placental microsomes and also the expression of E1-STS mRNA in more detail. As the major proportion of hydroxytibolone metabolites circulate in a sulphated form, the ability of the 3alpha-sulphate and 3alpha,17beta-disulphate metabolites to inhibit E1-STS activity was also examined. In MCF-7 cells, tibolone and its 3beta-hydroxylated metabolite were relatively potent inhibitors; they inhibited activity by 48 % and 46 %, respectively. In these cells, the 3alpha-sulphate and 3alpha,17beta-disulphate metabolites of tibolone inhibited E1-STS activity by 95% and 79% at 10 microM, respectively. No effects of tibolone or its metabolites on the expression of E1-STS mRNA in MCF-7 cells were detected. Using T-47D breast cancer cells, evidence was obtained that the sulphated metabolites of tibolone could continue to inhibit E1-STS activity after removal of the drugs and extensive washing of cells. In placental microsomes, however, the 3beta-hydroxy metabolite was the most potent inhibitor with an IC50 of 20.5 microM; the sulphated metabolites were less potent. Neither tibolone nor its metabolites had any inhibitory effect on the conversion of oestrone to oestradiol in breast cancer cells. Results from this study have confirmed that tibolone and its metabolites can inhibit E1-STS activity. This may explain the absence of breast stimulation as observed in clinical studies.
authors.affiliation: Dept. of Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St. Mary's Hospital, London, W2 1NY, UK. a.purohit@ic.ac.uk
authors.forename: A
authors.initials: A
authors.lastname: Purohit
authors.forename: B
authors.initials: B
authors.lastname: Malini
authors.forename: C
authors.initials: C
authors.lastname: Hooymans
authors.forename: S P
authors.initials: SP
authors.lastname: Newman
mesh_terms: D001943:Breast Neoplasms / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004970:Estrone / Q000378:metabolism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000201:enzymology; D009652:Norpregnenes / Q000494:pharmacology*; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013429:Sulfatases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D020847:Estrogen Receptor Modulators; D009652:Norpregnenes; D012333:RNA, Messenger; D020845:Selective Estrogen Receptor Modulators; D004970:Estrone; D004958:Estradiol; D013429:Sulfatases; C020121:estrone sulfatase; C027385:tibolone