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Inhibition of oestrone sulphatase activity by tibolone and its metabolites
A Purohit1, B Malini, C Hooymans
1Dept. of Endocrinology and Metabolic Medicine, Imperial College School of Medicine, St. Mary's Hospital, London, W2 1NY, UK. a.purohit@ic.ac.uk
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.
Insights
Tibolone and its metabolites inhibit oestrone sulphatase (E1-STS) activity, potentially explaining why tibolone does not stimulate breast tissue during hormone replacement therapy. This inhibition was observed in breast cancer cells and placental microsomes.
Area of Science:
- Endocrinology
- Pharmacology
- Molecular Biology
Background:
- Tibolone is a hormone replacement therapy drug with estrogenic effects on bone and vasculature.
- Unlike other estrogens, tibolone does not appear to stimulate breast tissue proliferation.
- This lack of breast stimulation may be linked to the inhibition of oestrone sulphatase (E1-STS) by tibolone and its metabolites.
Purpose of the Study:
- To investigate the ability of tibolone and its metabolites to inhibit E1-STS activity.
- To examine the effect of tibolone and its metabolites on E1-STS mRNA expression.
- To assess the inhibitory potential of tibolone's sulphated metabolites on E1-STS activity.
Main Methods:
- Assessing E1-STS activity inhibition in intact MCF-7 and T-47D breast cancer cells.
- Evaluating E1-STS activity in placental microsomes.
- Measuring E1-STS mRNA expression in MCF-7 cells.
- Testing tibolone, its hydroxy metabolites, and sulphated metabolites (3alpha-sulphate, 3alpha,17beta-disulphate).
Main Results:
- Tibolone and its 3beta-hydroxy metabolite significantly inhibited E1-STS activity in MCF-7 cells (48% and 46%).
- Sulphated metabolites (3alpha-sulphate, 3alpha,17beta-disulphate) were potent inhibitors in MCF-7 cells (95% and 79% at 10 microM).
- Sulphated metabolites showed sustained inhibition in T-47D cells even after drug removal.
- The 3beta-hydroxy metabolite was the most potent inhibitor in placental microsomes (IC50 = 20.5 microM).
- No effects on E1-STS mRNA expression or conversion of oestrone to oestradiol were detected.
Conclusions:
- Tibolone and its metabolites effectively inhibit E1-STS activity.
- This inhibition provides a potential mechanism for the lack of breast tissue stimulation observed with tibolone therapy.
- The sulphated metabolites play a significant role in E1-STS inhibition, particularly in breast cancer cells.
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