Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Tibolone is used for hormone replacement therapy and acts in a tissue-specific manner being oestrogenic on CNS and bone but not on breast tissues or endometrium. The ability of tibolone and its metabolites to inhibit steroid sulphatase (STS) activity has a crucial role in regulating its tissue-specific effects. In this study, we have examined the ability of tibolone and its non-sulphated and sulphated metabolites to inhibit STS activity in different enzyme preparations and in intact cells. For this, we have used an 'extracellular' method, which measures the amount of product released into culture medium, and an 'intracellular' method, which assesses the extent of product formation within cells. In addition, the nature by which tibolone and some of its metabolites inhibit STS activity was investigated using intact cells and an enzyme kinetic method. In MCF-7 and T47D breast cancer cells and JEG-3 choriocarcinoma cells, which have high STS activity, tibolone and its metabolites were relatively potent inhibitors of STS activity (33-57% inhibition at 10 microM) using the extracellular assay method. In HOS-TE-85 osteoblast-like cells, tibolone and its Delta-4 metabolite were relatively inactive whereas the 3alpha/3beta-hydroxy metabolites and their sulphated conjugates inhibited activity by 39-55%. When STS activity was assessed in HOS-TE-85 cells using an 'intracellular' method tibolone and its 3beta-hydroxy metabolite were inactive. Pre-treatment of breast cancer cells and JEG-3 cells, and removal of drugs prior to assaying for STS activity, revealed that in these cells tibolone and its metabolites were acting mainly as reversible inhibitors. This finding was confirmed in an enzyme kinetic study to measure concentration-dependent STS inhibition. In HOS-TE-85 cells, pre-treatment of cells and removal of compounds before assaying for remaining STS activity indicated that some tibolone metabolites appeared to stimulate STS activity. Possible mechanisms by which this might occur are discussed but, if confirmed, this could contribute to the positive oestrogenic effects that tibolone has on bone.

Original publication

DOI

10.1016/j.jsbmb.2005.01.021

Type

Journal article

Journal

J Steroid Biochem Mol Biol

Publication Date

02/2005

Volume

94

Pages

229 - 237

Keywords

Enzyme Inhibitors, Estrogen Replacement Therapy, Estrone, Female, Humans, Kinetics, Microsomes, Norpregnenes, Placenta, Pregnancy, Steryl-Sulfatase