Effect of Org OD14 (LIVIAL (R)) and its metabolites on human estrogen sulphotransferase activity in the hormone-dependent MCF-7 and T-47D, and the hormone-independent MDA-MB-231, breast cancer cell lines

The concentration of estrogen sulphates (ES) is particularly high in tumour al breast tissues in post-menopausal women. It is well known that during th e post-menopausal phase the levels of circulating estrogens are very low, s uggesting the local production of these hormones in the breast cancer tissu e itself. Breast cancer cells possess all the enzymes involved in the last steps of estradiol (E-2) formation, as well as in its transformation (e.g.: sulphotransferase). As ES are not biologically active the formation of thi s conjugate is an important transformation pathway in the control of E-2. C onsequently it was interesting to investigate the factors which reglate the sulphotransferase ase activity. In the present study, we explored the effect of Org OD14; the active substa nce in Livial (R) and of its main metabolites (Org 4094 Org 30126, Org OM-3 8) on the estrogen sulphotransferase activity in the hormone-dependent: MCF -7, T-47D, and hormone-independent: MDA-MB-231, human breast cancer cell li nes. After 24 hours incubation at 37 degrees of physiological concentration s of estrone ([H-3]-E-1; 5x10(-9) mol/l), it was observed that the sulphotr ansferase activity is detectable in MCF-7 and T-47D cells, since the concen trations of ES found were 14.90 and 17.30 pmol/mg DNA, respectively, wherea s in MDA-MB-231 cells the concentration of ES found was only 2.01 pmol/mg D NA. Sulphates are found exclusively in the culture medium which suggests th at as soon as the sulphate is biosynthesized if is secreted into the medium . Org OD14, Org 30126, and Org 4094 have a biphasic effect on sulphotransfe rase activity in the hormone-dependent cells only. At low doses (5x10(-8) m ol/l) these compounds stimulate this enzyme by 63, 101, and 51%, respective ly in the MCF-7 cells, and by 41, 102, and 80%, respectively in the T-47D c ells. No stimulatory effect was detected with Org OM-38. At high concentrat ions (5x10(-5) mol/l) Org OD14 and its three metabolites inhibit the sulpho transferase activity in MCF-7 and T-47D cells by 50-70%. In conclusion, the stimulatory effect provoked at low doses by Org OD14 and its metabolites (Org 4094 Org 30126) on the estrogen sulphotransferase inv olved in the biosynthesis of the inactive estrogen sulphates in estrogen-de pendent breast cancer cells, can contribute to the protection of breast tis sue in postmenopausal women with hormone replacement therapy.