Tibolone: a compound with tissue specific inhibitory effects on sulfatase.
The aim was to test whether sulfatase activity is differently regulated by tibolone in human bone, endometrium and breast cells since selective inhibition of sulfatases in various tissues may contribute to the tissue-specificity of tibolone. Tibolone, its 3 alpha- and 3 beta-hydroxy metabolites and their 3-sulfated forms, and its Delta(4)-isomer strongly (70-90%) inhibited the sulfatase activity in human breast cell lines (two T-47D clones) and intermediately (8-43%) in human endometrial cells (HEC-1A). In contrast, they did not inhibit sulfatase in two human osteoblast-like cell lines (MG 63, HOS TE-85). The specific sulfatase inhibitor, EMATE, showed inhibition in all cell lines. Just as estrone sulfate, 3 alpha-sulfated tibolone was also converted by sulfatase to the unconjugated 3 alpha-hydroxy-tibolone intracellularly in all cell lines. The tissue specific inhibition pattern of sulfatase activity by tibolone and its metabolites suggest that tibolone could be protective against development of mammary carcinomas, whereas it retains favorable estrogenic effects on bone.
de Gooyer
M E
ME
Department of Pharmacology, Research and Development Laboratories, NV Organon, Room No RE1417, PO Box 20, 5340 BH Oss, The Netherlands. marcel.degooyer@organon.com
Kleyn
G T
GT
Smits
K C
KC
Ederveen
A G
AG
Verheul
H A
HA
Kloosterboer
H J
HJ
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry / Q000494:pharmacology; D001940:Breast / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D002460:Cell Line; D004717:Endometrium / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004970:Estrone / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D006801:Humans; D009652:Norpregnenes / Q000737:chemistry / Q000494:pharmacology*; D009928:Organ Specificity; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology; D013429:Sulfatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D004791:Enzyme Inhibitors; D009652:Norpregnenes; C088768:estrone-3-O-sulfamate; D004970:Estrone; D013429:Sulfatases; C027385:tibolone