Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding.
Animal and human tissues contain a microsomal protein that binds nonsteroidal antiestrogens with high affinity and specificity. The functions of these binding sites and the identity of their natural ligands are unknown. Following a report that certain sterols inhibit [3H]tamoxifen binding to this si...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
1989-02-01
|
| Series: | Journal of Lipid Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S002222752038384X |
| _version_ | 1818383719645315072 |
|---|---|
| author | P L Hwang A Matin |
| author_facet | P L Hwang A Matin |
| author_sort | P L Hwang |
| collection | DOAJ |
| description | Animal and human tissues contain a microsomal protein that binds nonsteroidal antiestrogens with high affinity and specificity. The functions of these binding sites and the identity of their natural ligands are unknown. Following a report that certain sterols inhibit [3H]tamoxifen binding to this site, we attempted to define the structural requirements for maximal inhibition of [3H]tamoxifen binding to rat liver antiestrogen-binding sites. Our studies identified 5 alpha-cholestan-3 beta-ol-7-one (7-ketocholestanol) as the most potent sterol, having an inhibitory activity that was 12% that of unlabeled tamoxifen and an equilibrium dissociation constant of 6.3 nM. Structural features that appeared important for the inhibitory activity of this sterol include the presence of i) a hydrocarbon side chain at C17; ii) an oxygen function at C7; iii) a hydroxyl group at C3; and iv) the absence of a double-bond between C5 and C6. Saturation analysis and kinetic studies of [3H]tamoxifen binding in the presence of varying concentrations of 7-ketocholestanol clearly indicated that this sterol competed directly with tamoxifen for the antiestrogen-binding site. Unlike tamoxifen, this sterol did not bind to the estrogen receptor. These features make 7-ketocholestanol a potentially valuable tool for studying the properties and functions of this site. |
| first_indexed | 2024-12-14T03:10:50Z |
| format | Article |
| id | doaj.art-537aef7432fa43a28077e17dba8dbf26 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T03:10:50Z |
| publishDate | 1989-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-537aef7432fa43a28077e17dba8dbf262022-12-21T23:19:16ZengElsevierJournal of Lipid Research0022-22751989-02-01302239245Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding.P L Hwang0A Matin1Department of Physiology, National University of Singapore.Department of Physiology, National University of Singapore.Animal and human tissues contain a microsomal protein that binds nonsteroidal antiestrogens with high affinity and specificity. The functions of these binding sites and the identity of their natural ligands are unknown. Following a report that certain sterols inhibit [3H]tamoxifen binding to this site, we attempted to define the structural requirements for maximal inhibition of [3H]tamoxifen binding to rat liver antiestrogen-binding sites. Our studies identified 5 alpha-cholestan-3 beta-ol-7-one (7-ketocholestanol) as the most potent sterol, having an inhibitory activity that was 12% that of unlabeled tamoxifen and an equilibrium dissociation constant of 6.3 nM. Structural features that appeared important for the inhibitory activity of this sterol include the presence of i) a hydrocarbon side chain at C17; ii) an oxygen function at C7; iii) a hydroxyl group at C3; and iv) the absence of a double-bond between C5 and C6. Saturation analysis and kinetic studies of [3H]tamoxifen binding in the presence of varying concentrations of 7-ketocholestanol clearly indicated that this sterol competed directly with tamoxifen for the antiestrogen-binding site. Unlike tamoxifen, this sterol did not bind to the estrogen receptor. These features make 7-ketocholestanol a potentially valuable tool for studying the properties and functions of this site.http://www.sciencedirect.com/science/article/pii/S002222752038384X |
| spellingShingle | P L Hwang A Matin Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding. Journal of Lipid Research |
| title | Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding. |
| title_full | Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding. |
| title_fullStr | Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding. |
| title_full_unstemmed | Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding. |
| title_short | Interactions of sterols with antiestrogen-binding sites: structural requirements for high-affinity binding. |
| title_sort | interactions of sterols with antiestrogen binding sites structural requirements for high affinity binding |
| url | http://www.sciencedirect.com/science/article/pii/S002222752038384X |
| work_keys_str_mv | AT plhwang interactionsofsterolswithantiestrogenbindingsitesstructuralrequirementsforhighaffinitybinding AT amatin interactionsofsterolswithantiestrogenbindingsitesstructuralrequirementsforhighaffinitybinding |