Tamoxifen: Difference between revisions
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[[Image:800px-Tamoxifen.svg.png|right|thumb|200px|chemical structure of tamoxifen]] | |||
Tamoxifen is a common breast cancer drug (Nolvadex, Istubal, and Valodex). In molecular biology tamoxifen activates enzymes inactivated by fusion to a modified estrogen receptor (ER). This is employed, for example, in the timed activation of Cre recombinase in CreER mice. | Tamoxifen is a common breast cancer drug (Nolvadex, Istubal, and Valodex). In molecular biology tamoxifen activates enzymes inactivated by fusion to a modified estrogen receptor (ER). This is employed, for example, in the timed activation of Cre recombinase in CreER mice. | ||
== Chemical data for tamoxifen == | |||
{| {{table}} | |||
|- | |||
! tamoxifen forumlation | |||
! molecular weight | |||
! pKa' | |||
! equilibrium solubility in water at 37°C | |||
! see also | |||
|- | |||
| tamoxifen free base | |||
| 371.51 g/mol | |||
| 8.85 | |||
| <0.01% at 20ºC (insoluble in water) | |||
| [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=T5648&N5=SEARCH_CONCAT_PNO Sigma] [http://www.rxlist.com/cgi/generic/tamox.htm RX] | |||
|- | |||
| 4-hydroxytamoxifen (OHT) | |||
| 387.51 g/mol | |||
| ? | |||
| ? | |||
| [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=H7904&N5=SEARCH_CONCAT_PNO Sigma] [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=449459 PubChem] | |||
|- | |||
| tamoxifen citrate | |||
| 563.62 g/mol | |||
| 8.85 | |||
| 0.5 mg/mL | |||
| [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=T9262&N5=SEARCH_CONCAT_PNO Sigma] [http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=2733525 PubChem] | |||
|} | |||
== Molecular mechanism of action == | == Molecular mechanism of action == | ||
[[Image:Tamoxifen(OH).gif|right|thumb|150px|chemical structure of tamoxifen and 4-hydroxy-tamoxifen]] | |||
Tamoxifen competitively binds to GPCR type and intracellular type estrogen receptors (ER). Binding to the intracellular ER on tumours and other tissue targets produces a nuclear complex that decreases DNA synthesis and inhibits estrogen effects ([http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1246 diagram of estrogen & tamoxifen mechanism]). It thus acts as an estrogen antagonists which inhibits the growth of some tumours dependent on estrogen stimulation. | Tamoxifen competitively binds to GPCR type and intracellular type estrogen receptors (ER). Binding to the intracellular ER on tumours and other tissue targets produces a nuclear complex that decreases DNA synthesis and inhibits estrogen effects ([http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=endocrin&part=A972&rendertype=box&id=A1246 diagram of estrogen & tamoxifen mechanism]). It thus acts as an estrogen antagonists which inhibits the growth of some tumours dependent on estrogen stimulation. | ||
Tamoxifen itself is a prodrug, having relatively little affinity for the estrogen receptor. It is metabolised in the liver by the cytochrome P450 to active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen. | Tamoxifen itself is a prodrug, having relatively little affinity for the estrogen receptor. It is metabolised in the liver by the cytochrome P450 to active metabolites such as 4-hydroxytamoxifen (see figure) and N-desmethyl-4-hydroxytamoxifen. | ||
== Activation of ER-fusion proteins == | == Activation of ER-fusion proteins == | ||
| Line 11: | Line 44: | ||
Proteins fused to an estrogen receptor (ER) domain are sequestered by heat shock proteins (hsp). Administration of tamoxifen to an often modified ER with increased affinity for tamoxifen over the natural substrate estrogen, releases the fusion protein. In the case of an enzyme-ER fusion, like CreER, it can than act on its substrate. | Proteins fused to an estrogen receptor (ER) domain are sequestered by heat shock proteins (hsp). Administration of tamoxifen to an often modified ER with increased affinity for tamoxifen over the natural substrate estrogen, releases the fusion protein. In the case of an enzyme-ER fusion, like CreER, it can than act on its substrate. | ||
== Stability == | == Stability & storage == | ||
Chemical stability (tamoxifen citrate [http://www.sigmaaldrich.com/etc/medialib/docs/Sigma/productinformationsheet2/t9262pis.Par.0001.File.tmp/t9262pis.pdf]) | |||
* stable for at least 2 years when stored desiccated at 2-8°C in the dark | |||
* hygroscopic at high relative humidities | |||
* sensitive to UV light | |||
Metabolism | |||
* distribution half-life: 7-14 hours | * distribution half-life: 7-14 hours | ||
* elimination half-life: 5-7 days (range: 3-21 days) | * elimination half-life: 5-7 days (range: 3-21 days) | ||
* elimination half-life of N-desmethyltamoxifen (major metabolite): 9-14 days | * elimination half-life of N-desmethyltamoxifen (major metabolite): 9-14 days | ||
(estimates based on limited data probably from humans [http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~zDYrnM:1:bhl]) | (estimates based on limited data probably from humans [http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~zDYrnM:1:bhl]) | ||
== Protocols using tamoxifen == | |||
* [[Tamoxifen administration to mice]] | |||
== See also == | == See also == | ||
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* [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=T5648|SIGMA&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC Tamoxifen] and [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=T9262|SIGMA&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC Tamoxifen citrate datasheets] on the Sigma website | * [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=T5648|SIGMA&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC Tamoxifen] and [http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=T9262|SIGMA&N5=SEARCH_CONCAT_PNO|BRAND_KEY&F=SPEC Tamoxifen citrate datasheets] on the Sigma website | ||
* [http://en.wikipedia.org/wiki/Estrogen_receptor Estrogen receptor in the Wikipedia] | * [http://en.wikipedia.org/wiki/Estrogen_receptor Estrogen receptor in the Wikipedia] | ||
[[Category:Material]] | |||
Latest revision as of 06:00, 7 April 2009
Tamoxifen is a common breast cancer drug (Nolvadex, Istubal, and Valodex). In molecular biology tamoxifen activates enzymes inactivated by fusion to a modified estrogen receptor (ER). This is employed, for example, in the timed activation of Cre recombinase in CreER mice.
Chemical data for tamoxifen
| tamoxifen forumlation | molecular weight | pKa' | equilibrium solubility in water at 37°C | see also |
|---|---|---|---|---|
| tamoxifen free base | 371.51 g/mol | 8.85 | <0.01% at 20ºC (insoluble in water) | Sigma RX |
| 4-hydroxytamoxifen (OHT) | 387.51 g/mol | ? | ? | Sigma PubChem |
| tamoxifen citrate | 563.62 g/mol | 8.85 | 0.5 mg/mL | Sigma PubChem |
Molecular mechanism of action
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Tamoxifen competitively binds to GPCR type and intracellular type estrogen receptors (ER). Binding to the intracellular ER on tumours and other tissue targets produces a nuclear complex that decreases DNA synthesis and inhibits estrogen effects (diagram of estrogen & tamoxifen mechanism). It thus acts as an estrogen antagonists which inhibits the growth of some tumours dependent on estrogen stimulation.
Tamoxifen itself is a prodrug, having relatively little affinity for the estrogen receptor. It is metabolised in the liver by the cytochrome P450 to active metabolites such as 4-hydroxytamoxifen (see figure) and N-desmethyl-4-hydroxytamoxifen.
Activation of ER-fusion proteins
Proteins fused to an estrogen receptor (ER) domain are sequestered by heat shock proteins (hsp). Administration of tamoxifen to an often modified ER with increased affinity for tamoxifen over the natural substrate estrogen, releases the fusion protein. In the case of an enzyme-ER fusion, like CreER, it can than act on its substrate.
Stability & storage
Chemical stability (tamoxifen citrate [1])
- stable for at least 2 years when stored desiccated at 2-8°C in the dark
- hygroscopic at high relative humidities
- sensitive to UV light
Metabolism
- distribution half-life: 7-14 hours
- elimination half-life: 5-7 days (range: 3-21 days)
- elimination half-life of N-desmethyltamoxifen (major metabolite): 9-14 days
(estimates based on limited data probably from humans [2])
