4-hydroxytamoxifene

Marques, M. M. Beland, F. A. Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide. Carcinogenesis 1997, 18, 1949-1954. 

A relatively stable QM is produced by initial P450-catalyzed aromatic hydroxylation of the SERM tamoxifen to yield 4-hydroxytamoxifen, followed by a cytochrome P450-catalyzed direct two-electron oxidation (Scheme 10.9).7 58 This QM is extremely long lived at physiological pH and temperature (tl/2 3 h, Table 10.2),59 most likely... 

McLuckie, K. I. Routledge, M. N. Brown, K. Gaskell, M. Farmer, P. B. Roberts, G. C. Martin, E. A. DNA adducts formed from 4-hydroxytamoxifen are more mutagenic than those formed by alpha-acetoxytamoxifen in a shuttle vector target gene replicated in human Ad293 cells. Biochemistry 2002, 41, 8899-8906. 

Smith CL, Nawaz Z, O Malley BW (1997) Coactivator and corepressor regulation of the agonist/antagonist activity of the mixed antiestrogen, 4-hydroxytamoxifen. Mol Endocrinol 11 657... 

Osborne CK, Coronado E, Allred DC, Wiebe V, DeGregorio M (1991) Acquired tamoxifen resistance correlation with reduced breast tumor levels of tamoxifen and isomerization of trans-4-hydroxytamoxifen. J Natl Cancer Inst 83 1477-1482... 

Freiss G, Rochefort H, Vignon F (1990) Mechanisms of 4-hydroxytamoxifen antigrowth factor activity in breast cancer cells alterations of growth factor receptor binding sites and tyroxine kinase activity. Biochem Biophys Res Commun 919-926... 

Poulin R, Merand Y, Poirier D et al. (1989) Antiestrogenic properties of keoxifene, trans-4-hydroxytamoxifen, and ICI 164384, a new steroidal antiestrogen, in ZR-75-1 human breast cancer cells. Breast cancer Res Treat 14 65-76... 

Both unsymmetrical diols and alkenes can be prepared by applying these methods to mixtures of two different carbonyl compounds. An excess of one component can be used to achieve a high conversion of the more valuable reactant. A mixed reductive deoxygenation using TiCl4/Zn has been used to prepare 4-hydroxytamoxifen, the active antiestrogenic metabolite of tamoxifen. 

Wiseman H, Cannon M, Arnstein HRV, Halliwell B. Mechanism of inhibition of lipid peroxidation by tamoxifen and 4-hydroxytamoxifen introduced into liposomes. Similarity to cholesterol... 

Crewe HK et al (2002) Metabolism of tamoxifen by recombinant human cytochrome P450 enzymes formation of the 4-hydroxy, 4 -hydroxy and N-desmethyl metabolites and isomerization of trans-4-hydroxytamoxifen. Drug Metab Dispos 30 869-874... 

Sun D et al (2006) Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants. Breast Cancer Res 8 R50... 

Chen G et al (2002) 4-Hydroxytamoxifen sulfation metabolism. J Biochem Mol Toxicol 16 279-285... 

Nishiyama T et al (2002) Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sul-fotransferases. Biochem Pharmacol 63 1817-1830... 

Falany JL et al (2006) Sulfation of raloxifene and 4-hydroxytamoxifen by human cytosolic sulfotransferases. Drug Metab Dispos 34 361-368... 

IusufD et al (2011) P-glycoprotein (ABCB1) transports the primary active tamoxifen metabolites endoxifen and 4-hydroxytamoxifen and restricts their brain penetration. J Pharmacol ExpTher 337 710-717... 

Fig. 16. Basal ERp transcriptional activation by SRC-1 is AF-2 independent. (A) Dose-dependent activation of ERa and ERP by SRC-1 in absence of Eg. Cos-1 cells were transfected with ERETKLuc reporter along with ERa or ERP and increasing amounts of SRC-1 expression plasmids. Luciferase activities were normalized with P-Gal expression and results are expressed as factor by which response exceeds basal levels (-) and represent the mean SEM of three independent experiments. (B) Pure antiestrogen EM-652 but not the mixed antagonist 4-hydroxytamoxifen (OHT) inhibits basal ERP transcriptional activation by SRC-1. Cos-1 cells were transfected with ERETKLuc along with equivalent amounts of ERP and SRC-1 expression plasmids and incubated with increasing amounts of OHT or EM-652 prior to being assayed for luciferase activity. The maximal induction by SRC-1 alone (solid bar) was defined as 100%. Basal level in absence of SRC-1 is indicated by an open bar. (C) Basal activity of an ERP AF-2 mutant is induced by SRC-1. Cos-1 cells were transfected with ERETKLuc reporter and equivalent amounts of ERP or ERP L509A AF-2 mutant and SRC-1 (solid bars) expression plasmids. Cells were then treated with 10 nM Eg (striated bars) or left untreated (open and solid bars) for 16 hours prior to harvest. Results are plotted as factor by which induction exceeds basal levels (Tremblay et al, 1999).

Fig. 3.44 Second-derivative absorption spectra oflOpM 4-hydroxytamoxifen in DMPC liposomes at different lipid concentrations. The nominal concentration of DM PC in suspensions was 0 (curve 0), 21 (1), 28 (2), 42 (3),...

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