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Tamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1,2-diphenylbut-1-ene], a nonsteroidal antiestrogen, induces liver tumors in rats by a genotoxic mechanism. The mechanism of DNA adduct formation is believed to proceed via the formation of a reactive carbocation at the α-position from the α-hydroxylated metabolite. Molecular mechanics calculations [Kuramochi, H. (1996) J. Med. Chem. 39, 2877−2886] have predicted that 4-substitution will affect the stability of the carbocation and thus will alter its reactivity toward DNA. We have synthesized the putative α-hydroxylated metabolites of 4-hydroxytamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-1-(4-hydroxyphenyl)-3-hydroxy-2-phenylbut-1-ene] and idoxifene [(Z)-1-(4-iodophenyl)-3-hydroxy-2-phenyl-1-(4-(2-(N-pyrrolidino)ethoxy)phenyl)but-1-ene] and compared their reactivities with DNA with that of α-hydroxytamoxifen [(E)-1-(4-(2-(N,N-dimethylamino)ethoxy)phenyl)-3-hydroxy-1,2-diphenylbut-1-ene]. As predicted, the bis-hydroxylated compound reacted with DNA in aqueous solution at pH 5 to give 12-fold greater levels of adducts than α-hydroxytamoxifen, whereas α-hydroxyidoxifene gave one-half the number of adducts. The results demonstrate that idoxifene presents a significantly lower genotoxic hazard than tamoxifen for the treatment and prophylaxis of breast cancer.
Author(s): Hardcastle IR, Horton MN, Osborne MR, Hewer A, Jarman M, Phillips DH
Publication type: Article
Publication status: Published
Journal: Chemical Research in Toxicology
Year: 1998
Volume: 11
Issue: 4
Pages: 369-374
Print publication date: 12/03/1998
ISSN (print): 0893-228X
ISSN (electronic): 1520-5010
Publisher: American Chemical Society
URL: http://dx.doi.org/10.1021/tx970198+
DOI: 10.1021/tx970198+
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