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Tamoxifen metabolism in rat liver microsomes: identification of a dimeric metabolite derived from free radical intermediates by liquid chromatography/mass spectrometry
Author(s) -
Jones Russell M.,
Yuan ZhiXin,
Lim Chang Kee
Publication year - 1999
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/(sici)1097-0231(19990228)13:4<211::aid-rcm436>3.0.co;2-l
Subject(s) - chemistry , metabolite , adduct , dimer , mass spectrometry , microsome , dna adduct , tamoxifen , reactive intermediate , electrospray ionization , chromatography , stereochemistry , biochemistry , enzyme , organic chemistry , cancer , medicine , breast cancer , catalysis
Tamoxifen has been shown to be a potent liver carcinogen in rats, and generates covalent DNA adducts. On‐line high performance liquid chromatography/electrospray ionisation mass spectrometry (HPLC/ESI‐MS) has been used to further study the metabolites of tamoxifen formed by rat liver microsomes in the presence of NADPH with a view to identifying potential reactive metabolites which may be responsible for the formation of DNA adducts, and liver carcinogenesis. A metabolite has been detected with a protonated molecule at m/z 773. The mass of this compound is consistent with a dimer of hydroxylated tamoxifen ( m/z 388). Analysis of 4‐hydroxytamoxifen incubated with a rat liver microsomal preparation showed the formation of a similar metabolite with an apparent MH + ion at m/z 773, believed to be a dimer of 4‐hydroxytamoxifen formed by a free radical reaction. The retention time for this metabolite from 4‐hydroxytamoxifen is identical to that of the tamoxifen metabolite, suggesting that these two compounds are the same. The levels of the dimer were higher when 4‐hydroxytamoxifen was used as substrate and, in addition, two isomers were detected. It is proposed that tamoxifen was first converted to arene oxides which react with DNA or to 4‐hydroxytamoxifen, either directly or via 3,4‐epoxytamoxifen, which then undergoes activation via a free radical reaction to give reactive intermediates which can then react with DNA and protein, or with themselves, to give the dimers ( m/z 773). Copyright © 1999 John Wiley & Sons, Ltd.