Abstract
Despite the beneficial effects of tamoxifen in the treatment and prevention of breast cancer, long-term usage of this popular antiestrogen has been linked to an increased risk of developing endometrial cancer in women. One of the suggested pathways leading to the potential toxicity of tamoxifen involves its oxidative metabolism to 4-hydroxytamoxifen, which may be further oxidized to an electrophilic quinone methide. Alternatively, tamoxifen could undergoO-dealkylation to givecis/trans-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene, which is commonly known as metabolite E. Because of its structural similarity to 4-hydroxytamoxifen, metabolite E could also be biotransformed to a quinone methide, which has the potential to alkylate DNA and may contribute to the genotoxic effects of tamoxifen. To further probe the chemical reactivity/toxicity of such an electrophilic species, we have prepared metabolite E quinone methide chemically and enzymatically and examined its reactivity with glutathione (GSH) and DNA. Like 4-hydroxytamoxifen quinone methide, metabolite E quinone methide is quite stable; its half-life under physiological conditions is around 4 h, and its half-life in the presence of GSH is approximately 4 min. However, unlike the unstable GSH adducts of 4-hydroxytamoxifen quinone methide, metabolite E GSH adducts are stable enough to be isolated and characterized by NMR and liquid chromatography/tandem mass spectrometry (LC/MS/MS). Reaction of metabolite E quinone methide with DNA generated exclusively deoxyguanosine adducts, which were characterized by LC/MS/MS. These data suggest that metabolite E has the potential to cause cytotoxicity/genotoxicity through the formation of a quinone methide.
Footnotes
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Send reprint requests to: Judy L. Bolton, Ph.D., Department of Medicinal Chemistry and Pharmacognosy (M/C 781), College of Pharmacy, University of Illinois at Chicago, 833 South Wood St., Chicago, IL 60612-7231. E-mail: judy.bolton{at}uic.edu
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This work was supported by National Institutes of Health Grant CA79870.
- Abbreviations used are::
- Metabolite E
- cis/trans-1,2-diphenyl-1-(4-hydroxyphenyl)-but-1-ene
- ME-SG
- glutathione conjugate of metabolite E
- GSH
- glutathione
- dG
- deoxyguanosine
- LC/MS/MS
- liquid chromatography/tandem mass spectrometry
- Bis-Tris
- bis[2-hydroxyethyl]iminotris[hydroxymethyl]methane
- HPLC
- high-performance liquid chromatography
- P450
- cytochrome P450
- Received November 28, 2000.
- Accepted February 13, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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