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Minor products of reaction of DNA with alpha-acetoxytamoxifen

Lookup NU author(s): Dr Ian HardcastleORCiD

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Abstract

The drug tamoxifen shows evidence of genotoxicity and induces liver tumours in rats. Covalent DNA adducts have been detected in the liver of rats treated with tamoxifen and these arise, at least in part, from its metabolite alpha-hydroxytamoxifen. This probably undergoes conjugation in the liver tissue to give an ester, which alkylates DNA. We have prepared alpha-acetoxytamoxifen as a model for this reactive intermediate and studied its reaction with DNA in vitro. The products of this reaction were chromatographically identical to DNA adducts found in the liver of rats treated with tamoxifen. We have isolated three of these products as the nucleosides TG1, TG2 and TA1 and identified them by ultraviolet, mass and proton magnetic resonance spectroscopy. TG1 and TG2 were tamoxifen-deoxyguanosine adducts in which the alpha-position of tamoxifen was linked to the amino group of guanine; TG1, (E)-4-[4-[2-(dimethylamino)ethoxy]phenyl]-3,4-diphenyl-2- (9beta-de oxyribofuranosyl-6-oxopurin-2-ylamino)-3-butene; TG2, (Z) isomer of TG1. In TG2, the tamoxifen group had undergone trans-cis isomerization. The minor product TA1 was a tamoxifen-deoxyadenosine adduct, where linkage was through the amino group of adenine: (E)-4-[4- [2-(dimethylamino) ethoxy]phenyl]-3,4-diphenyl-2-(9beta- deoxyribofuranosylpurin -6-ylamino)-3-butene. These three adducts accounted for >90% of the reaction products (approximately 67% TG1, 18% TG2 and 7% TA1); trace products included other stereoisomers of these and dinucleotide adducts which resisted enzymatic digestion.


Publication metadata

Author(s): Osborne MR, Hardcastle IR, Phillips DH

Publication type: Article

Publication status: Published

Journal: Carcinogenesis

Year: 1997

Volume: 18

Issue: 3

Pages: 539-543

ISSN (print): 0143-3334

ISSN (electronic): 1460-2180

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/carcin/18.3.539

DOI: 10.1093/carcin/18.3.539


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