Synthesis and investigation of alpha-hydroxy-N,N-didesmethyltamoxifen as a proximate carcinogen in the metabolic activation of tamoxifen.

doi:10.1021/TX030010O

Paper

Synthesis and investigation of alpha-hydroxy-N,N-didesmethyltamoxifen as a proximate carcinogen in the metabolic activation of tamoxifen.

Published Aug 9, 2003 · G. Gamboa da Costa, M. M. Marques, J. Freeman

Chemical research in toxicology

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7

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Abstract

Tamoxifen is an adjuvant chemotherapeutic agent for the treatment of breast cancer and a chemoprotective agent for breast cancer prevention. Despite being beneficial in regard to breast cancer, tamoxifen is known to increase the risk of endometrial cancer and thromboembolic events in women; in addition, it induces liver tumors in rats and endometrial tumors in rats and mice. Tamoxifen and its metabolite, N-desmethyltamoxifen, are metabolically activated to DNA binding electrophiles through alpha-hydroxylation, followed by O-esterification, primarily via sulfation. In the present study, we have investigated whether a second desmethylated metabolite of tamoxifen, N,N-didesmethyltamoxifen, is also involved in the metabolic activation of this antiestrogen to a genotoxic species. Alpha-hydroxy-N,N-didesmethyltamoxifen was synthesized, further activated by sulfation, and then reacted with DNA. After enzymatic hydrolysis to deoxynucleosides, HPLC analysis indicated the formation of one major DNA adduct, which was characterized as (E)-alpha-(deoxyguanosin-N(2)-yl)-N,N-didesmethyltamoxifen. Using (32)P-postlabeling, in combination with HPLC, the same adduct was detected in liver DNA from rats treated intraperitoneally with alpha-hydroxy-N,N-didesmethyltamoxifen. In contrast, only a low extent of adduct formation could be found in rats administered N,N-didesmethyltamoxifen. These data indicate that although alpha-hydroxy-N,N-didesmethyltamoxifen can be converted to a genotoxin in rat liver, this pathway is a minor one in the metabolic activation of tamoxifen.

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Animal Study

Study Snapshot

Alpha-hydroxy-N,N-didesmethyltamoxifen can be converted to a genotoxin in rat liver, but this pathway is a minor one in the metabolic activation of tamoxifen.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Synthesis and investigation of alpha-hydroxy-N,N-didesmethyltamoxifen as a proximate carcinogen in the metabolic activation of tamoxifen.

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References

Citations

Structure determination, synthesis, and biological evaluation of a metabolite of the selective α1D adrenoceptor antagonist TAK-259

The metabolite 2a of TAK-259, identified from monkey urine samples, shows no affinity for any known 1 adrenoceptor subtype.

Is tamoxifen a genotoxic carcinogen in women?

Tamoxifen may be a genotoxic carcinogen in women, with its potential role in endometrial cancer based on its ability to induce rat liver tumors.

Effect of N,N-didesmethyltamoxifen upon DNA adduct formation by tamoxifen and α-hydroxytamoxifen

N,N-didesmethyltamoxifen does not impair the metabolism of tamoxifen to a reactive electrophile in rats.

Rapid on-line profiling of estrogen receptor binding metabolites of tamoxifen.

High-resolution screening (HRS) methodology effectively profiles estrogen receptor binding metabolites of tamoxifen, offering potential for drug discovery and development.

Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods.

The study demonstrated remarkably good agreement for TAM-DNA adduct measurements among diverse methods, indicating a high degree of reproducibility in rat liver dosimetry.