Journal Article

Activation of tamoxifen and its metabolite α-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes

David H. Phillips, Paul L. Carmichael, Alan Hewer, Kathleen J. Cole, Ian R. Hardcastle, Grace K. Poon, Adrian Keogh and Alastair J. Strain

in Carcinogenesis

Volume 17, issue 1, pages 89-94
Published in print January 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.1.89
Activation of tamoxifen and its metabolite α-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes

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The metabolic activation of tamoxifen and its metabolite α-hydroxytamoxifen in primary cultures of rat, mouse and human hepatocytes has been compared. The extent of formation of DNA adducts in these cells was measured by 32P-postlabelling, using either nuclease P1 digestion or sorbent extraction of DNA digests to enhance the sensitivity of the assay. DNA adducts were readily detected in rat hepatocytes treated with 1 or 10 μM tamoxifen (mean levels 18.2 and 89.8 adducts/108 nucleotides respectively). Similar levels of adducts were formed by mouse hepatocytes (15.0 ± 1.8 adducts/108 nucleotides, 10 μM tamoxifen). However DNA adducts were not detected in tamoxifen-treated human hepatocytes with a detection limit for the assay of 4 adducts/1010 nucleotides. Treatment of rat cells with α-hydroxytamoxifen resulted in 15- to 63-fold higher levels of adducts than with comparable concentrations of tamoxifen. A similar level of adducts was also seen in mouse hepatocytes treated with α-hydroxytamoxifen at the 1 μM concentration (173.9 ± 4.1 adducts/108 nucleotides). Treatment of human cells with α-hydroxytamoxifen resulted in DNA adduct formation at levels (1.94 ± 0.89 and 18.9 ± 17.9 adducts/108 nucleotides at 1 and 10 μM respectively) ∼300-fold lower than those in rat hepatocytes. The presence of α-hydroxytamoxifen in the culture medium from experiments where cells were incubated with tamoxifen was monitored by mass spectrometry. Concentrations were found to be ∼50-fold lower in the medium from human hepatocytes than from rat and mouse hepatocytes.

Journal Article.  0 words. 

Subjects: Clinical Cytogenetics and Molecular Genetics

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