Activation of tamoxifen and its metabolite α-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes
| Autor: | Ian R. Hardcastle, David H. Phillips, G.K. Poon, Kathleen J. Cole, Paul L. Carmichael, Alastair J. Strain, Adrian Keogh, Alan Hewer |
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| Rok vydání: | 1996 |
| Předmět: |
Adult
Male Cancer Research Adolescent Metabolite Biology DNA Adducts Mice chemistry.chemical_compound Species Specificity medicine Animals Humans Nucleotide Child skin and connective tissue diseases Biotransformation chemistry.chemical_classification Nuclease Estrogen Antagonists General Medicine Metabolism Middle Aged Rats Inbred F344 In vitro Rats Tamoxifen medicine.anatomical_structure Liver chemistry Biochemistry Cell culture Hepatocyte biology.protein Female hormones hormone substitutes and hormone antagonists DNA |
| Zdroj: | Carcinogenesis. 17:89-94 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/17.1.89 |
| Popis: | The metabolic activation of tamoxifen and its metabolite alpha-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 microM tamoxifen (mean levels 18.2 and 89.8 adducts/10(8) nucleotides respectively). Similar levels of adducts were formed by mouse hepatocytes (15.0 +/- 1.8 adducts/10(8) nucleotides, 10 microM tamoxifen). However DNA adducts were not detected in tamoxifen-treated human hepatocytes with a detection limit for the assay of 4 adducts/10(10) nucleotides. Treatment of rat cells with alpha-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 alpha-hydroxytamoxifen at the 1 microM concentration (173.9 +/- 4.1 adducts/10(8) nucleotides). Treatment of human cells with alpha-hydroxytamoxifen resulted in DNA adduct formation at levels (1.94 +/- 0.89 and 18.9 +/- 17.9 adducts/10(8) nucleotides at 1 and 10 microM respectively) approximately 300-fold lower than those in rat hepatocytes. The presence of alpha-hydroxytamoxifen in the culture medium from experiments where cells were incubated with tamoxifen was monitored by mass spectrometry. Concentrations were found to be approximately 50-fold lower in the medium from human hepatocytes than from rat and mouse hepatocytes. |
| Databáze: | OpenAIRE |
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