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

Schild, Laura J.; Phillips, David H.; Osborne, Martin R.; Hewer, Alan; Beland, Frederick A.; Churchwell, Mona I.; Brown, Karen; Gaskell, Margaret; Wright, Elizabeth A.; Poirier, Miriam C.

doi:10.1093/mutage/gei015

Cited by 14 publications

(10 citation statements)

References 36 publications

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“…Two data sets falling within the endogenous background level, while one data set was above the endogenous background and the fourth data set was partially above the background level. When the TAM adducts calculated at the BMD 10 were based on data generated using different analytical methods (35), the values obtained did not vary by more than a factor of 2 (not shown), which is much less than the differences observed between different animal studies.…”

Section: Tumour Incidence Data and Bmd 10 Calculationmentioning

confidence: 82%

“…This results in the following decreasing order for DNA adduct formation at a dose of 1 mg/kg bw/day: AfB1 (40480 adducts/10 8 nt) . DNA adduct formation and tumour incidence respectively) (34,35) .SA (4 adducts/10 8 nt) . ME (1 adducts/10 8 nt).…”

Section: Data On In Vivo Dna Adduct Formationmentioning

confidence: 99%

“…Fig.2. Illustration of the dose-response curves for DNA adduct formation with the range of accepted BMD 10 values (dashed lines) derived from in vivo data on liver tumour incidence, representing the data for male rats treated with: (A) 2-AAF, (B) AfB1, (C) MeIQx, (E) SA, (F) ME and female rats treated with (D) TAM(34,35).…”

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confidence: 99%

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Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays

et al. 2011

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This study aimed at quantitatively comparing the occurrence/formation of DNA adducts with the carcinogenicity induced by a selection of DNA-reactive genotoxic carcinogens. Contrary to previous efforts, we used a very uniform set of data, limited to in vivo rat liver studies in order to investigate whether a correlation can be obtained, using a benchmark dose (BMD) approach. Dose-response data on both carcinogenicity and in vivo DNA adduct formation were available for six compounds, i.e. 2-acetylaminofluorene, aflatoxin B1, methyleugenol, safrole, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and tamoxifen. BMD(10) values for liver carcinogenicity were calculated using the US Environmental Protection Agency BMD software. DNA adduct levels at this dose were extrapolated assuming linearity of the DNA adduct dose response. In addition, the levels of DNA adducts at the BMD(10) were compared to available data on endogenous background DNA damage in the target organ. Although for an individual carcinogen the tumour response increases when adduct levels increase, our results demonstrate that when comparing different carcinogens, no quantitative correlation exists between the level of DNA adduct formation and carcinogenicity. These data confirm that the quantity of DNA adducts formed by a DNA-reactive compound is not a carcinogenicity predictor but that other factors such as type of adduct and mutagenic potential may be equally relevant. Moreover, comparison to background DNA damage supports the notion that the mere occurrence of DNA adducts above or below the level of endogenous DNA damage is neither correlated to development of cancer. These data strongly emphasise the need to apply the mode of action framework to understand the contribution of other biological effect markers playing a role in carcinogenicity.

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Section: Tumour Incidence Data and Bmd 10 Calculationmentioning

confidence: 82%

Section: Data On In Vivo Dna Adduct Formationmentioning

confidence: 99%

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Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays

et al. 2011

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“…Rabbit antiserum, elicited against DNA containing 2.4% modification with dG- N 2 -TAM, was employed in the TAM-DNA CIA as previously described (25) with additional specific details below. For the TAM-DNA standard curve we used DNA modified to 4.8 dG- N 2 -TAM adducts/10 6 nucleotides, and serial dilutions were carried out to give 6.630 to 0.009 fmol dG- N 2 -TAM per well.…”

Section: Methodsmentioning

confidence: 99%

Tamoxifen Induces Expression of Immune Response–Related Genes in Cultured Normal Human Mammary Epithelial Cells

Schild-Hay

Leil²,

Divi³

et al. 2009

Cancer Research

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Use of tamoxifen is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented tamoxifen-induced gene expression changes in cultured normal human mammary epithelial cells (strains 5, 16, and 40), established from tissue taken at reduction mammoplasty from three individuals. Cells exposed to 0, 10, or 50 Mmol/L of tamoxifen for 48 hours were evaluated for (E)-A-(deoxyguanosine-N 2 -yl)-tamoxifen (dG-N 2 -TAM) adduct formation using TAM-DNA (DNA modified with dG-N 2 -TAM) chemiluminescence immunoassay, gene expression changes using National Cancer Institute DNAoligonucleotide microarray, and real-time PCR. At 48 hours, cells exposed to 10 and 50 Mmol/L of tamoxifen were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N 2 -TAM adducts. For microarrays, cells were exposed to 10 Mmol/L of tamoxifen and genes with expression changes of >3-fold were as follows: 13 genes up-regulated and 1 downregulated for strain 16; 17 genes up-regulated for strain 5, and 11 genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, MXI, and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all three strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. Real-time PCR revealed the upregulation of IFNA1 and confirmed the tamoxifen-induced upregulation of the five other genes identified by microarray, with the exception of GIP3 and MX1, which were not upregulated in strain 40. Induction of IFN-related genes in the three normal human mammary epithelial cell strains suggests that, in addition to hormonal effects, tamoxifen exposure may enhance immune response in normal breast tissue.

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“…The DNA samples were hydrolyzed to nucleosides and analyzed for ( E )‐α‐(deoxyguanosin‐ N 2 ‐yl)‐tamoxifen (dG‐Tam) and ( E )‐α‐(deoxyguanosin‐ N 2 ‐yl)‐ N ‐desmethyltamoxifen (dG‐DesMeTam) by electrospray ionization tandem mass spectrometry (ES‐MS/MS) coupled with on‐line sample preparation and high‐performance liquid chromatography (HPLC) [28] as described by Schild et al [29].…”

Section: Methodsmentioning

confidence: 99%

Epigenetic reprogramming of liver cells in tamoxifen‐induced rat hepatocarcinogenesis

Tryndyak

Kovalchuk

Muskhelishvili

et al. 2007

Molecular Carcinogenesis

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Tamoxifen, a nonsteroidal anti-estrogen, is a potent genotoxic hepatocarcinogen in rats, with both tumor initiating and promoting properties. Recently it has been demonstrated that genotoxic carcinogens, in addition to exerting genotoxic effects, often cause epigenetic alterations and these induced epigenetic changes may play important mechanistic role in carcinogenesis. In the present study, we investigated the role of tamoxifen-induced epigenetic changes in hepatocarcinogenic process. The results of the study showed that exposure of female F344 rats to tamoxifen resulted in progressive loss of CpG methylation in regulatory sequences of long interspersed nucleotide elements (LINE-1) and prominent increase in expression of LINE-1 elements and c-myc proto-oncogene. The accumulation of tamoxifen-induced DNA lesions was accompanied by the decreased level of Rad51, Ku70, and DNA polymerase beta (Polbeta) proteins that play a crucial role in maintenance of genomic stability. Furthermore, feeding rats with tamoxifen-containing diet led to increased regenerative cell proliferation, as indicated by the increased level of Ki-67 and proliferating cell nuclear antigen (PCNA) proteins. These data indicate that exposure of animals to genotoxic hepatocarcinogen tamoxifen led to early phenotypical alterations in livers characterized by emergence of epigenetically reprogrammed cells with a specific cancer-related epigenetic phenotype prior to tumor formation.

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

Cited by 14 publications

References 36 publications

Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays

Quantitative comparison between in vivo DNA adduct formation from exposure to selected DNA-reactive carcinogens, natural background levels of DNA adduct formation and tumour incidence in rodent bioassays

Tamoxifen Induces Expression of Immune Response–Related Genes in Cultured Normal Human Mammary Epithelial Cells

Epigenetic reprogramming of liver cells in tamoxifen‐induced rat hepatocarcinogenesis

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