Inefficient Repair of Tamoxifen-Dna Adducts in Rats and Mice

Kim, Sung Yeon; Suzuki, N.; Laxmi, Y. R. Santosh; Shibutani, Shinya

doi:10.1124/dmd.105.007013

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…Tamoxifen is related to aneuploidy induction and DNA damage in animal hepatocytes (Sargent et al 1994;Kim et al 2006), and human hepatocytes (Kim et al 2005). It is believed that the toxic effect of tamoxifen on hepatocytes is due to the appearance of reactive metabolites during their metabolism (Park et al 2005).…”

Section: Introductionmentioning

confidence: 96%

Liver iron overload induced by tamoxifen in diabetic and non-diabetic female Wistar rats

et al. 2007

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Tamoxifen (TX), a drug used in the treatment of breast cancer, may cause hepatic changes in some patients. The consequences of its use on the liver tissues of rats with or without diabetes mellitus (DM) have not been fully explored. The purpose of this study was to evaluate the correlation between plasma hepatic enzyme levels and the presence of iron overload in the hepatic tissue of female Wistar rats with or without streptozotocin-induced DM and using TX. Female rats were studied in control groups: C-0 (non-drug users), C-V (sorbitol vehicle only) and C-TX (using TX). DM (diabetic non-drug users) and DM-TX (diabetics using TX) were the test groups. Sixty days after induced DM, blood samples were collected for glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST) alkaline phosphatase (ALP) and bilirubin measures. Hepatic fragments were processed and stained with hematoxylin and eosin, Masson's trichrome, Perls. The hepatic iron content was quantified by atomic absorption spectrometry. AST, ALT and ALP levels were significantly elevated in the DM and DM-TX groups, with unchanged bilirubin levels. Liver iron overload using Perls stain and atomic absorption spectrometry were observed exclusively in groups C-TX and DM-TX. There was positive correlation between AST, ALT and ALP levels and microscopic hepatic siderosis intensity in group DM-TX. In conclusion, TX administration is associated with liver siderosis in diabetic and non-diabetic rats. In addition, TX induced liver iron overload with unaltered hepatic function in non-diabetic rats and may be a useful tool for investigating the biological control of iron metabolism.

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Section: Introductionmentioning

confidence: 96%

Liver iron overload induced by tamoxifen in diabetic and non-diabetic female Wistar rats

et al. 2007

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“…The o-quinone resulting from oxidation of the catechol metabolite, 3,4-diOHTAM, can alkylate amino acid residues on proteins, even though the functional significance of the binding of active metabolites of tamoxifen to proteins is still unclear. The o-quinone can cause damage to cellular DNA through generation of reactive oxygen species, and/or alkylation of DNA [4,[21][22][23]. There is now good evidence that -OHTAM plays an important role in the formation of the electrophilic species responsible for tamoxifen-mediated DNA and protein damage ( Fig.…”

Section: Tamoxifen Metabolismmentioning

confidence: 99%

“…Nevertheless the E forms of these adducts predominate [20][21][22][23]. Scarce studies have addressed this topic and consequently many conjugates/adducts were never detected in biological fluids because they have never been specifically looked for yet.…”

Section: Tamoxifen Metabolismmentioning

confidence: 99%

An Electrochemical Outlook on Tamoxifen Biotransformation: Current and Future Prospects

Garrido¹,

Garrido²,

Oliveira‐Brett³

et al. 2011

CDM

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Tamoxifen is a nonsteroidal antiestrogen that is currently and widely used in the treatment of breast cancer in all of its stages, in adjuvant therapy as a long-term suppressant of tumor recurrence and also as a chemopreventive agent in women that are in high risk of developing this type of estrogen-dependent cancer. From a toxicological and (bio)analytical point of view the knowledge of the metabolic pathways of a drug is found to be extremely important. So, in the present work the most important tamoxifen biotransformation steps were reviewed in the light of recent pharmacological data. This overview also includes the current controversy concerning tamoxifen DNA-damaging (genotoxic) versus non-genotoxic mechanisms. A special focus will be given to the putative application of electrochemical methods as a modern and reliable analytical tool for determination of tamoxifen and its metabolites. Moreover, the potential of DNA electrochemical sensors for detection of structural damage to DNA as a basis for toxicity screening is highlighted. Future prospects looking for the importance of developing new analytical methodologies are also discussed.

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“…With the addition of a hydroxyl group, 4-OH-TAM has been shown to have a higher potency than TAM both in vitro and in vivo corresponding to a higher affinity for the ER (9). Of interest is the effect of 4-OH-TAM in ER-negative tissues, such as the rat (10) and mouse livers (11), where TAM-DNA adducts and 4-OH-TAM-induced DNA adducts have been demonstrated. Moreover, a study by Shibutani et al demonstrated TAM-DNA adduct formation in ER-positive tissues, such as the human endometrium (12).…”

Section: Introductionmentioning

confidence: 98%

In vitro cytotoxicity of 4′-OH-tamoxifen and estradiol in human endometrial adenocarcinoma cells HEC-1A and HEC-1B

Cuevas

Lindeman

2014

Oncology Reports

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Tamoxifen (TAM), used to treat estrogen receptor (ER)-positive breast cancer, is a well known estrogen antagonist in the breast, but a partial estrogen agonist in the endometrium. In addition, TAM metabolites, such as 4'-hydroxy-tamoxifen (4-OH-TAM), have been shown to be more potent than the parent compound. The objective of this study was to determine the effects of 4-OH-TAM and estradiol (E2) on two human endometrial adenocarcinoma cell lines, HEC-1B and HEC-1A. When HEC-1B cells were treated with lower concentrations (10-1,000 nM) of 4-OH-TAM or E2 for 1-3 days, no significant difference in the percentage of cell survival was observed among the varying concentrations. At higher 4-OH-TAM or E2 concentrations (1-100 µM), HEC-1B and HEC-1A cells responded similarly with an obvious decrease in cell growth noted at 10 and 100 µM 4-OH-TAM and 100 µM E2. In order to address the observed cell death, DNA laddering was performed at various time intervals with 4-OH-TAM (10 µM) or E2 (10 or 50 µM). DNA gel electrophoresis failed to show the typical laddering pattern (180-200 bp) observed in apoptosis. Furthermore, western blot analysis of caspase-8 and -3 failed to demonstrate caspase activity. These results suggest that apoptosis was not the underlying cellular mechanism of cell death. Due to the lack of apoptotic markers, a cytotoxic (cell death) effect was differentiated from a cytostatic (growth inhibition) effect confirming that cell death had occurred. In summary, micromolar concentrations of 4-OH-TAM induced a non-apoptotic cytotoxic effect in the endometrium; however further studies are needed to elucidate the cytotoxic pathway being utilized.

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Inefficient Repair of Tamoxifen-Dna Adducts in Rats and Mice

Cited by 11 publications

References 28 publications

Liver iron overload induced by tamoxifen in diabetic and non-diabetic female Wistar rats

Liver iron overload induced by tamoxifen in diabetic and non-diabetic female Wistar rats

An Electrochemical Outlook on Tamoxifen Biotransformation: Current and Future Prospects

In vitro cytotoxicity of 4′-OH-tamoxifen and estradiol in human endometrial adenocarcinoma cells HEC-1A and HEC-1B

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