Tamoxifen−DNA Adducts Detected in the Endometrium of Women Treated with Tamoxifen

Shibutani, Shinya; Suzuki, N.; Terashima, Isamu; Sugarman, Steven; Grollman, Arthur P.; Pearl, Michael L.

doi:10.1021/tx990033w

Cited by 85 publications

(59 citation statements)

References 40 publications

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“…The full benefits of tamoxifen as a breast cancer therapeutic agent are compromised by its low incidence of endometrial cancer (Fornander et al, 1993;Kedar et al, 1994), and the formation of genotoxic tamoxifen-DNA adducts has been proposed to be a key step in this carcinogenic response (Shibutani et al, 1999). A major mechanism for this genotoxicity begins with the cytochrome P450-mediated oxidation of tamoxifen to a-hydroxytamoxifen (a-OHTAM), which then undergoes sulfation catalyzed by hSULT2A1 to form an electrophilic a-sulfooxy intermediate that reacts with DNA to form covalent adducts (Shibutani et al, 1998a).…”

Section: Discussionmentioning

confidence: 99%

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

Squirewell

Qin

Duffel

2014

Drug Metabolism and Disposition

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Although tamoxifen is a successful agent for treatment and prevention of estrogen-dependent breast cancer, its use has been limited by the low incidence of endometrial cancer. Human hydroxysteroid sulfotransferase 2A1 (hSULT2A1) catalyzes the formation of an a-sulfooxy metabolite of tamoxifen that is reactive toward DNA, and this has been implicated in its carcinogenicity. Also, hSULT2A1 functions in the metabolism of steroid hormones such as dehydroepiandrosterone (DHEA) and pregnenolone (PREG). These roles of hSULT2A1 in steroid hormone metabolism and in generating a reactive metabolite of tamoxifen led us to examine its interactions with tamoxifen and several of its major metabolites. We hypothesized that metabolites of tamoxifen may regulate the catalytic activity of hSULT2A1, either through direct inhibition or through serving as alternate substrates for the enzyme. We found that 4-hydroxy-N-desmethyltamoxifen (endoxifen) is a potent inhibitor of hSULT2A1-catalyzed sulfation of PREG and DHEA, with K i values of 3.5 and 2.8 mM, respectively. In the hSULT2A1-catalyzed sulfation of PREG, 4-hydroxytamoxifen (4-OHTAM) and N-desmethyltamoxifen (N-desTAM) exhibited K i values of 12.7 and 9.8 mM, respectively, whereas corresponding K i values of 19.4 and 17.2 mM were observed with DHEA as substrate. A K i value of 9.1 mM was observed for tamoxifen-N-oxide with DHEA as substrate, and this increased to 16.9 mM for the hSULT2A1-catalyzed sulfation of PREG. Three metabolites were substrates for hSULT2A1, with relative sulfation rates of 4-OHTAM > N-desTAM > > endoxifen. These results may be useful in interpreting ongoing clinical trials of endoxifen and in improving the design of related molecules.

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Section: Discussionmentioning

confidence: 99%

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

Squirewell

Qin

Duffel

2014

Drug Metabolism and Disposition

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“…For measurements of DNA binding, the generally preferred method is the 32 P-postlabeling assay (Reddy, 2000). However, because BaP has been well established to bind covalently to DNA after enzymatic bioactivation (Xue and Warshawsky, 2005), we used the simpler radiolabeling assay, which has been modified and refined (Shibutani et al, 1999;Walle et al, 2003). EpiOral tissues were incubated with 1 M [ 3 H]BaP alone for specified times or for 24 h together with 25 M quercetin, resveratrol, chrysin, or 5,7-dimethoxyflavone.…”

Section: Methodsmentioning

confidence: 99%

“…The tissue inserts were washed, and the tissues peeled off the membranes and homogenized with a Polytron homogenizer in 1 ml of 1% SDS/10 mM EDTA/20 mM Tris-HCl (pH 7.4). The homogenate was then incubated at 37°C for 30 min with 0.2 mg of RNase A and 0.5 mg of proteinase K (Shibutani et al, 1999). After extraction with phenol/chloroform/isoamyl alcohol (four times) and precipitation of DNA with sodium acetate and ethanol, the pellets were washed twice with ethanol and dissolved in water.…”

Section: Methodsmentioning

confidence: 99%

Benzo[a]pyrene-Induced Oral Carcinogenesis and Chemoprevention: Studies in Bioengineered Human Tissue

Walle¹,

Walle²,

Sedmera³

et al. 2006

Drug Metabolism and Disposition

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ABSTRACT:Oral cancer, originating from smoking-induced lesions of the basal cells in the complex stratified oral epithelium, is difficult to treat. Early detection of premalignant lesions, e.g., leukoplakia, has suggested the possibility of chemopreventive measures, such as topical application of antimutagenic/antiproliferative dietary or pharmaceutical agents. As an extension of a study in human oral epithelial cell monolayers, we determined the carcinogen, i.e., benzo

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“…Studies investigating the presence of tamoxifen DNA adducts in human tissues have reported conflicting results, and there is much debate over this issue and whether tamoxifen-induced DNA damage might be a contributing factor in the development of cancers in women (4). Low levels of the major dG-N 2 -tam lesion formed in rat liver have been detected in leukocytes and endometrial tissue of tamoxifen-treated women by two groups using 32 P-postlabeling analysis (21)(22)(23). However, in each case, adducts were only observed in samples from a fraction of the patients, indicating variability in tamoxifen metabolic activation, the formation or repair of DNA adducts.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose

et al. 2007

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Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14 C]-labeled therapeutic (20 mg) dose, f18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N 2 -tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/10 9 nucleotides. No [14 C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to A-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of interindividual variability, when present, it was f10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo [4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

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Tamoxifen−DNA Adducts Detected in the Endometrium of Women Treated with Tamoxifen

Cited by 85 publications

References 40 publications

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

Endoxifen and Other Metabolites of Tamoxifen Inhibit Human Hydroxysteroid Sulfotransferase 2A1 (hSULT2A1)

Benzo[a]pyrene-Induced Oral Carcinogenesis and Chemoprevention: Studies in Bioengineered Human Tissue

Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose

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