FORMATION OF TAMOXIFEN-DNA ADDUCTS VIA <i>O</i>-SULFONATION, NOT <i>O</i>-ACETYLATION, OF α-HYDROXYTAMOXIFEN IN RAT AND HUMAN LIVERS

Kim, Sung Yeon; Laxmi, Y. R. Santosh; Suzuki, N.; Ogura, K.; Watabe, Tadashi; Duffel, Michael W.; Shibutani, Shinya

doi:10.1124/dmd.105.005330

Cited by 31 publications

(29 citation statements)

References 28 publications

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“…Tamoxifen is used as the standard adjuvant endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for the disease (34). The increased incidence of endometrial cancers in patients treated with tamoxifen has been attributed to genotoxic damage induced by tamoxifen-DNA adducts after O-sulfation of tamoxifen by SULT (35). To our knowledge, AF is the only reported anticancer agent for which activation by SULTs is required for its therapeutic activity.…”

Section: Discussionmentioning

confidence: 99%

Activation of Aminoflavone (NSC 686288) by a Sulfotransferase Is Required for the Antiproliferative Effect of the Drug and for Induction of Histone γ-H2AX

et al. 2006

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Aminoflavone (AF) is entering clinical trials. We recently reported that AF induces DNA-protein cross-links (DPC) and ;-H2AX in MCF-7 human breast cancer cells. To elucidate the mechanism of action of AF and provide biomarkers indicative of AF activity, we correlated AF activity profile (GI 50 ) with gene expression patterns in the NCI-60 cell lines. Sulfotransferases (SULT) showed the highest positive correlation coefficients among f14,000 probe sets analyzed (r = 0.537, P < 0.001). Stable transfection of SULT1A1 into AF-resistant MDA-MB-231 cells sensitized these cells to AF. AF produced DPCs, ;-H2AX foci, and S-phase arrest in the SULT1A1-transfected but not in the parent MDA-MB-231 cells. Conversely, cells in which SULT1A1 was knocked down by small interfering RNA failed to induce ;-H2AX. Inhibition of SULTs and cytochrome P450 (CYP) enzymes by natural flavonoids blocked the antiproliferative activity of AF and the formation of AF-DNA adducts. AF also induces SULT1A1 and CYP expression in MCF-7 cells, suggesting the existence of an aryl hydrocarbon receptormediated positive feedback for AF activation by CYP and SULT1A1. Metabolism studies showed that AF can be oxidized by CYP at two amino groups to form N-hydroxyl metabolites that are substrates for bioactivation by SULTs. We propose that both N-sulfoxy-groups can be further converted to nitrenium ions that form adducts with DNA and proteins. The results reported here show the importance of SULT1A1 and CYP for AF activation and anticancer activity. They also suggest using SULT1A1 and ;-H2AX as biomarkers for prediction of AF activity during patient selection and monitoring of clinical trials. (Cancer Res 2006; 66(19): 9656-64)

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Section: Discussionmentioning

confidence: 99%

Activation of Aminoflavone (NSC 686288) by a Sulfotransferase Is Required for the Antiproliferative Effect of the Drug and for Induction of Histone γ-H2AX

et al. 2006

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“…However, sulfonation is not always beneficial, and tamoxifen, which is used in treating breast cancer, provides an example of a drug where sulfonation has been suggested to be important for the development of an associated adverse reaction, namely an increased incidence of endometrial cancer. Thus, it has been suggested that tamoxifen-DNA adducts are formed via O-sulfonation (56). As a further example, sulfonation phenotype could potentially influence both the efficacy and side-effects of apomorphine, for which sulfonation is the major metabolic pathway in humans (57).…”

Section: Resultsmentioning

confidence: 99%

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Clayton

Baker

Lindon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

690

573

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We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by 1 H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.T he effects of drug treatments can vary greatly between different individuals, and pharmacogenomics has been widely advocated as a potential means of personalizing human drug treatments to increase drug efficacy and to decrease adverse reactions (1-6). However, environmental factors (such as nutritional status, gut bacterial activities, age, disease, and other drug use) are also important determinants of individual metabolic phenotypes, which modulate drug metabolism, efficacy, and toxicity. Such environmental complications, which may also alter gene expression, will tend to limit the usefulness of predictions of drug-induced responses that are based only on genomic differences (7,8). For instance, for many classes of compound, enzyme induction state, which is environmentally determined, influences drug metabolism and toxicity and this is not captured in genomic data. Recognizing this important limitation of pharmacogenomics, a different approach to personalized drug treatment has recently been proposed wherein predose metabolite profiling would instead be used to predict a subject's responses to potential drug interventions (9). This ''pharmacometabonomic'' approach has a number of major advantages, which include the ready availability and relative ease of analysis of biofluids, such as urine and blood plasma, as well as the fact that ...

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“…Attempts to determine whether tamoxifen therapy can lead to DNA adducts in the human endometrium have yielded conflicting results (Greaves et al, 1993;Hemminki et al, 1996;Carmichael et al, 1999;Shibutani et al, 2000;Sharma et al, 2003b;Beland et al, 2004). Studies in experimental model systems suggest that sulfation of ␣-hydroxylated tamoxifen metabolites mediates DNA adduct formation (Shibutani et al, 1998;Kim et al, 2005a). In addition, covalent binding to proteins and to 2Ј-deoxyguanosine via CYP3A4 and/or CYP2D6 catalyzed formation of 3,4-dihydroxytamoxifen, and subsequent bioactivation has been reported in human and rat liver microsomes (Dehal and Kupfer, 1999).…”

mentioning

confidence: 99%

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

Andersson

Helmestam²,

Żebrowska³

et al. 2009

Drug Metab Dispos

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FORMATION OF TAMOXIFEN-DNA ADDUCTS VIA O-SULFONATION, NOT O-ACETYLATION, OF α-HYDROXYTAMOXIFEN IN RAT AND HUMAN LIVERS

Cited by 31 publications

References 28 publications

Activation of Aminoflavone (NSC 686288) by a Sulfotransferase Is Required for the Antiproliferative Effect of the Drug and for Induction of Histone γ-H2AX

Activation of Aminoflavone (NSC 686288) by a Sulfotransferase Is Required for the Antiproliferative Effect of the Drug and for Induction of Histone γ-H2AX

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Tamoxifen-Induced Adduct Formation and Cell Stress in Human Endometrial Glands

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