A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism

Potter, Gerard A.; McCague, Raymond; Jarman, Michael

doi:10.1093/carcin/15.3.439

Cited by 113 publications

(63 citation statements)

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“…Although many candidates were described [75][76][77][78], the metabolite found to be responsible for the initiation of rat liver carcinogenesis is α-hydroxytamoxifen [79][80][81][82][83] (Figure 5) Alpha-hydroxytamoxifen has been resolved into R-(+) and S-(−) enantiomers. Metabolism by rat liver microsomes gave equal amounts of the two forms, but in hepatocytes the R form gave 8x the level of DNA adducts as the S form.…”

Section: Basic Mechanisms Of Tamoxifen Metabolismmentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Basic Mechanisms Of Tamoxifen Metabolismmentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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“…[14][15][16][17][18][19][20][21] Although N-desmethyltamoxifen, tamoxifen N-oxide, and 4-hydroxytamoxifen are major metabolites of tamoxifen, DNA adducts of these metabolites are hardly detected in the liver, 19,22) suggesting that these metabolites might be considered primarily as detoxification forms.…”

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confidence: 99%

The gene expression of hepatic proteins responsible for DNA repair and cell proliferation in tamoxifen‐induced hepatocarcinogenesis

Kasahara¹,

Kuwayama²,

Hashiba³

et al. 2003

Cancer Science

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Altered gene expression of the DNA repair-and cell proliferationassociated proteins/enzymes was examined during the process of tamoxifen-induced hepatocarcinogenesis in female Sprague-Dawley rats. When rats were treated by gavage with a single dose of tamoxifen (20 mg/kg body weight) or with the same dose given at 24-h intervals for 2, 12 or 52 weeks, no histopathological change was observed in the liver after 2 weeks. Pathologically altered cell foci and placental form of glutathione-S-transferase (GST-P)-positive foci were observed in the liver after 12 weeks of treatment. Treatment for 52 weeks resulted in the formation of liver hyperplastic nodules that strongly expressed GST-P. During the process of carcinogenesis, changes in hepatic gene expression of DNA repair proteins/enzymes (XPA and XPC, xeroderma pigmentosum complementation groups A and C, respectively; APE, apurinic/apyrimidinic endonuclease) and of cell proliferation-associated proteins (c-myc; PCNA, proliferating cell nuclear antigen; cyclin D1, cyclin B, and p34cdc2) were examined by RT-PCR. The gene expression of XPA and APE was increased by the tamoxifen treatment for 2 or 12 weeks, but no increase was observed after the 52-week treatment. In addition, no significant change in XPC gene expression occurred at any period examined. The gene expression of c-myc, PCNA, and cyclin D1 was increased in a timedependent fashion up to 12 weeks of treatment, and this increase was maintained up to 52 weeks of treatment. The gene expression of cyclin B and p34cdc2 was increased after the 1-day treatment, reverted to the control level at 2 and 12 weeks of treatment, and was remarkably increased after the 52-week treatment. In the present study, we demonstrate the altered gene expression of various proteins/enzymes involved in DNA repair, cell growth and the cell cycle during the process of tamoxifen-induced hepatocarcinogenesis. We discuss the relationship between the altered gene expression and hepatocarcinogenesis. (Cancer Sci 2003; 94: 582-588) otent hepatocarcinogenicity of the antiestrogen tamoxifen in rats has been reported, [1][2][3][4] although tamoxifen is widely used not only as an anticancer drug, 5,6) but also as a chemopreventive agent 7) for breast cancer. This hepatocarcinogenesis is thought to occur through the chemical modification of DNA by tamoxifen metabolites.8-13) α-(N 2 -Deoxyguanosinyl)tamoxifen is detected as a major DNA adduct of tamoxifen in the rat liver, and the adduct has been shown to be formed through metabolic activations, α-hydroxylation and O-sulfation, of tamoxifen. [14][15][16][17][18][19][20][21] Although N-desmethyltamoxifen, tamoxifen N-oxide, and 4-hydroxytamoxifen are major metabolites of tamoxifen, DNA adducts of these metabolites are hardly detected in the liver, 19,22) suggesting that these metabolites might be considered primarily as detoxification forms.Recently, we 23) have investigated changes in the drug-metabolizing enzymes involved in forming tamoxifen metabolites during the process of tamoxifen-induced hepa...

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“…The finding that tamoxifen can form DNA adducts led to the development of the second generation anti-estrogen, toremifene (Fareston) (143)(144)(145). In advanced disease, toremifene has been shown to be comparable to tamoxifen in terms of response rates as well as toxicities.…”

Section: Anti-estrogen Therapy For Breast Cancermentioning

confidence: 99%

Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer

Hanstein

Djahansouzi²,

Dall³

et al. 2004

European Journal of Endocrinology

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Evidence for a role of ovarian factors in the growth of metastatic breast cancer was first recognized over 100 years ago. Today, anti-estrogens are central to the treatment of breast cancer of all stages. We now understand that the action of estrogen is mediated by the estrogen receptors (ER) which are members of the nuclear receptor family of ligand-regulated transcription factors. In this article we review the molecular mechanisms through which ER activates transcription of target genes and through which available anti-estrogens mediate their therapeutic effects. We discuss possible mechanisms of failure of treatment with current anti-estrogens and how newer anti-estrogens under development attempt to address these problems. In addition an expanded view of the molecular mechanisms of estrogen action is leading to the development of novel selective ER modulators or SERMs.European Journal of Endocrinology 150 243-255

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A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism

Cited by 113 publications

References 0 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

The gene expression of hepatic proteins responsible for DNA repair and cell proliferation in tamoxifen‐induced hepatocarcinogenesis

Insights into the molecular biology of the estrogen receptor define novel therapeutic targets for breast cancer

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