Activation of tamoxifen and its metabolite α-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes

Phillips, David H.; Carmichael, Paul L.; Hewer, Alan; Cole, Kathleen J.; Hardcastle, Ian R.; Poon, Grace K.; Keogh, Adrian; Strain, Alastair J.

doi:10.1093/carcin/17.1.89

Cited by 90 publications

(38 citation statements)

References 30 publications

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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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“…Interestingly, the urinary metabolite profile of the dietary carcinogen 2-amino-1-methyl-6-phenyimidazo [4,5-b ]pyridine (PhIP) has recently been described as a possible predictor of DNA adduct levels in colon tissue of humans administered a dietary relevant dose of [2][3][4][5][6][7][8][9][10][11][12][13][14] C]-PhIP (45). PhIP is bioactivated by CYP1A2 to 2-N-hydroxy-PhIP, which is subsequently esterified, producing the ultimate DNA-reactive species, O-sulfonyl or Oacetyl esters.…”

Section: Cancer Researchmentioning

confidence: 99%

“…These liver tumors are considered to arise through a genotoxic mechanism. Tamoxifen activation involves conversion to a-hydroxytamoxifen, catalyzed primarily by CYP3A4 in humans (12,13). This metabolite can then be further conjugated, generating the more reactive a-sulfate ester, but whether this step actually occurs in human tissues has not yet been confirmed (14).…”

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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“…[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.…”

mentioning

confidence: 99%

“…[8][9][10][11][12][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.…”

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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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Activation of tamoxifen and its metabolite α-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes

Cited by 90 publications

References 30 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

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

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

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