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Research ArticleArticle

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

Sung Yeon Kim, Y. R. Santosh Laxmi, Naomi Suzuki, Kenichiro Ogura, Tadashi Watabe, Michael W. Duffel and Shinya Shibutani
Drug Metabolism and Disposition November 2005, 33 (11) 1673-1678; DOI: https://doi.org/10.1124/dmd.105.005330
Sung Yeon Kim
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Y. R. Santosh Laxmi
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Naomi Suzuki
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Kenichiro Ogura
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Tadashi Watabe
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Michael W. Duffel
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Shinya Shibutani
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Abstract

Tamoxifen (TAM) is used as the standard endocrine therapy for breast cancer patients and as a chemopreventive agent for women at high risk for this disease. Unfortunately, treatment of TAM increases the incidence of endometrial cancer; this may be due to the genotoxic damage induced by TAM metabolites. Formation of TAM-DNA adducts in rat liver correlates with the development of hepatocarcinoma. TAM-DNA adducts are proposed to be formed through O-sulfonation and/or O-acetylation of α-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not been extensively investigated. Rat or human hydroxysteroid sulfotransferases (HST), acetyltransferases, and liver cytosol were incubated with calf thymus DNA, α-OHTAM, and either 3′-phosphoadenosine 5′-phosphosulfate (PAPS) or acetyl coenzyme A (acetyl-CoA) as a cofactor and analyzed for TAM-DNA adduct formation, using 32P postlableling/polyacrylamide gel electrophoresis analysis. TAM-DNA adduct was formed when PAPS, not acetyl-CoA, was used. No TAM-DNA adducts were produced using human N-acetyltransferase I and II. HST antibody inhibited approximately 90% of TAM-DNA adduct formation generated by the cytosol or HST, suggesting that HST is primarily involved in the formation of TAM-DNA adducts. The formation of TAM-DNA adducts with rat liver cytosol and HST was much higher than that of human liver cytosol and HST. Our results indicate that TAM-DNA adducts are formed via O-sulfonation, not O-acetylation, of α-hydroxylated TAM and its metabolites.

Footnotes

  • This research was supported by Grants ES09418 (to S.S.) from the National Institute of Environmental Health Sciences and CA38683 (to M.W.D.) from the National Cancer Institute.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.005330.

  • ABBREVIATIONS: TAM, tamoxifen; α-OHTAM, α-hydroxytamoxifen; fr, fraction(s); dG-N2-TAM, α-(N2-deoxyguanosinyl)tamoxifen; α-OH-N-desTAM, α-hydroxy-N-desmethyltamoxifen; α-OHTAM N-oxide, α-hydroxytamoxifen N-oxide; dG-N2-N-desTAM, α-(N2-deoxyguanosinyl)-N-desmethyltamoxifen; HST, hydroxysteroid sulfotransferase(s); dG3′p-N2-TAM, dG3′p-monophosphate-N2-tamoxifen; PAPS, 3′-phosphoadenosine 5′-phosphosulfate; acetyl-CoA, acetyl coenzyme A; NAT, N-acetyltransferase; DHEA, dehydroepiandrosterone; PAGE, polyacrylamide gel electrophoresis; HPLC, high-performance liquid chromatography.

    • Received April 26, 2005.
    • Accepted August 11, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 33 (11)
Drug Metabolism and Disposition
Vol. 33, Issue 11
1 Nov 2005
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Research ArticleArticle

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

Sung Yeon Kim, Y. R. Santosh Laxmi, Naomi Suzuki, Kenichiro Ogura, Tadashi Watabe, Michael W. Duffel and Shinya Shibutani
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1673-1678; DOI: https://doi.org/10.1124/dmd.105.005330

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Research ArticleArticle

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

Sung Yeon Kim, Y. R. Santosh Laxmi, Naomi Suzuki, Kenichiro Ogura, Tadashi Watabe, Michael W. Duffel and Shinya Shibutani
Drug Metabolism and Disposition November 1, 2005, 33 (11) 1673-1678; DOI: https://doi.org/10.1124/dmd.105.005330
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