DMD Noab BioDiscoveries - Shaping Drug Discovery

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on August 11, 2005; DOI: 10.1124/dmd.105.005330

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.105.005330v1
33/11/1673    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Kim, S. Y.
Right arrow Articles by Shibutani, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, S. Y.
Right arrow Articles by Shibutani, S.


Received for publication April 26, 2005.
Revised June 24, 2005.
Accepted for publication August 11, 2005.

Formation of Tamoxifen-DNA Adducts via O-Sulfonation, not O-Acetylation, of {alpha}-Hydroxytamoxifen in Rat and Human Livers

Sung Yeon Kim 1, Y. R. Santosh Laxmi 1, Naomi Suzuki 1, Kenichiro Ogura 2, Tadashi Watabe 2, Michael W. Duffel 3, Shinya Shibutani 1*

1 State University of New York at Stony Brook 2 Tokyo University of Pharmacy and Life Science 3 The University of Iowa

* Address correspondence to: E-mail: shinya{at}pharm.sunysb.edu

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 {alpha}-hydroxylated TAM and its metabolites. However, the role of O-sulfonation and O-acetylation in the formation of TAM-DNA adducts has not extensively investigated. Rat or human hydroxysteroid sulfotransferaes (HST), acetyltransferases and liver cytosol was incubated with calf thymus DNA, {alpha}-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 {alpha}-hydroxylated TAM and its metabolites.


Key words: acetyltransferases, chemical carcinogenesis, DNA adducts, drug toxicity, phase II drug metabolism, sulfotransferases


This article has been cited by other articles:


Home page
 Cancer Res.Home page
L.-h. Meng, U. Shankavaram, C. Chen, K. Agama, H.-q. Fu, F. J. Gonzalez, J. Weinstein, and Y. Pommier
Activation of Aminoflavone (NSC 686288) by a Sulfotransferase Is Required for the Antiproliferative Effect of the Drug and for Induction of Histone {gamma}-H2AX
Cancer Res., October 1, 2006; 66(19): 9656 - 9664.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2005 by the American Society for Pharmacology and Experimental Therapeutics.