Abstract
A long-term treatment with tamoxifen (TAM) to women increases the risk of developing endometrial cancer. The cancer may result from genotoxic damage induced by this drug. In fact, TAM-DNA adducts were detected in the liver of rats treated with TAM and initiated to develop hepatocellular carcinomas. To explore the distribution and repair rate of TAM-DNA adducts, the level of TAM-DNA adducts in all tissues of rats and mice was monitored for 28 days and 7 days, respectively, after the termination of TAM treatment, using 32P-postlabeling/polyacrylamide gel electrophoresis and 32P-postlabeling/HPLC analyses. TAM-DNA adducts were formed specifically in the liver of rodents. In rats, the level of hepatic TAM-DNA adducts was decreased only to 43% in 28 days, indicating that the half-life of adducts was approximately 25 days. Among trans [fraction (fr)-1 and fr-2]- and cis (fr-3 and fr-4)-isoforms of TAM-DNA adducts, a trans-form (fr-1) was removed much more slowly than other adducts, indicating that the repair rate of TAM-DNA adducts varied depending on the structure of isoforms. The repair rate of TAM-DNA adducts was also compared between nucleotide excision repair-deficient (Xpc knockout) and wild mice. Although the level of hepatic TAM-DNA adducts observed with Xpc knockout mice was slightly higher than that of the wild type, the removal of TAM-DNA adducts in both mice was only 20% in 7 days. Thus, TAM-DNA adducts are not efficiently repaired from the targeted tissue, leading to the development of cancer.
Footnotes
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This research was supported by Grant ES09418 from the National Institute of Environmental Health Sciences.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.007013.
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ABBREVIATIONS: TAM, tamoxifen; dG, 2′-deoxyguanosine; N-desTAM, N-desmethyltamoxifen; TAM N-oxide, tamoxifen N-oxide; dG-N2-TAM, α-(N2-deoxyguanosinyl)tamoxifen; dG-N2-N-desTAM, α-(N2-deoxyguanosinyl)-N-desmethyltamoxifen; fr, fraction; NER, nucleotide excision repair; PAGE, polyacrylamide gel electrophoresis; AAF, acetylaminofluorene.
- Received August 25, 2005.
- Accepted November 15, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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