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Drug Metabolism and Disposition Fast Forward
First published on November 18, 2005; DOI: 10.1124/dmd.105.007013

0090-9556/06/3402-311-317$20.00
DMD 34:311-317, 2006

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INEFFICIENT REPAIR OF TAMOXIFEN-DNA ADDUCTS IN RATS AND MICE

Sung Yeon Kim, Naomi Suzuki, Y. R. Santosh Laxmi, and Shinya Shibutani

Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York

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.

Address correspondence to: Shinya Shibutani, Department of Pharmacological Sciences, State University of New York at Stony Brook, 1 Nicolls Road, Stony Brook, NY 11794-8651. E-mail: shinya{at}pharm.stonybrook.edu






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