Received for publication August 25, 2005.
Revised November 14, 2005.
Accepted for publication November 15, 2005.

Inefficient Repair of Tamoxifen-DNA Adducts in Rats and Mice

Abstract

A long-term treatment of tamoxifen (TAM) to women increases the risk of developing endometrial cancer. It 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 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- (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 slower 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 the nucleotide excision repair deficient (Xpc knockout) and the 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.

Key words: chemical carcinogenesis, distribution, DNA adducts, sulfotransferases