title: Inefficient repair of tamoxifen-DNA adducts in rats and mice.
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.
authors.affiliation: Department of Pharmacological Sciences, State University of New York at Stony Brook, 1 Nicolls Road, Stony Brook, NY 11794-8651, USA.
authors.forename: Sung Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Naomi
authors.initials: N
authors.lastname: Suzuki
authors.forename: Y R Santosh
authors.initials: YR
authors.lastname: Laxmi
authors.forename: Shinya
authors.initials: S
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics / Q000494:pharmacology; D018736:DNA Adducts / Q000032:analysis*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity; D013629:Tamoxifen / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C501002:Xpc protein, mouse; D013629:Tamoxifen