Journal Article

Mutations induced by α-hydroxytamoxifen in the <i>lacI</i> and <i>cII</i> genes of Big Blue transgenic rats

Tao Chen, Goncıalo Gamboa da Costa, M.Matilde Marques, Sharon D. Shelton, Frederick A. Beland and Mugimane G. Manjanatha

in Carcinogenesis

Volume 23, issue 10, pages 1751-1758
Published in print October 2002 | ISSN: 0143-3334
Published online October 2002 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/23.10.1751
Mutations induced by α-hydroxytamoxifen in the lacI and cII genes of Big Blue transgenic rats

More Like This

Show all results sharing this subject:

  • Clinical Cytogenetics and Molecular Genetics

GO

Show Summary Details

Preview

The antiestrogen tamoxifen is widely used for the treatment of breast cancer and more recently for the prevention of breast cancer. A concern over the use of tamoxifen as a chemopreventive agent is its carcinogenicity in rat liver, through a genotoxic mechanism involving α-hydroxylation, esterification, and DNA adduct formation, primarily by reaction with dG. In a recent study [Gamboa da Costa et al., Cancer Lett., 176, 37–45 (2002)], we demonstrated a significant increase in the mutant frequency in the lacI gene of Big Blue rats treated with tamoxifen, and a further increase in rats administered α-hydroxytamoxifen. In the present study, we have assessed mutation induction by tamoxifen and α-hydroxytamoxifen in the liver cII gene of Big Blue rats and have characterized the types of mutations induced by α-hydroxytamoxifen in the liver lacI and cII genes. The mutant frequencies in the liver cII gene were 80 ± 13 × 10–6 in the control, 112 ± 13 × 10–6 in the tamoxifen-treated group (P < 0.01 vs. control), and 942 ± 114 × 10–6 in the α-hydroxytamoxifen-treated animals (P < 0.001 vs. control; P < 0.001 vs. tamoxifen). Molecular analysis of the mutants indicated that the α-hydroxytamoxifen-induced mutational spectrum differed significantly from the control spectrum, but was very similar to the spectrum induced by tamoxifen for both the lacI and cII genes [Davies et al., Environ. Mol. Mutagen., 28, 430–433 (1996); Davies et al., Carcinogenesis, 20, 1351–1356 (1999)]. G:C → T:A transversion was the major type of mutation induced by α-hydroxytamoxifen and tamoxifen, while G:C → A:T transition was the main type of mutation in the control. These results support the hypothesis that α-hydroxytamoxifen is a major proximate tamoxifen metabolite causing the initiation of tumors in the liver of rats treated with tamoxifen.

Journal Article.  5126 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.