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Mutational specificity: Mutational spectra of tamoxifen‐induced mutations in the livers of lacl transgenic rats
Author(s) -
Davies Reginald,
Oreffo Victor I. C.,
Bayliss Stuart,
Dinh PhuongAnh,
Lilley Kathryn S.,
White Ian N. H.,
Smith Lewis L.,
Styles Jerry A.
Publication year - 1996
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/(sici)1098-2280(1996)28:4<430::aid-em19>3.0.co;2-g
Subject(s) - tamoxifen , mutant , point mutation , biology , mutagenesis , gene , mutation , transgene , microbiology and biotechnology , genetics , genetically modified mouse , dna , cancer research , cancer , breast cancer
Tamoxifen, an important drug in breast cancer treatment, causes liver cancer in rats. The standard range of in vitro tests have failed to show that it causes DNA damage, but 32 P‐postlabelling and DNA‐binding studies have shown that tamoxifen forms DNA adducts in rat liver. In 1995 a transgenic rat (Big Blue™; Stratagene, La Jolla, CA) became available which harbours the bacterial lacl gene, thereby allowing the in vivo study of tamoxifen mutagenesis. Recently, we [Styles JA et al. (1996): Toxicologist 30; 161] showed that tamoxifen caused an increase in the mutation frequency at the lacl gene in these transgenic rats. In this study, we report on our preliminary analysis of the mutational spectra of 33 control and 38 tamoxifen‐induced mutant lacl genes. Plasmid DNA containing the lacl gene was isolated from the mutant phages and its DNA sequence determined. In the control animal group, 81% of the mutant lacl genes were point mutations, whilst in the tamoxifen‐treated group, 62% of the mutant lacl genes were point mutations. Of the tamoxifen‐induced mutants, 43% were GC → TA transversions and 70% of point mutations. In the control group, GC → TA transversions were 19% of all mutations and 24% of point mutations. Thus, compared with control animals, tamoxifen treatment had significantly increased the proportion of GC → TA transversions. © 1996 Wiley‐Liss, Inc.