Mutational specificity: Mutational spectra of tamoxifen-induced mutations in the livers of lacl transgenic rats

✍ Scribed by Reginald Davies; Victor I. C. Oreffo; Stuart Bayliss; Phuong-Anh Dinh; Kathryn S. Lilley; Ian N. H. White; Lewis L. Smith; Jerry A. Styles

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: English
• Weight: 320 KB
• Volume: 28
• Category: Article
• ISSN: 0893-6692
• DOI: 10.1002/(sici)1098-2280(1996)28:4<430::aid-em19>3.0.co;2-g

✦ Synopsis

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 32P-postlabelling and DNA-binding studies have shown that tamoxifen forms DNA adducts in rat liver. In 1995 a transgenic rat (Big BlueTM; Stratagene, La Jolla, CA) became available which harbours the bacterial /ad gene, thereby allowing the in vivo study of tamoxifen mutogenesis. Recently, we [Styles JA et al.

(1 996): Toxicologist 30; 1611 showed that tamoxifen caused an increase in the mutation frequency at the loclgene in these transgenic rats. In this study, we report on our preliminary analysis of the mutational spectra of 33 control and 38 tamoxifen-in-duced mutant lac/ genes. Plasmid DNA containing the lac/ gene was isolated from the mutant phages and its DNA sequence determined. In the control animal group, 81 % of the mutant lac/ genes were point mutations, whilst in the tamoxifen-treated group, 62% of the mutant l a d 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.