Tamoxifen induces G : C -> T : A mutations in the cII gene in the liver oflambda/lacI transgenic rats but not at 5 '-CpG-3 ' dinucleotide sequences as found in the lacI transgene

Tamoxifen, a rat liver carcinogen, can induce mutations in the lacI gene in the livers of lambda/lacI transgenic rats. However, the presence of persis tent tamoxifen adducts on the liver DNA raises the possibility that some co ntribution to the mutagenesis from ex vivo mutations during the in vitro la d assay cannot be ruled out. To address this issue, mutagenesis at the cll gene of the transgenic shuttle vector was determined using a selection base d assay which is unaffected by the presence of tamoxifen-DNA adducts. Femal e lambda/lacI transgenic rats were dosed orally with tamoxifen (20 mg/kg bo dy wt) daily for 6 weeks, causing a 3.2-fold increase in the mutant frequen cy (MF) in the cII gene compared with that obtained with solvent treated an imals. This was similar to the MF found previously at the lad gene and conf irms that tamoxifen is mutagenic in vivo. The major class of mutation induc ed by tamoxifen in the cll gene was G:C-->T:A transversions as was found pr eviously in the lad gene. However, in the one unreplicated study of mutatio ns in the p53 gene of liver tumours induced by tamoxifen, no G:C-->T:A tran sversions were found; possible differences between mutagenesis in normal an d tumour tissues are explored, The major proportion of the G:C-->:A transve rsions occurred at 5'-CpG-3' dinucleotide (CpG) sites in the lacI gene, but not at such sites in the cll gene. The methylation of CpG sites greatly en hances the targeting of deoxyguanosine by carcinogens, thus this finding mi ght be explained by differences in the methylation patterns at their respec tive CpG sites; however nothing is known about the methylation status of ei ther the lacI nor the cll gene in this transgenic rat. This study raises th e important issue of which target genes (mammalian or transgenic) should be used as endpoints in mammalian mutagenesis assays.