Tamoxifen mutagenesis and carcinogenesis in livers of lambda/lacI transgenic rats: selective influence of phenobarbital promotion

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to fe male lambda/lacI transgenic rats caused a 4-fold increase in mutation frequ ency (MF) at the lad gene locus in the livers of dosed animals compared wit h controls. After cessation of dosing, the MF showed a further increase wit h time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of simi larly treated animals resulted in no increase in mutation frequency compare d with TAM alone. Treatment with phenobarbital or TAM + phenobarbital resul ted in time-dependent increases in liver weight compared with the correspon ding controls. There was an increase in cell proliferation in the phenobarb ital and TAM + phenobarbital groups, and at 24 weeks in the TAM dosed anima ls compared with controls. There was also a progressive increase in the num ber of GST-P expressing foci in the livers of TAM and TAM + phenobarbital r ats compared with controls. The induction of cell proliferation and GSTP fo ci in the rat liver by phenobarbital is consistent with its ability to prom ote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regar ded as being representative of the rat genome in general (albeit that the g ene is bacterial) the above observations suggest that promotion by tamoxife n confers selective advantage on mutated genes at loci that contribute to t he tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation. (C) 2 001 Elsevier Science Ireland Ltd. All rights reserved.