TAMOXIFEN CAUSES GENE-MUTATIONS IN THE LIVERS OF LAMBDA LACI TRANSGENIC RATS/

Tamoxifen, a rat liver carcinogen, was administered to female lambda/l acI transgenic rats at a dose of 20 mg/kg body weight by gavage for 6 weeks, and the animals were sacrificed 2 weeks later, Tamoxifen induce d liver DNA adducts and caused a significant increase in mutation freq uency (IMF) of approximately 3-fold at the lad gene in liver DNA, Live r DNA from animals dosed with tamoxifen at 10 mg/kg also showed a simi lar increase in MF, The mutations were characterized by a raised propo rtion of: (a) G:C to T:A transversions; (b) insertions of base pairs; and (c) deletions of pairs of G:C base pairs, These observations indic ate that tamoxifen induces a distinct spectrum of mutations compared w ith that found in controls, Toremifene, a noncarcinogenic analogue of tamoxifen with similar estrogenic/antiestrogenic properties examined a t 20 mg/kg body weight using the same dosing regime as tamoxifen was n ot mutagenic, A single oral dose of the rat liver carcinogen aflatoxin B-1 (0.5 mg/kg) also significantly raised the MF. In conclusion, alth ough tamoxifen is not mutagenic in regulatory short-term tests, it is a gene mutagen in the rat liver.