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

• Published in: Cancer letters 2001-01, Vol.162 (1), p.117-122
• Main Authors: Styles, Jerry A., Davies, Reginald, Fenwick, Simon, Walker, Joseph, White, Ian N.H., Smith, Lewis L.
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Proteins - genetics; Biological and medical sciences; Cell Division - drug effects; Drug toxicity and drugs side effects treatment; Escherichia coli Proteins; Estrogen Antagonists - toxicity; Female; Glutathione Transferase - metabolism; Initiation; Lac Repressors; Liver - drug effects; Liver - pathology; Liver Neoplasms, Experimental - chemically induced; Medical sciences; Miscellaneous (drug allergy, mutagens, teratogens...); Mutagens - toxicity; Mutation; Organ Size - drug effects; Pharmacology. Drug treatments; Phenobarbital - toxicity; Promotion; Rats; Rats, Inbred F344; Repressor Proteins - genetics; Tamoxifen; Tamoxifen - toxicity; Transgenic
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/S0304-3835(00)00627-3

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to female lambda/ lacI transgenic rats caused a 4-fold increase in mutation frequency (MF) at the lacI gene locus in the livers of dosed animals compared with controls. After cessation of dosing, the MF showed a further increase with time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of similarly treated animals resulted in no increase in mutation frequency compared with TAM alone. Treatment with phenobarbital or TAM+phenobarbital resulted in time-dependent increases in liver weight compared with the corresponding controls. There was an increase in cell proliferation in the phenobarbital and TAM+phenobarbital groups, and at 24 weeks in the TAM dosed animals compared with controls. There was also a progressive increase in the number of GST-P expressing foci in the livers of TAM and TAM + phenobarbital rats compared with controls. The induction of cell proliferation and GSTP foci in the rat liver by phenobarbital is consistent with its ability to promote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regarded as being representative of the rat genome in general (albeit that the gene is bacterial) the above observations suggest that promotion by tamoxifen confers selective advantage on mutated genes at loci that contribute to the tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation.