Tamoxifen causes gene mutations in the livers of lambda/lacI transgenic rats.
Tamoxifen, a rat liver carcinogen, was administered to female lambda/lacI 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 induced liver DNA adducts and caused a significant increase in mutation frequency (MF) of approximately 3-fold at the lacI gene in liver DNA. Liver DNA from animals dosed with tamoxifen at 10 mg/kg also showed a similar increase in MF. The mutations were characterized by a raised proportion 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 indicate that tamoxifen induces a distinct spectrum of mutations compared with that found in controls. Toremifene, a noncarcinogenic analogue of tamoxifen with similar estrogenic/antiestrogenic properties examined at 20 mg/kg body weight using the same dosing regime as tamoxifen was not mutagenic. A single oral dose of the rat liver carcinogen aflatoxin B1 (0.5 mg/kg) also significantly raised the MF. In conclusion, although tamoxifen is not mutagenic in regulatory short-term tests, it is a gene mutagen in the rat liver.
Davies
R
R
MRC Toxicology Unit, University of Leicester, United Kingdom.
Oreffo
V I
VI
Martin
E A
EA
Festing
M F
MF
White
I N
IN
Smith
L L
LL
Styles
J A
JA
D000348:Aflatoxins / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D018736:DNA Adducts / Q000378:metabolism; D005260:Female; D008099:Liver / Q000737:chemistry*; D009152:Mutagenicity Tests; D009153:Mutagens / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013629:Tamoxifen / Q000494:pharmacology*; D017312:Toremifene / Q000494:pharmacology
D000348:Aflatoxins; D018736:DNA Adducts; D009153:Mutagens; D013629:Tamoxifen; D017312:Toremifene