DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumour formation.
Tamoxifen was administered in the diet (420 p.p.m.) to female F344 (Fischer), Wistar (LAC-P) and LEW (Lewis) rats to determine for each strain the early morphological and biochemical changes associated with the subsequent development of liver cancer. Hepatic DNA damage, as determined by 32P-postlabelling, showed a cumulative increase with time from 500 adducts/10(8) nucleotides at 30 days to almost 3000 adducts/10(8) nucleotides after 180 days, with little difference between strains at this time point. A significant strain difference was found in the number of adducts present in the Fischer rats at 90 days, compared to the Wistar and Lewis strains. There was a marked strain differences in the time to development of liver tumours. After 6 months treatment, both Wistar and Lewis rats had tumours while none were seen in the Fischer animals. After 11 months, all of the Wistar and Lewis rats had developed liver carcinoma, while the Fischer rats developed liver carcinoma by 20 months. Depression in cell proliferation, relative to age-matched controls, was seen in the livers of Fischer rats after six months of exposure to tamoxifen, in contrast to an increase in the Wistar and Lewis rats. This observation is consistent with the promotion of foci to tumours and the subsequent progression of tumours to carcinomas in the latter two strains. These data may assist in establishing the possible risk factors, such as extent of DNA damage and increased liver cell proliferation, to women with long-term prophylactic exposure to tamoxifen.
Carthew
P
P
MRC Toxicology Unit, University of Leicester, UK.
Rich
K J
KJ
Martin
E A
EA
De Matteis
F
F
Lim
C K
CK
Manson
M M
MM
Festing
M F
MF
White
I N
IN
Smith
L L
LL
D000818:Animals; D002455:Cell Division; D004247:DNA / Q000096:biosynthesis; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D005260:Female; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced*; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D017208:Rats, Wistar; D013629:Tamoxifen / Q000378:metabolism / Q000633:toxicity*; D013997:Time Factors
D018736:DNA Adducts; D013629:Tamoxifen; D004247:DNA