Carcinogenesis, Vol 18, 303-313, Copyright © 1997 by Oxford University Press
JA Styles, A Davies, R Davies, IN White and LL Smith
Tamoxifen and its analogues 4-hydroxytamoxifen, toremifene, 4-
hydroxytoremifene, clomifene and droloxifene were tested for clastogenic
effects in a human lymphoblastoid cell line (MCL-5) expressing elevated
native CYP1A1 and containing transfected CYP1A2, CYP2A6, CYP2E1 and CYP3A4
and epoxide hydrolase and in a cell line containing only the viral vector
(Ho1). MCL-5 or Ho1 cells were incubated with 4-hydroxytamoxifen,
4-hydroxytoremifene, clomifene or droloxifene and the incidence of
micronuclei estimated. With MCL-5 cells there was an increase in
micronuclei with 4-hydroxytamoxifen, 4- hydroxytoremifene and clomifene but
not with droloxifene. With Ho1 cells only 4-hydroxytamoxifen and
4-hydroxytoremifene caused an increase in micronuclei. MCL-5 cells were
incubated with tamoxifen, 4- hydroxytamoxifen, toremifene, droloxifene,
clomifene or diethylstilbestrol (0.25-10 microg/ml) for 48 h and subjected
to 3 h treatment with vinblastine (0.25 microg/ml) to arrest cells in
metaphase. The incidence of cells with chromosomal numerical aberrations
(aneuploidy) was increased in cells treated with tamoxifen,
4-hydroxytamoxifen, toremifene, clomifene and diethylstilbestrol but not
droloxifene. The frequency of cells with structural abnormalities
(excluding gaps) was increased in cells treated with tamoxifen and
toremifene but not 4-hydroxytamoxifen, clomifene, droloxifene or
diethylstilbestrol. The clastogenic activities of tamoxifen (35 mg/kg),
toremifene (36.3 mg/kg), droloxifene (35.2 mg/kg) and diethylstilbestrol
(25 mg/kg) were compared in groups of four female Wistar rats. Each
chemical was dissolved in glycerol formal, administered as a single dose by
gavage and hepatocytes isolated by collagenase perfusion 24 h later. The
cells were cultured in the presence of epidermal growth factor (40 ng/ml)
for 48 h, colchicine (10 microg/ml) being added for the final 3 h of
incubation. At least 100 chromosomal spreads were examined from each animal
for the presence of numerical and structural abnormalities. The incidences
of aneuploidy following treatment were: tamoxifen 81%, toremifene 46%,
droloxifene 9.6%, diethylstilbestrol 45.7%, vehicle control 5.3%. The
incidences of chromosomal structural abnormalities excluding gaps were:
tamoxifen 4.3%, toremifene 0.8%, droloxifene 0.5%, diethylstilbestrol 0.8%,
control 0.5%. The incidence of chromosomal structural aberrations excluding
gaps in the treated animals was not statistically significantly different
from controls except in the tamoxifen-treated group. Tamoxifen (35 mg/kg
per os) and toremifene (36.3 mg/kg per os) were dosed to rats for 4 weeks
and chromosomal spreads made from hepatocytes. The incidences of aneuploidy
were: tamoxifen 94%, toremifene 57%, control 6.5%. The incidences of
chromosomal aberrations excluding gaps were: tamoxifen 12%, toremifene 1%,
control 0.5%. The incidence of tamoxifen-induced chromosomal structural
abnormalities was significantly elevated compared with control levels. The
results demonstrate that tamoxifen and toremifene are the only two drugs
tested in the study that cause chromosomal structural and numerical
aberrations in vitro and tamoxifen is the only drug that induces both these
effects in rat liver cells stimulated to divide in culture following oral
dosing. Since chromosomal mutations require cell division for their
manifestation and tamoxifen is the only compound of those tested that
causes hyperplasia in the rat liver, chromosomal aberrations and aneuploidy
in the rat liver would only be expected to occur following treatment with
tamoxifen alone, although aneuploidy could be induced by toremifene in
conjunction with a promoter such as phenobarbitone.
ARTICLES
Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells)
Medical Research Council Laboratories, Toxicology Unit, University of Leicester, UK.
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