| Summary: | Tamoxifen, a widely used therapeutic agent in the treatment of breast cancer, is
known to suppress growth hormone (GH) secretion in rats and consequently may alter
hepatic levels of several cytochrome P450 (CYP) isozymes that are regulated by the pattern
of GH secretion. The present study was undertaken to examine the effect of tamoxifen on the
expression of hepatic CYP enzymes in the rat.
Tamoxifen was administered to nine adult male and female Long Evans rats at a dose
of 5 mg per rat s.c. once daily for two consecutive days while control rats received the
vehicle (peanut oil) only. Rats were killed five weeks after treatment and liver microsomes
prepared. Administration of tamoxifen resulted in a significant decrease in mean weight gain
in male and female rats compared to controls, but liver weight as a percent of body weight
was not affected. Serum estradiol levels and total CYP content of hepatic microsomes were
also unchanged. The profile of testosterone metabolites was not affected in tamoxifen-treated
male rats but was significantly (p<0.05) altered in tamoxifen-treated female rats, indicating
that tamoxifen's effects were sex-specific and hormone-mediated. Tamoxifen treatment
significantly increased testosterone 6p-hydroxylase activity and significantly decreased
testosterone 7a-hydroxylase activity but did not significantly affect j9-nitrophenol
hydroxylase or pentoxyresorufin O-depentylase activities. Immunoquantitation studies
revealed that tamoxifen treatment significantly decreased CYP2A1 levels but had no
significant effect on CYP2C7, CYP2E1 or CYP3A levels in adult female rats. Thus,
tamoxifen treatment caused a significant decrease in the expression of CYP2A1 and its
associated monooxygenase activity, but had no apparent effect on the expression of CYP3A
even though testosterone 6[3-hydroxylase activity was significantly increased. Monoclonal
antibodies against CYP3A1 and CYP3A2 were used to determine if either isozyme was
present but neither protein was detected.
In comparison, neonatal ovariectomy did not significantly affect hepatic microsomal
CYP2A1, CYP2E1 or CYP3A protein levels but significantly decreased CYP2C7 protein
levels, whereas adult estradiol treatment significantly increased hepatic expression of
CYP2A1, CYP2C7 and CYP3A and significantly decreased expression of CYP2E1 in adult
female rats. The data indicate that estradiol levels influence the expression of these
isozymes.
In conclusion, the results demonstrate that brief treatment with tamoxifen has a
prolonged effect on hepatic expression of CYP in the adult female rat and that this effect
differs from that produced by neonatal ovariectomy. The mechanism by which tamoxifen
alters CYP-mediated enzyme activity and protein levels is not apparent and requires further
study. === Pharmaceutical Sciences, Faculty of === Graduate
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