| Summary: | Tamoxifen, a partial estrogen antagonist in humans, is used widely in the treatment of breast
cancer and suppresses growth hormone plasma levels in rats up to seven weeks after treatment.
The purpose of the present study was to determine if tamoxifen treatment results in long-term
alterations of hormonally regulated cytochrome P450 enzymes.
Female rats were injected subcutaneously with tamoxifen at 0.5, 5, 20, 50, 100, or 200 mg/kg
for two consecutive days. Male rats were injected subcutaneously with tamoxifen at 200 mg/kg
for two consecutive days. Blood samples were taken at regular time intervals. Rats were killed
36 days after treatment and hepatic microsomes were prepared.
Administration of tamoxifen decreased body weight gain in male and female rats.
Testosterone 7α-hydroxylase activity and cytochrome P450 2A1 content were decreased in
hepatic microsomes from tamoxifen treated female rats by 40% and 35%, respectively. In
hepatic microsomes from tamoxifen treated male rats, testosterone 7α-hydroxylase activity was
increased by 70% and testosterone 2a- and 16oc-hydroxylase activities and cytochrome P450
2C11 content was decreased by approximately 44% and 30%, respectively.
Administration of tamoxifen decreased peak growth hormone plasma levels in male and
female rats, but did not affect the average and nadir growth hormone plasma levels.
In plasma of rats treated at 50 mg/kg, tamoxifen was detected at one day and at twelve days
after treatment but not at 24 or 36 days after treatment. 4-Hydroxytamoxifen was detected at one
and twelve days after treatment. In plasma of rats treated with tamoxifen at a dosage of 200
mg/kg, 4-hydroxytamoxifen was detected up to 36 days after treatment.
The results of the present study indicate that tamoxifen treatment suppressed body weight
gain, blunted peak growth hormone plasma levels, and resulted in long-term alterations of specific hepatic cytochrome P450 enzymes in male and female rats. These effects are different
from the previously reported direct, short-term effects of tamoxifen on hepatic cytochrome P450
2B and 3A enzymes. The effects of tamoxifen on cytochrome P450 enzymes are not believed to
be mediated solely by the effects of tamoxifen on growth hormone plasma levels. More likely,
the effects of tamoxifen on cytochrome P450 enzymes were caused by its estrogenic or
antiestrogenic effects. Alternatively, the effects could have been caused by a residual tamoxifen
metabolite that remained in rat tissues at concentrations below the limits of quantitation of the
HPLC assay. === Pharmaceutical Sciences, Faculty of === Graduate
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