UBC Theses and Dissertations
Influence of tamoxifen on hormonally regulated cytochrome P450 enzyme expression in rats Ickenstein, Ludger Markus
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.
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