Effect of tamoxifen on hepatic cytochrome P450 expression in adult female rats

• Main Author: Holsmer, Susan Lorraine
• Format: Others
• Language: English
• Published: 2009
• Online Access: http://hdl.handle.net/2429/3575

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