Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus

This study compares the actions of oestradiol, tamoxifen, toremifene and ra loxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxyla se by the compounds showed a rapid biphasic response, while for creatine ki nase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest i nduction level, followed by tamoxifen or toremifene and then raloxifene. RT -PCP, demonstrated that all compounds decreased oestrogen receptor (ER,) al pha, ER beta and ER beta2 gene expression, 8-24 h after the first dose, sug gesting that down-regulation of ER is not the primary cause of the differen ce in efficacy between these compounds. Using cDNA arrays, expression of 51 2 genes was examined in the uteri of oestradiol- or tamoxifen- treated rats . Both compounds resulted in the up-regulation of heat-shock protein 27, te lomerase-associated protein 1 and secretin. However, most surprising was th e marked downregulation of Wilms' tumour and retinoblastoma genes. We specu late that this may result in a loss of regulation of the transition from th e G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.