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 raloxifene on enzyme and gene expression in uterine tissues of ovariectomised rats over 72 h. The time-course for the induction of ornithine decarboxylase by the compounds showed a rapid biphasic response, while for creatine kinase brain type (BB) there was a continued increase over 72 h. The efficacy of induction showed that, with both markers, oestradiol gave the highest induction level, followed by tamoxifen or toremifene and then raloxifene. RT-PCR demonstrated that all compounds decreased oestrogen receptor (ER) alpha, ERbeta and ERbeta2 gene expression, 8-24 h after the first dose, suggesting that down-regulation of ER is not the primary cause of the difference in efficacy between these compounds. Using cDNA arrays, expression of 512 genes was examined in the uteri of oestradiol- or tamoxifen-treated rats. Both compounds resulted in the up-regulation of heat-shock protein 27, telomerase-associated protein 1 and secretin. However, most surprising was the marked down-regulation of Wilms' tumour and retinoblastoma genes. We speculate that this may result in a loss of regulation of the transition from the G1 to the S phase in the cell cycle and may make cells more vulnerable to the carcinogenic effects of tamoxifen in this tissue.
Green
A R
AR
MRC Centre for Mechanisms of Human Toxicity, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK. ag41@le.ac.uk
Parrott
E L
EL
Butterworth
M
M
Jones
P S
PS
Greaves
P
P
White
I N
IN
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D018929:Cell Culture Techniques; D003402:Creatine Kinase / Q000378:metabolism; D052276:Creatine Kinase, BB Form; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology; D017312:Toremifene / Q000494:pharmacology; D014599:Uterus / Q000187:drug effects* / Q000201:enzymology
D018931:Antineoplastic Agents, Hormonal; D007527:Isoenzymes; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; D020849:Raloxifene Hydrochloride; D004958:Estradiol; D017312:Toremifene; D003402:Creatine Kinase; D052276:Creatine Kinase, BB Form; D009955:Ornithine Decarboxylase