title: Comparisons of the effects of tamoxifen, toremifene and raloxifene on enzyme induction and gene expression in the ovariectomised rat uterus.
abstract: 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.
authors.affiliation: MRC Centre for Mechanisms of Human Toxicity, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK. ag41@le.ac.uk
authors.forename: A R
authors.initials: AR
authors.lastname: Green
authors.forename: E L
authors.initials: EL
authors.lastname: Parrott
authors.forename: M
authors.initials: M
authors.lastname: Butterworth
authors.forename: P S
authors.initials: PS
authors.lastname: Jones
authors.forename: P
authors.initials: P
authors.lastname: Greaves
authors.forename: I N
authors.initials: IN
authors.lastname: White
mesh_terms: 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
chemical_list: 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