Quantifiable mRNA transcripts for tamoxifen-metabolising enzymes in human endometrium

• DOI: 10.1016/j.tox.2008.04.009
• Publication Date: 2008-04-24T14:51:57Z
• Authors: Maneesh N. Singh; Helen F. Stringfe...; Michael J. Walsh; Kate M. Ashton; Evangelos Paraske...; Khalil R. Abdo; Pierre L. Martin-...; David H. Phillips; Francis L. Martin
• Keywords: Adult; Antineoplastic Agents, Hormonal; Messenger; 610; Antineoplastic Agents; Tamoxifen/*pharmacokinetics; Cytochrome P-450 Enzyme System/*genetics/metabolism; Endometrium/*enzymology; Endometrium; 03 medical and health sciences; Endometrial Neoplasms/*enzymology/genetics; 0302 clinical medicine; Cytochrome P-450 Enzyme System; 616; RNA, Messenger/*metabolism; 80 and over; Humans; RNA, Messenger; Biotransformation; Aged; Aged, 80 and over; Neoplastic; Sulfotransferases/genetics/metabolism; Hormonal; Antineoplastic Agents, Hormonal/*pharmacokinetics; Carcinoma/*enzymology/genetics; Carcinoma; Middle Aged; Endometrial Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; Tamoxifen; Gene Expression Regulation; RNA; Female; Sulfotransferases

Tamoxifen has been used in the management of receptor-positive breast cancer for >20 years. Usage confers an elevated risk of developing endometrial carcinoma. Its mechanism of carcinogenicity remains unresolved with controversy as to whether or not this is mediated through a genotoxic mechanism. Usage is not only associated with an elevated occurrence of endometrioid endometrial carcinoma, but also type 2 and mixed epithelial-stromal tumours (MESTs) that have a poorer prognosis. Following hysterectomy, endometrial tissues (n=18) classified as benign (n=6), non-tamoxifen-associated carcinoma (n=6) and tamoxifen-associated carcinoma (n=6) were obtained; quantitative gene expression was performed. Employing real-time RT-PCR, the relative gene expressions of phase I/II metabolic enzymes CYP1A2, CYP1B1 and CYP3A4, cathechol-O-methyltransferase (COMT) and SULT2A1 were ascertained. Measurable mRNA transcripts, especially for those genes associated with tamoxifen bioactivation, were quantifiable in all the tissues examined. Whether this is evidence that generation of genotoxic tamoxifen metabolites may occur in human endometrial tissue remains to be ascertained.