Quantifiable mRNA transcripts for tamoxifen-metabolising enzymes in human endometrium

Abstract 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 m...

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Bibliographic Details
Published in:Toxicology (Amsterdam) 2008-07, Vol.249 (1), p.85-90
Main Authors: Singh, Maneesh N, Stringfellow, Helen F, Walsh, Michael J, Ashton, Kate M, Paraskevaidis, Evangelos, Abdo, Khalil R, Martin-Hirsch, Pierre L, Phillips, David H, Martin, Francis L
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Antineoplastic Agents, Hormonal - pharmacokinetics
Biological and medical sciences
Biotransformation
Carcinoma - enzymology
Carcinoma - genetics
CYP3A4
Cytochrome P-450 Enzyme System - genetics
Cytochrome P-450 Enzyme System - metabolism
Emergency
Endometrial carcinoma
Endometrial Neoplasms - enzymology
Endometrial Neoplasms - genetics
Endometrium - enzymology
Female
Female genital diseases
Gene Expression Regulation, Neoplastic
Genotoxic
Gynecology. Andrology. Obstetrics
Humans
Medical sciences
Middle Aged
RNA, Messenger - metabolism
Selective oestrogen receptor modulator
Sulfotransferases - genetics
Sulfotransferases - metabolism
SULT2A1
Tamoxifen
Tamoxifen - pharmacokinetics
Toxicology
Tumors
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Summary:Abstract 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.
ISSN:0300-483X
1879-3185
DOI:10.1016/j.tox.2008.04.009