Expression of cytochrome P450 genes encoding enzymes active in the metabolism of tamoxifen in human uterine endometrium.
Long-term tamoxifen therapy is associated with increased risk of uterine endometrial cancer and benign alterations. Tamoxifen is metabolized to reactive intermediates by endometrial tissue, and tamoxifen therapy-induced DNA adducts have been found in human endometrium. Since metabolic activation is often catalyzed by cytochrome P450 (CYP) enzymes, the expression profile of individual xenobiotic-metabolizing CYP genes was studied in human uterine endometrium by reverse transcriptase-polymerase chain reaction. The following CYP mRNAs were detected: CYP2B6, CYP2C, CYP2E1, CYP3A4, CYP3A5, CYP4B1, and CYP11A. Amplification of CYP1A1, CYP1A2, CYP2A6, CYP2D6, CYP2F1, CYP3A7, and CYP19 was not found. CYP3A5 and CYP4B1 transcripts were found only in samples from premenopausal women. These data suggest that the human endometrial epithelium has the potential of producing CYP enzymes known to generate genotoxic intermediates from tamoxifen and metabolites that affect oestrogen receptors.
Hukkanen
J
J
Department of Pharmacology and Toxicology, University of Oulu, Finland.
Mäntylä
M
M
Kangas
L
L
Wirta
P
P
Hakkola
J
J
Paakki
P
P
Evisalmi
S
S
Pelkonen
O
O
Raunio
H
H
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism*; D015139:Blotting, Southern; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004717:Endometrium / Q000201:enzymology*; D004965:Estrogen Antagonists / Q000378:metabolism*; D005260:Female; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger; D013629:Tamoxifen / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D012333:RNA, Messenger; D013629:Tamoxifen; D003577:Cytochrome P-450 Enzyme System