Tamoxifen activates CYP3A4 and MDR1 genes through steroid and xenobiotic receptor in breast cancer cells.
Cytochrome P450 monooxygenase 3A4 (CYP3A4) and P-glycoprotein, encoded by multidrug resistance 1 (MDR1) gene, are responsible for the metabolism of endogenous steroids, prescribed drugs, and xenobiotics. Both genes are regulated by steroid and xenobiotic receptor (SXR), a member of nuclear hormone receptors. Various endogenous steroids and drugs function as ligands of SXR. Although CYP3A4, MDR1, and SXR are expressed mainly in the liver and the small intestine, these gene products are also expressed in breast cancer cells. Because tamoxifen (TAM) is known to be metabolized by CYP3A4 and P-glycoprotein, we investigated the effect of TAM on these SXR-targeted genes in breast cancer cells. Transient transfection-based reporter gene assays showed 4-hydroxy TAM activated the SXR-mediated transcription through CYP3A4 and MDR1 promoters in a ligand- and receptor concentration-dependent manner. We confirmed the binding of 4-hydroxy TAM to SXR by ligand binding assay. Moreover, semiquantitative RT-PCR studies revealed that 4-hydroxy TAM activated the expression of CYP3A4 and MDR1 mRNA in MCF-7 cells. These results suggest that TAM induces CYP3A4 and MDR1 gene expression through SXR, which may affect TAM metabolic pathway in breast cancer cells.
Nagaoka
Rin
R
Department of Integrative Physiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
Iwasaki
Toshiharu
T
Rokutanda
Nana
N
Takeshita
Akira
A
Koibuchi
Yukio
Y
Horiguchi
Jun
J
Shimokawa
Noriaki
N
Iino
Yuichi
Y
Morishita
Yasuo
Y
Koibuchi
Noriyuki
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000230:Adenocarcinoma / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004965:Estrogen Antagonists / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D019450:Genes, MDR; D006801:Humans; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism / Q000502:physiology*; D047488:Retinoid X Receptors / Q000378:metabolism; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000378:metabolism*; D014158:Transcription, Genetic
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018931:Antineoplastic Agents, Hormonal; D004965:Estrogen Antagonists; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D013629:Tamoxifen; C016601:afimoxifene; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human