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Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications

Sane, Rucha S.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

Abstract Details

2006, PhD, University of Cincinnati, Pharmacy : Pharmaceutical Sciences.
Tamoxifen is a widely used antiestrogen in the treatment and prevention of breast cancer. Some of its unresolved problems include the occurrence of drug-drug interactions, acquired resistance and endometrial carcinogenesis. Here we hypothesized that tamoxifen and/or its metabolites induce drug metabolizing enzymes and transporters and these inductive effects entail activation of the human pregnane X receptor (hPXR). First, we evaluated the activity and expression of key phase I and II enzymes, Cytochrome P450 (CYP) 3A4 and UDP-Glucuronyltransferase and drug transporter, P-glycoprotein, in primary human hepatocytes and LS174T colon carcinoma cell line. Tamoxifen and 4-hydroxytamoxifen (4-OHT) exhibited significant induction of CYP3A4 and moderate induction of UGT1A1 and P-gp in hepatocytes. In LS174T cells tamoxifen/4OHT moderately induced UGT1A1 and P-gp but failed to induce CYP3A4. This apparent tissue-specific difference in CYP3A4 induction by tamoxifen may be related to the observed differences in the expression of transcription factors such as hPXR and glucocorticoid receptor in (GRá) these cells. Next, in promoter-reporter assays we observed that tamoxifen/4-OHT are efficient activators of hPXR. Attenuation of hPXR in human hepatocytes employing siRNA against hPXR caused a corresponding decrease in the extent of CYP3A4 induction indicating that induction by tamoxifen/4-OHT primarily results from their interactions with hPXR. Examination of the role of other receptors revealed that GRá potentiates hPXR mediated CYP3A4 promoter activation by the antiestrogens. However, activated estrogen receptor appeared to suppress the basal transcription of CYP3A4 in these assays. Based on our pre-clinical data, we initiated a clinical study to assess CYP3A4 induction in breast cancer patients who are prescribed the tamoxifen regimen (20 mg/day). Midazolam, a drug metabolized by CYP3A4, was employed as a probe for CYP3A4 activity. In four patients evaluated thus far, we have noted a distinct trend towards increased midazolam clearance, indicative of increased CYP3A4 activity, following steady state tamoxifen dosing (day 42) compared to basal CYP3A4 activity, evaluated prior to initiating tamoxifen therapy. Thus, our study suggests that tamoxifen/4-OHT upregulate CYP3A4, which has implications for optimizing the clinical use of tamoxifen and the development of new antiestrogens that do not carry the risk of drug interactions, acquired drug resistance and endometrial carcinogenesis.
Rucha Desai (Advisor)
187 p.
Health Sciences, General
Tamoxifen; CYP3A4; Cytochrome P450; Enzyme induction; drug metabolism; human hepatocytes; UDP-glucuronosyl transferase; P-glycoprotein; Pregnane X Receptor; PXR; LS174T

Recommended Citations

Citations

  • Sane, R. S. (2006). Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

    APA Style (7th edition)

  • Sane, Rucha. Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications. 2006. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615.

    MLA Style (8th edition)

  • Sane, Rucha. "Differential Induction of Drug Metabolizing Enzymes and Drug Transporters by Tamoxifen: Molecular Mechanisms and Clinical Implications." Doctoral dissertation, University of Cincinnati, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1143410615

    Chicago Manual of Style (17th edition)

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© 2006, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.