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Research ArticleENDOCRINE AND REPRODUCTIVE

Persistent Suppression of Hepatic CYP2A1 Expression and Serum Triiodothyronine Levels by Tamoxifen in Intact Female Rats: Dose-Response Analysis and Comparison with 4-Hydroxytamoxifen, Fulvestrant (ICI 182,780), and 17β-Estradiol-3-benzoate

Ludger M. Ickenstein and Stelvio M. Bandiera
Journal of Pharmacology and Experimental Therapeutics August 2002, 302 (2) 584-593; DOI: https://doi.org/10.1124/jpet.102.034744
Ludger M. Ickenstein
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Stelvio M. Bandiera
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Abstract

Tamoxifen, a nonsteroidal antiestrogen, is used widely in the treatment of breast cancer and is undergoing evaluation as a chemopreventive agent. In this study, we investigated several long-term effects of tamoxifen in intact adult female rats following acute treatment at various dosages. The effects of tamoxifen on somatic growth, growth hormone (GH) levels, thyroid hormone levels, and on hepatic cytochrome P450 (P450) expression were compared with those of fulvestrant (ICI 182,780), 17β-estradiol-3-benzoate, and 4-hydroxytamoxifen under the same experimental conditions. Each compound was injected s.c. for two consecutive days, and rats were killed 37 days after treatment. Tamoxifen decreased body weight and serum triiodothyronine (T3) levels at dosages ranging from 0.5 to 200 mg/kg. Ovary weight, uterus weight, peak plasma GH concentration, and hepatic CYP2A1 content were decreased 37 days after treatment with tamoxifen at a dosage of 20 mg/kg, but expression of other P450 enzymes was not affected. However, tamoxifen and 4-hydroxytamoxifen could not be detected in plasma by high performance liquid chromatography analysis at this time, which suggests that the effects of tamoxifen were mediated indirectly. 4-Hydroxytamoxifen exhibited effects similar to those of tamoxifen, indicating that this metabolite contributes to the in vivo activity of tamoxifen. Estradiol benzoate decreased CYP2A1 and increased CYP3A hepatic levels, but had no effect on serum T3 concentration. In contrast, treatment with ICI 182,780 had little or no effect on the endpoints measured. In summary, 2-day tamoxifen treatment of intact adult female rats resulted in persistent suppression of somatic growth, serum T3 levels, and hepatic CYP2A1 expression.

Footnotes

  • ↵1 Current address: British Columbia Cancer Agency, 601 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 4E6.

  • This work was funded by a grant from the Medical Research Council of Canada (MT-13479).

  • Results of the study were presented in part at the 38th Annual Meeting of the Society of Toxicology, New Orleans, LA, March 14–18, 1999.

  • DOI: 10.1124/jpet.102.034744

  • Abbreviations:
    P450
    cytochrome P450
    GH
    growth hormone
    HPLC
    high performance liquid chromatography
    PAGE
    polyacrylamide gel electrophoresis
    T3
    triiodothyronine
    T4
    thyroxine
    • Received February 18, 2002.
    • Accepted April 29, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 302 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 302, Issue 2
1 Aug 2002
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Persistent Suppression of Hepatic CYP2A1 Expression and Serum Triiodothyronine Levels by Tamoxifen in Intact Female Rats: Dose-Response Analysis and Comparison with 4-Hydroxytamoxifen, Fulvestrant (ICI 182,780), and 17β-Estradiol-3-benzoate
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Research ArticleENDOCRINE AND REPRODUCTIVE

Persistent Suppression of Hepatic CYP2A1 Expression and Serum Triiodothyronine Levels by Tamoxifen in Intact Female Rats: Dose-Response Analysis and Comparison with 4-Hydroxytamoxifen, Fulvestrant (ICI 182,780), and 17β-Estradiol-3-benzoate

Ludger M. Ickenstein and Stelvio M. Bandiera
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 584-593; DOI: https://doi.org/10.1124/jpet.102.034744

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Research ArticleENDOCRINE AND REPRODUCTIVE

Persistent Suppression of Hepatic CYP2A1 Expression and Serum Triiodothyronine Levels by Tamoxifen in Intact Female Rats: Dose-Response Analysis and Comparison with 4-Hydroxytamoxifen, Fulvestrant (ICI 182,780), and 17β-Estradiol-3-benzoate

Ludger M. Ickenstein and Stelvio M. Bandiera
Journal of Pharmacology and Experimental Therapeutics August 1, 2002, 302 (2) 584-593; DOI: https://doi.org/10.1124/jpet.102.034744
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