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Vol. 30, Issue 5, 608-612, May 2002
Division of Pharmaceutical Sciences, College of Pharmacy, and
Department of Molecular and Cellular Physiology, University of
Cincinnati Medical Center, Cincinnati, Ohio (P.B.D., S.C.N., R.S.S.,
D.J.B., A.R.B.); and Departments of High-Throughput Biology and Systems
Research, GlaxoSmithKline Inc., Research Triangle Park, North Carolina
(L.B.M., B.J.G.)
Tamoxifen is a widely utilized antiestrogen in the treatment and
chemoprevention of breast cancer. Clinical studies document that
tamoxifen administration markedly enhances the systemic elimination of
other drugs. Additionally, tamoxifen enhances its own clearance following repeated dosing. The mechanisms that underlie these clinically important events remain unresolved. Here, we report that
tamoxifen and its metabolite 4-hydroxytamoxifen markedly induce
cytochrome P450 3A4, a drug-metabolizing enzyme of central importance, in primary cultures of human hepatocytes. Tamoxifen and
4-hydroxytamoxifen (1-10 µM) significantly increased the CYP3A4 expression and activity (measured as the rate of testosterone 6
-hydroxylation). Maximal induction was achieved at the 5 µM level. At this level, tamoxifen and 4-hydroxytamoxifen caused a 1.5- to
3.3-fold (mean, 2.1-fold) and 3.4- to 17-fold (mean, 7.5-fold) increase
in the CYP3A4 activity, respectively. In comparison, rifampicin
treatment resulted in a 6- to 16-fold (mean, 10.5-fold) increase. We
also observed corresponding increase in the CYP3A4 immunoreactive
protein and mRNA levels. Furthermore, tamoxifen and 4-hydroxytamoxifen
efficaciously activated the human pregnane X receptor (hPXR; also known
as the steroid xenobiotic receptor), a key regulator of
CYP3A4 expression. The efficacy of tamoxifen and
4-hydroxytamoxifen relative to rifampicin for hPXR activation was ~30
and 60%, respectively. Our results indicate that the mechanism of
tamoxifen-mediated alteration in drug clearance pathways in humans may
involve CYP3A4 induction by the parent drug and/or its
metabolite. Furthermore, the CYP3A4 induction may be a result of hPXR
activation. These findings have important implications for optimizing
the use of tamoxifen and in the development of newer antiestrogens.
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