PT  - JOURNAL ARTICLE
AU  - Pankaj B. Desai
AU  - Srikanth C. Nallani
AU  - Rucha S. Sane
AU  - Linda B. Moore
AU  - Bryan J. Goodwin
AU  - Donna J. Buckley
AU  - Arthur R. Buckley
TI  - Induction of Cytochrome P450 3A4 in Primary Human Hepatocytes and Activation of the Human Pregnane X Receptor by Tamoxifen and 4-Hydroxytamoxifen
AID  - 10.1124/dmd.30.5.608
DP  - 2002 May 01
TA  - Drug Metabolism and Disposition
PG  - 608--612
VI  - 30
IP  - 5
4099  - http://dmd.aspetjournals.org/content/30/5/608.short
4100  - http://dmd.aspetjournals.org/content/30/5/608.full
SO  - Drug Metab Dispos2002 May 01; 30
AB  - 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 6β-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 ofCYP3A4 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. The American Society for Pharmacology and Experimental Therapeutics