Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen
Induction of cytochrome P450 3A4 in primary human hepatocytes and activation of the human pregnane X receptor by tamoxifen and 4-hydroxytamoxifen
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DOI：
10.1124/dmd.30.5.608
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发表时间：
2002-05-01
影响因子：
3.9
通讯作者：
Buckley, AR
中科院分区：
文献类型：
--
作者：
Desai, PB;Nallani, SC;Buckley, AR
他莫昔芬是一种广泛用于治疗和化学预防乳腺癌的抗雌激素。临床研究证明，他莫昔芬给药显著增强了其他药物的全身消除。此外，他莫昔芬在重复给药后增强其自身的清除率。这些具有临床意义的事件的潜在机制仍未得到解决。在这里，我们报告说，他莫昔芬及其代谢产物4-羟基他莫昔芬显着诱导细胞色素P450 3A 4，药物代谢酶的核心重要性，在原代培养的人肝细胞。他莫昔芬和4-羟基他莫昔芬（1-10 μ M）显著增加CYP 3A 4的表达和活性（以睾酮6 β-羟基化的速率测量）。在5 μ M水平达到最大诱导。在该水平下，他莫昔芬和4-羟基他莫昔芬分别导致CYP 3A 4活性增加1.5- 3.3倍（平均2.1倍）和3.4- 17倍（平均7.5倍）。相比之下，利福平治疗导致6- 16倍（平均10.5倍）增加。我们还观察到CYP 3A 4免疫反应性蛋白和mRNA水平相应增加。此外，他莫昔芬和4-羟基他莫昔芬有效地激活了人甾烷X受体（hPXR;也称为类固醇异生素受体），这是CYP 3A 4表达的关键调节因子。他莫昔芬和4-羟基他莫昔芬相对于利福平对hPXR激活的有效性分别为30%和60%。我们的研究结果表明，他莫昔芬介导的药物清除途径在人类中的改变的机制可能涉及CYP 3A 4诱导的母体药物和/或其代谢产物。此外，CYP 3A 4诱导可能是hPXR激活的结果。这些发现对优化他莫昔芬的使用和开发新的抗雌激素药物具有重要意义。
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 muM) significantly increased the CYP3A4 expression and activity (measured as the rate of testosterone 6beta-hydroxylation). Maximal induction was achieved at the 5 muM 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 similar to30 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.