文章：

CYP2D6和他莫昔芬：DNA在乳腺癌中的作用

CYP2D6 and tamoxifen: DNA matters in breast cancer

原文发布日期：2009-08-01

DOI: 10.1038/nrc2683

类型: Review Article

开放获取: 否

要点：

1. The selective oestrogen receptor modulator tamoxifen is the most widely used antioestrogen for the treatment of hormone-dependent breast cancer.
2. Hepatic, drug-metabolizing cytochrome P450s (CYPs) catalyse the oxidation of tamoxifen to several metabolites. The metabolites, endoxifen and 4-hydroxytamoxifen, have greater binding affinities for oestrogen receptors and suppress cell proliferation more effectively than tamoxifen does. Plasma concentrations of endoxifen are considerably higher than those of 4-hydroxytamoxifen, suggesting that endoxifen is the main pharmacologically active species of tamoxifen in vivo. The conversion of tamoxifen to endoxifen is predominantly catalysed by CYP2D6.
3. Many polymorphisms in CYP2D6 have been identified. In Caucasian populations, 6–10% of people inherit two alleles containing polymorphisms and/or a gene deletion, leading to no protein expression or the expression of a protein with no CYP2D6 enzymatic activity. These individuals have impaired metabolism of CYP2D6 substrates and are called poor metabolizers of CYP2D6. Some drugs, such as the antidepressants fluoxetine or paroxetine, are potent inhibitors of CYP2D6 and can confer a poor metabolizer phenotype on individuals with normal CYP2D6 activity.
4. The findings of pharmacokinetic studies indicate that the conversion of endoxifen is reduced in poor metabolizers of CYP2D6, either by genotype or by co-prescribed fluoxetine or paroxetine, which are commonly prescribed to manage hot flashes.
5. Recent data suggest that poor metabolizers of CYP2D6 do not derive as much benefit from tamoxifen therapy as other patients do; however, some studies have yielded conflicting results.
6. The analysis of CYP2D6 genotype might represent an early example of a pharmacogenetic tool for optimizing breast cancer therapy; however, the findings of larger, well-designed studies that support the current data are necessary before a change in clinical practice is advocated.

要点翻译：

1. 选择性雌激素受体调节剂他莫昔芬是治疗激素依赖性乳腺癌最广泛使用的抗雌激素药物。
2. 肝脏药物代谢细胞色素P450酶（CYPs）催化他莫昔芬氧化为多种代谢物。代谢产物endoxifen和4-羟他莫昔芬与雌激素受体的结合亲和力高于他莫昔芬，抑制细胞增殖的效果也更显著。endoxifen的血浆浓度显著高于4-羟他莫昔芬，表明endoxifen是他莫昔芬在体内的主要药理活性成分。他莫昔芬向endoxifen的转化主要由CYP2D6催化。
3. CYP2D6存在多种已知基因多态性。在高加索人群中，6-10%的个体遗传了两个含多态性等位基因和/或基因缺失，导致无法表达蛋白或表达无CYP2D6酶活性的蛋白。这类个体对CYP2D6底物的代谢能力受损，被称为CYP2D6弱代谢者。某些药物（如抗抑郁药氟西汀或帕罗西汀）是CYP2D6强效抑制剂，可使具有正常CYP2D6活性的个体呈现弱代谢者表型。
4. 药代动力学研究表明，无论是因基因型导致，还是因联合使用常用于控制潮热的氟西汀或帕罗西汀所致，CYP2D6弱代谢者体内endoxifen的转化率均会降低。
5. 最新数据表明，CYP2D6弱代谢者从他莫昔芬治疗中获得的疗效不及其他患者，但部分研究得出了相互矛盾的结果。
6. CYP2D6基因型分析可能成为优化乳腺癌治疗的早期药物遗传学工具范例，但当前临床实践的变革仍需获得更多设计严谨的大型研究数据支持。

英文摘要：

Tamoxifen is the most widely used anti-oestrogen for the treatment of hormone-dependent breast cancer. The pharmacological activity of tamoxifen is dependent on its conversion by the hepatic drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6) to its abundant metabolite, endoxifen. Patients with reduced CYP2D6 activity, as a result of either their genotype or induction by the co-administration of drugs that inhibit CYP2D6 function, produce little endoxifen and seem to derive inferior therapeutic benefit from tamoxifen. Here we review the existing data that relate CYP2D6 genotypes to response to tamoxifen and discuss whether the analysis of the CYP2D6 genotype might be an early example of a pharmacogenetic tool for optimizing breast cancer therapy.

摘要翻译： 

他莫昔芬是治疗激素依赖性乳腺癌最常用的抗雌激素药物。其药理活性依赖于通过肝脏药物代谢酶细胞色素P450 2D6（CYP2D6）转化为其主要活性代谢产物——恩度昔芬。CYP2D6活性降低的患者，无论是由于基因型还是因合用抑制CYP2D6功能的药物，其体内恩度昔芬生成减少，似乎从他莫昔芬治疗中获益较少。本文回顾了现有关于CYP2D6基因型与他莫昔芬疗效关系的数据，并探讨CYP2D6基因型分析是否可能成为优化乳腺癌治疗的早期药物遗传学工具。

原文链接：

CYP2D6 and tamoxifen: DNA matters in breast cancer