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他莫昔芬(tamoxifen,TAM)作为最常用的非甾体类抗雌激素药物,广泛用于雌激素受体/孕激素受体阳性的乳腺癌患者的辅助治疗。TAM主要通过肝脏的细胞色素P450酶代谢为活性产物4-羟基他莫昔芬(4-OHTAM)和N-去甲基-4-羟基-他莫昔芬(EDF),从而发挥药理作用。4-OH-TAM和EDF与受体结合的能力比TAM高30至100倍,从而能够有效的抑制雌激素受体依赖的乳腺癌细胞的细胞周期。CYP3A4和CYP2D6作为TAM主要代谢酶参与其代谢形成活性代谢物,这两种细胞色素酶都具有等位基因多的特点。CYP3A4和CYP2D6的基因多态性会影响TAM在患者体内的活性代谢物的血药浓度,从而可能会影响其治疗效果。参与TAM体内过程的主要转运体的基因多态性也会影响TAM在患者体内的血药浓度,进而影响接受TAM治疗的乳腺癌患者的临床预后效果。本文总结了TAM体内过程相关的代谢酶及转运体等的基因多态性与TAM活性代谢物浓度/疗效/不良反应的相关性,为进一步的药物基因组学研究以及临床合理用药提供参考。
Tamoxifen (TAM), the most commonly used non-steroidal antiestrogen, is widely used in the adjuvant treatment of estrogen receptor / progesterone receptor-positive breast cancer patients. TAM is metabolized mainly by the liver’s cytochrome P450 enzyme to the active products 4-hydroxytamoxifen (4-OHTAM) and N-desmethyl-4-hydroxy-tamoxifen (EDF) to exert pharmacological effects. The ability of 4-OH-TAM and EDF to bind to receptors is 30 to 100 times greater than that of TAM, thereby effectively inhibiting the cell cycle of estrogen receptor-dependent breast cancer cells. CYP3A4 and CYP2D6, as the main metabolizing enzymes of TAM, are involved in the metabolism of CYP3A4 and CYP2D6 to form active metabolites. Both cytochromes have the characteristics of many alleles. Genetic polymorphisms of CYP3A4 and CYP2D6 affect the plasma concentrations of active metabolites of TAM in patients and may affect their therapeutic efficacy. Genetic polymorphisms of the major transporters involved in TAM processes also affect the plasma concentration of TAM in patients and thus the clinical outcome of breast cancer patients receiving TAM. This article summarizes the correlation between TAM in vivo process-related metabolic enzymes and transporters and other genetic polymorphisms and the concentration of active metabolites / efficacy / adverse reactions of TAM, providing reference for further pharmacogenomic research and clinical rational drug use.