他莫昔芬药物基因组学研究进展  

Advances in the research of pharmacogenomics of tamoxifen

作　　者：熊巍[1,2] 赵佳佳[1] 王凌[1] 蒋学华[1] 陶晓秋 

机构地区：[1]四川大学华西药学院,四川成都610041 [2]四川省烟草质量监督检测站,四川成都610041

出　　处：《药学学报》2016年第9期1356-1367,共12页Acta Pharmaceutica Sinica

摘　　要：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） is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite （4-hydroxytamoxifen, 4-OH-TAM） and endoxifen （EDF）, which played a critical role in the therapy. 4-OH-TAM and EDF have 30- to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. CYP3A4 and CYP2D6, as the key drug-metabolizing enzymes in those metabolic actions, are known to have several alleles. Genetic polymorphisms of CYP2D6 and CYP3A4 will influence the plasma concentrations of active TAM metabolites and clinical outcomes for breast cancer patients treated with TAM. The genetic polymorphisms of drug transporters, involved in the disposition of active TAM metabolites, also have the potential to influence the plasma concentrations of active TAM metabolites and clinical outcome for the treatment of breast cancer. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of TAM with the metabolite concentration, efficacy and adverse effects of TAM, which provides a fundamental reference for further pharrnacogenomic study and clinical use of TAM.

关 键 词：4-羟基他莫昔芬 N-去甲基-4-羟基-他莫昔芬 基因多态性 CYP3A4 CYP2D6 P-糖蛋白 乳腺癌耐药蛋白 多药抗性相关蛋白 

分 类 号：R968[医药卫生—药理学]