Department of Basic Biomedical Sciences, Faculty of Biomedical Sciences, Cátedra Florencio Tejerina-Universidad Europea de Madrid, Universidad Europea de Madrid, Madrid, Spain.
PLoS One. 2013 Jul 29;8(7):e70183. doi: 10.1371/journal.pone.0070183. Print 2013.
Tamoxifen is a pro-drug widely used in breast cancer patients to prevent tumor recurrence. Prior work has revealed a role of cytochrome and sulfotransferase enzymes in tamoxifen metabolism. In this descriptive study, correlations were examined between concentrations of tamoxifen metabolites and genotypes for CYP2D6, CYP3A4, CYP3A5, SULT1A1, SULT1A2 and SULT1E1 in 135 patients with estrogen receptor-positive breast cancer. Patients were genotyped using the Roche-AmpliChip® CYP450 Test, and Real-Time and conventional PCR-RFLP. Plasma tamoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen, endoxifen and tamoxifen-N-oxide were isolated and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Significantly higher endoxifen levels were detected in patients with the wt/wt CYP2D6 compared to the v/v CYP2D6 genotype (p<0.001). No differences were detected in the remaining tamoxifen metabolites among CYP2D6 genotypes. Patients featuring the SULT1A22 and SULT1A23 alleles showed significantly higher plasma levels of 4-hydroxy-tamoxifen and endoxifen (p = 0.025 and p = 0.006, respectively), as likely substrates of the SULT1A2 enzyme. Our observations indicate that besides the CYP2D6 genotype leading to tamoxifen conversion to potent hydroxylated metabolites in a manner consistent with a gene-dose effect, SULT1A2 also seems to play a role in maintaining optimal levels of both 4-hydroxy-tamoxifen and endoxifen.
他莫昔芬是一种广泛用于乳腺癌患者预防肿瘤复发的前药。先前的工作揭示了细胞色素和磺基转移酶在他莫昔芬代谢中的作用。在这项描述性研究中，研究人员在 135 名雌激素受体阳性乳腺癌患者中，检查了他莫昔芬代谢物浓度与 CYP2D6、CYP3A4、CYP3A5、SULT1A1、SULT1A2 和 SULT1E1 基因型之间的相关性。患者使用罗氏公司的 AmpliChip® CYP450 测试、实时和常规 PCR-RFLP 进行基因分型。使用高效液相色谱-串联质谱系统分离和定量血浆中的他莫昔芬、4-羟基他莫昔芬、N-去甲基他莫昔芬、依西美坦和他莫昔芬-N-氧化物。与 v/v CYP2D6 基因型相比，wt/wt CYP2D6 基因型的患者中检测到的依西美坦水平显著更高（p<0.001）。在 CYP2D6 基因型中，未检测到其他他莫昔芬代谢物的差异。携带 SULT1A22 和 SULT1A23 等位基因的患者，血浆中 4-羟基他莫昔芬和依西美坦的水平显著升高（p=0.025 和 p=0.006），因为它们可能是 SULT1A2 酶的底物。我们的观察表明，除了 CYP2D6 基因型导致他莫昔芬转化为强效羟化代谢物的方式与基因剂量效应一致外，SULT1A2 似乎也在维持 4-羟基他莫昔芬和依西美坦的最佳水平方面发挥作用。
