谷胱甘肽 S-转移酶 A1*B 等位基因对芳香酶抑制剂依西美坦在人肝胞质和依西美坦治疗患者中的代谢的影响。
Influence of Glutathione-S-Transferase A1*B Allele on the Metabolism of the Aromatase Inhibitor, Exemestane, in Human Liver Cytosols and in Patients Treated With Exemestane.
机构信息
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington (I.T., J.T., S.L., C.J.W.W., G.C., P.L.) and Penn State University, College of Medicine, Division of Hematology and Oncology, Department of Medicine, Hershey, Pennsylvania (C.I.T.).
Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington (I.T., J.T., S.L., C.J.W.W., G.C., P.L.) and Penn State University, College of Medicine, Division of Hematology and Oncology, Department of Medicine, Hershey, Pennsylvania (C.I.T.)
出版信息
J Pharmacol Exp Ther. 2022 Sep;382(3):327-334. doi: 10.1124/jpet.122.001232. Epub 2022 Jul 6.
Exemestane (EXE) is used to treat postmenopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17-dihydroexemestane, is via glutathionylation by glutathione-S-transferase (GST) enzymes. The goal of the present study was to investigate the effects of genetic variation in EXE-metabolizing GST enzymes on overall EXE metabolism. Ex vivo assays examining human liver cytosols from 75 subjects revealed the genotype was associated with significant decreases in S-(androsta-1,4-diene-3,17-dion-6-ylmethyl)-L-glutathione ( = 0.034) and S-(androsta-1,4-diene-17-ol-3-on-6-ylmethyl)-L-gutathione ( = 0.014) formation. In the plasma of 68 ER+ breast cancer patients treated with EXE, the genotype was associated with significant decreases in both EXE-cysteine (cys) (29%, = 0.0056) and 17-DHE-cys (34%, = 0.032) as compared with patients with the genotype, with significant decreases in EXE-cys ( = 0.0067) and 17-DHE-cys ( = 0.028) observed in patients with increasing numbers of the allele. A near-significant ( = 0.060) trend was also observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary 17-DHE-Gluc levels were significantly increased (36%, = 0.00097 and 52%, = 0.0089; respectively) in patients with the genotype. No significant correlations were observed between the GSTM1 null genotype and EXE metabolite levels. These data suggest that the allele is associated with interindividual differences in EXE metabolism and may play a role in interindividual variability in overall response to EXE. SIGNIFICANCE STATEMENT: The present study is the first comprehensive pharmacogenomic investigation examining the role of genetic variability in GST enzymes on exemestane metabolism. The GSTA1 BB genotype was found to contribute to interindividual differences in the metabolism of EXE both ex vivo and in clinical samples from patients taking EXE for the treatment of ER+ breast cancer. Since GSTA1 is a major hepatic phase II metabolizing enzyme in EXE metabolism, the GSTA1*B allele may be an important biomarker for treatment outcomes and toxicities.
依西美坦（EXE）用于治疗雌激素受体阳性（ER+）乳腺癌的绝经后妇女。EXE 和其活性代谢物 17-二氢依西美坦的主要代谢途径是通过谷胱甘肽 S-转移酶（GST）酶的谷胱甘肽化。本研究的目的是研究 EXE 代谢 GST 酶的遗传变异对 EXE 整体代谢的影响。对 75 名受试者的人肝胞质液的离体测定表明， 基因型与 S-（雄甾-1,4-二烯-3,17-二酮-6-基甲基）-L-谷胱甘肽（ = 0.034）和 S-（雄甾-1,4-二烯-17-醇-3-酮-6-基甲基）-L-谷胱甘肽（ = 0.014）形成的显著降低相关。在 68 名接受 EXE 治疗的 ER+乳腺癌患者的血浆中， 基因型与 EXE-半胱氨酸（cys）（29%， = 0.0056）和 17-DHE-cys（34%， = 0.032）的显著降低相关与 基因型患者相比，具有 基因型的患者的 EXE-cys（ = 0.0067）和 17-DHE-cys（ = 0.028）显著降低，从同一患者的尿液中也观察到 EXE-cys 水平的接近显著（ = 0.060）趋势。相比之下， 基因型患者的血浆和尿液中 17-DHE-Gluc 水平显著升高（36%， = 0.00097 和 52%， = 0.0089；分别）。GSTM1 无效基因型与 EXE 代谢物水平之间未观察到显著相关性。这些数据表明， 等位基因与 EXE 代谢的个体间差异相关，并且可能在 EXE 总体反应的个体间变异性中起作用。意义声明：本研究是首次全面的药物基因组学研究，研究 GST 酶的遗传变异性在依西美坦代谢中的作用。发现 GSTA1BB 基因型与接受 EXE 治疗 ER+乳腺癌患者的离体和临床样本中 EXE 代谢的个体间差异有关。由于 GSTA1 是 EXE 代谢中主要的肝相 II 代谢酶，因此 GSTA1*B 等位基因可能是治疗结果和毒性的重要生物标志物。
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