| Popis: |
Background:Exemestane (EXE) is used to treat post-menopausal women diagnosed with estrogen receptor positive (ER+) breast cancer. A major mode of metabolism of EXE and its active metabolite, 17β-dihydroexemestane (17β-DHE), 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.Methods:Seventy-five normal human liver tissue bank specimens, and plasma and urine from 68 ER+ breast cancer patients receiving EXE, were included in this study. Samples were genotyped for GSTA1 and GSTM1 by real-time PCR. The EXE-GS and DHE-GS conjugation rates in human liver specimens and levels of EXE-cys, DHE-cys and DHE-Gluc in plasma and urine were determined by UPLC/MS.Results:Ex vivo assays examining human liver revealed the GSTA1 *B/*B genotype was associated with significant decreases in EXE-GS (26%, p=0.034) and DHE-GS (15%, p=0.014) formation. In the plasma of 68 ER+ breast cancer patients treated with EXE, the GSTA1 *B*B genotype was associated with significant decreases in both EXE-cys (29%, p=0.0056) and DHE-cys (34%, p=0.032). A near-significant (ptrend=0.060) trend was observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary DHE-Gluc levels were significantly increased (36%, p=0.00097; and 52%, p=0.0089, respectively) in patients with the GSTA1 *B*B genotype. No significant correlations were observed between GSTM1 genotype and EXE metabolite levels.Conclusions:These data suggest that the GSTA1*B allele is associated with interindividual variability in EXE metabolism and may play a role in overall response to EXE.Trial registration: retrospectively registered |
