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• W4284889417 abstract "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<i>β</i>-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 <i>GSTA1 *B*B</i> genotype was associated with significant decreases in S-(androsta-1,4-diene-3,17-dion-6<i>α</i>-ylmethyl)-L-glutathione (<i>P</i> = 0.034) and S-(androsta-1,4-diene-17<i>β</i>-ol-3-on-6<i>α</i>-ylmethyl)-L-gutathione (<i>P</i> = 0.014) formation. In the plasma of 68 ER+ breast cancer patients treated with EXE, the <i>GSTA1 *B*B</i> genotype was associated with significant decreases in both EXE-cysteine (cys) (29%, <i>P</i> = 0.0056) and 17<i>β</i>-DHE-cys (34%, <i>P</i> = 0.032) as compared with patients with the <i>GSTA1*A*A</i> genotype, with significant decreases in EXE-cys (<i>P_trend</i> = 0.0067) and 17<i>β</i>-DHE-cys (<i>P_trend</i> = 0.028) observed in patients with increasing numbers of the <i>GSTA1*B</i> allele. A near-significant (<i>P_trend</i> = 0.060) trend was also observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary 17<i>β</i>-DHE-Gluc levels were significantly increased (36%, <i>P</i> = 0.00097 and 52%, <i>P</i> = 0.0089; respectively) in patients with the <i>GSTA1 *B*B</i> genotype. No significant correlations were observed between the GSTM1 null genotype and EXE metabolite levels. These data suggest that the <i>GSTA1*B</i> allele is associated with interindividual differences in EXE metabolism and may play a role in interindividual variability in overall response to EXE. <h3>SIGNIFICANCE STATEMENT</h3> The present study is the first comprehensive pharmacogenomic investigation examining the role of genetic variability in GST enzymes on exemestane metabolism. The GSTA1 *B*B 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." @default.
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• W4284889417 date "2022-07-06" @default.
• W4284889417 modified "2023-10-18" @default.
• W4284889417 title "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" @default.
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• W4284889417 doi "https://doi.org/10.1124/jpet.122.001232" @default.
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