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

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 β -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 GSTA1 *B*B genotype was associated with significant decreases in S-(androsta-1,4-diene-3,17-dion-6 α -ylmethyl)-L-glutathione ( P = 0.034) and S-(androsta-1,4-diene-17 β -ol-3-on-6 α -ylmethyl)-L-gutathione ( 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-cysteine (cys) (29%, P = 0.0056) and 17 β -DHE-cys (34%, P = 0.032) as compared with patients with the GSTA1*A*A genotype, with significant decreases in EXE-cys ( P trend = 0.0067) and 17 β -DHE-cys ( P trend = 0.028) observed in patients with increasing numbers of the GSTA1*B allele. A near-significant ( P trend = 0.060) trend was also observed for urinary EXE-cys levels from the same patients. In contrast, plasma and urinary 17 β -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 the GSTM1 null genotype and EXE metabolite levels. These data suggest that the GSTA1*B 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 *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.

Upregulation of Hepatic Glutathione S-Transferase Alpha 1 Ameliorates Metabolic Dysfunction-Associated Steatosis by Degrading Fatty Acid Binding Protein 1

“…In searching for potential new targets for the development of effective drugs against MASLD, we found that glutathione S-transferase alpha 1 (GSTA1) may be related to the accumulation of lipid droplets (LD). GSTA1, a crucial phase II metabolic enzyme for biological transformation, provides cellular protection against carcinogens and plays a role in anti-mutagenesis and anti-tumor activities [17]. However, whether GSTA1 is involved in the accumulation of LD and can be used for the development of drugs against MASLD is still unknown.…”

Myricetin as a Potential Adjuvant in Chemotherapy: Studies on the Inhibition of Human Glutathione Transferase A1–1

“…The human alpha class GSTs subfamily includes five isoenzymes (hGSTA1–1 to hGSTA5–5), whose genes are located on chromosome 6p12.1–6p12.2. The isoenzyme hGSTA1–1 appears to be involved in a wide range of functions [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. It is expressed at high levels in liver, intestine, kidney, adrenal gland, and testis, and catalyzes the detoxification of a wide range of carcinogenic metabolites and several alkylating chemotherapeutic agents that are used in cancer therapy [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

“…The isoenzyme hGSTA1–1 appears to be involved in a wide range of functions [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. It is expressed at high levels in liver, intestine, kidney, adrenal gland, and testis, and catalyzes the detoxification of a wide range of carcinogenic metabolites and several alkylating chemotherapeutic agents that are used in cancer therapy [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. It also exhibits high peroxidase activity toward fatty acid and phosphatidyl hydroperoxides [ 10 ].…”

“…Several pieces of evidence have shown that GSTs are involved in MDR phenomenon through both a catalytic (ability to metabolize and inactivate anticancer agents) as well as a noncatalytic (regulation of cell-signaling mechanisms) function [ 5 , 11 , 13 , 14 , 15 ]. It is well established that the catalytic and noncatalytic roles of hGSTA1–1, in combination with its overexpression in several types of cancer cells, contribute to the development of MDR [ 14 , 15 , 16 ]. For instance, it has been found that hGSTA1–1 promotes lung cancer cell invasion and adhesion and mediates the effect of nicotine on lung cancer cell metastasis in vitro [ 13 ].…”

“…In addition, Liu et al, 2018 [ 15 ] showed that hGSTA1–1 suppressed tumor growth and induced cell apoptosis in A549 cell line, indicating that hGSTA1–1 contributes to the regulation of cell proliferation and apoptosis. More recently, Teslenko et al, 2022 [ 16 ] showed that the hGSTA1*B allele affects the metabolism of exemestane, an aromatase inhibitor, in human liver cytosols and can be therefore considered as an important biomarker for the therapeutic outcome and toxicity [ 16 ].…”