Glutathione<i>S</i>‐Transferases

Dostálek, Miroslav; Stark, Anna‐Katarina

doi:10.1002/9783527630905.ch5

Cited by 4 publications

(1 citation statement)

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“…Cytosolic GSTs compose the largest subfamily of GSTs and are traditionally recognized as the major GSTs involved in phase II metabolism ( Habig et al, 1974b ; Hayes et al, 2005 ; Jancova et al, 2010 ). They are largely expressed in human liver and detoxify a variety of endogenous compounds and exogenous xenobiotics, including environmental pollutants, carcinogens, many drugs, and chemotherapeutic agents ( Dostalek and Stark, 2012 ; Hanna and Anders, 2019 ). GSTs are also highly polymorphic and have been associated with an increased risk for a variety of cancers, variability in drug toxicity, cancer resistance, and altered drug metabolism ( Perera et al, 2002 ; Elhasid et al, 2010 ; Josephy, 2010 ; Allocati et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Characterization of Cytosolic Glutathione S-Transferases Involved in the Metabolism of the Aromatase Inhibitor, Exemestane

et al. 2021

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Exemestane (EXE) is a hormonal therapy used to treat estrogen receptor–positive breast cancer by inhibiting the final step of estrogen biosynthesis catalyzed by the enzyme aromatase. Cysteine conjugates of EXE and its active metabolite 17β-dihydro-EXE (DHE) are the major metabolites found in both the urine and plasma of patients taking EXE. The initial step in cysteine conjugate formation is glutathione conjugation catalyzed by the glutathione S -transferase (GST) family of enzymes. The goal of the present study was to identify cytosolic hepatic GSTs active in the GST-mediated metabolism of EXE and 17β-DHE. Twelve recombinant cytosolic hepatic GSTs were screened for their activity against EXE and 17β-DHE, and glutathionylated EXE and 17β-DHE conjugates were detected by ultra-performance liquid chromatography tandem mass spectrometry. GST α (GSTA) isoform 1, GST μ (GSTM) isoform 3 and isoform 1 were active against EXE, whereas only GSTA1 exhibited activity against 17β-DHE. GSTM1 exhibited the highest affinity against EXE with a Michaelis-Menten constant (K M ) value that was 3.8- and 7.1-fold lower than that observed for GSTA1 and GSTM3, respectively. Of the three GSTs, GSTM3 exhibited the highest intrinsic clearance against EXE (intrinsic clearance = 0.14 nl·min −1 ·mg −1 ). The K M values observed for human liver cytosol against EXE (46 μM) and 17β-DHE (77 μM) were similar to those observed for recombinant GSTA1 (53 and 30 μM, respectively). Western blot analysis revealed that GSTA1 and GSTM1 composed 4.3% and 0.57%, respectively, of total protein in human liver cytosol; GSTM3 was not detected. These data suggest that GSTA1 is the major hepatic cytosolic enzyme involved in the clearance of EXE and its major active metabolite, 17β-DHE. SIGNIFICANCE STATEMENT Most previous studies related to the metabolism of the aromatase inhibitor exemestane (EXE) have focused mainly on phase I metabolic pathways and the glucuronidation phase II metabolic pathway. However, recent studies have indicated that glutathionylation is the major metabolic pathway for EXE. The present study is the first to characterize hepatic glutathione S -transferase (GST) activity against EXE and 17β-dihydro-EXE and to identify GST α 1 and GST μ 1 as the major cytosolic GSTs involved in the hepatic metabolism of EXE.

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